OA16796A

OA16796A - Fused Benzoxazepinones as Ion channel modulators.

Info

Publication number: OA16796A
Application number: OA1201300515
Authority: OA
Inventors: Thao Perry; Jeff Zablocki; Chandrasekar Venkataramani; Michael Graupe; Juan Guerrero; Britton Kenneth CORKEY; Elfatih Elzein; Robert H Jiang; Rao V Kalla; Dmitry Koltun; Xiaofen Li; Ruben Martinez; Eric Q. PARKHILL
Original assignee: Gilead Sciences, Inc.
Priority date: 2011-07-01
Filing date: 2012-06-29
Publication date: 2016-01-04

Abstract

The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I:

Description

FUSED HETEROCYCLIC COMPOUNDS AS ION CH ANN EL MODULATORS

Cross-Reference to Rclatcd Applications |000l] Thîs application daims the benefit under 35 U.S.C. § l I9(e) to U.S. Provisional Application Serial Numbers 61/503,980, filed on July 1, 2011 and 61/582,160, filed on December 30, 2011, thc entirety of which are both incorporated lierein by référencé.

Field

10002] Tlie présent disclosure relates to novet compounds and to their use in the treatment of various diseases, including cardiovascular diseases and diabètes. The disclosure also relates to incthods for préparation of the compounds and to pharmaceutical compositions comprising such compounds.

Background [0003] The late sodium current (INaL) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal (INaL) enhancement, which contributes to the pathogenesis of both electrical and contactée dysfunction in mammals. See, for example, Pathophysiology and Pharmacology of the Cardiac “Late Sodium Current”, Pharmacology and Therapeutics 119 (2008) 326-339. Accordingly, compounds that selectively inhibit (INaL) in mammals are useful in treating such disease states.

[0004] One example of a sélective inhibitor of (INaL) is RANEXA®, a compound approved by the FDA for the treatment of chronic stable angina pectoris. RANEXA® has also been shown to be useful for the treatment of a variety of cardiovascular diseases, including ischemia-reperfusion injury, arrhythmia and unstable angina, and also for the treatment of diabètes. It would be désirable to provide novel compounds that selectively inhibit (INaL) in mammals and that hâve the similar or improved selectivity over peak INa inhibition of the cardiac sodium channel as RANEXA®. r/

Sunimary (00051 Accordingly, typical embodiments the présent disclosure provide novel compounds that fonction as late sodium channel blockers. In one embodiment, the disclosure provides compounds of Formula I:

wherein:

Z¹ and Z² are each independently selected from the group consisting of CR⁷ and N;

Z³ and Z⁴ are each independently selected from the group consisting of CR⁷, C-QR¹ and N, provided that one of Z³ and Z⁴ is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further provided that only one of Z¹, Z² and Z⁴ is N;

X is -O- or -NR⁶-;

Y is -C(O)-, -C(R)₂- or -S(O)₂-;

Q is a covalent bond, -O-Co-2 alkylene, -NR¹ '-Co-2 alkylene, C₂ alkylene,

C₂ alkenylene or C₂ alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CN, -SF5, -Si(CH₃)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)~OR²⁰, -N(R²)(R²²), -C(O)-N(R^2ü)(R²²), -N(R^2ü)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -OS(O)2-R^2ü, -S(O)2-N(R^2ü)(R²²), Cj.6 alkyl, C₂^ alkenyl, C_M alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.& alkyl, C₂_4 alkenyl, C₂_4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group (7( consisting of halo, -NO2, aryl, heterocyclyl, heteroaryl, C).6 alkyl, Cj-3 haloalkyl, cycioalkyl, -NiR²⁰)^²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C|_6 alkylene-R⁵, -L-R⁵, -L-C|^ alkylene-R⁵, -C|.₆ alkylene-L-R⁵or-Ci.6 alkylene-L-C|.6 alkylene-R⁵;

wherein each -C|.6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(0)-OR²⁶, -C(O)N(R^2O)(R²²), -N(R²⁰)-S(O)2-R²⁰, cycioalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycioalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C^6 alkyl, C2-4 alkynyl, halo, -NO2, cycioalkyl, aryl, heterocyclyl, heteroaryl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR^2ü, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH-, or -NHC(O)-; provided that when Y is -C(R^U)2-, then R² is -L-R⁵, -L-Ci-ô alkylene-R⁵, -C|_6 alkyleneL-R⁵or-C|.6 alkylene-L-Cj.6 alkylene-R⁵ and L is not -C(O)-; and when R² is -L-R⁵ or -L-C|.(, alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2or-NHC(O)-;

each R³ is independently hydrogen, deulerium, C|.(, alkyl, cycioalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci.(, alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycioalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2,

Ci-6 alkyi, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.c, alkyi, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, -N(R )(R ), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

or when Y is -C(O)-, then R² and one of R³ can join together with the atom to which they are attached to fonn a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cj.6 alkyi, -O-R²⁰, -N(R^2O)(R²²), -N(R^2g)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C|.6 alkyi is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, C’i^, alkyi, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|„6 alkyi is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, Cι-t, alkyi, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cj.f, alkyi, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R^2t’)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atom to which they are attachcd form an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|_6 alkyl, C2.4 alkynyi, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Ci.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^’XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci_6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -NfR^XR²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, C|.₆ alkyl or cycloalkyl;

wherein said Cialkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR^2ü, -QOJ-NtR^XR²²), -CN and -O-R²⁰;

R⁷ is hydrogen, halo, -O-R²⁰ or C i-& alkyl;

R¹¹ is hydrogen or C|_.| alkyl; Λ jn λλ

R and R are in each instance independently selected from the group consisting of hydrogen, C|.₆ alkyl, C2.6 alkenyl, C2.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C2.6 alkenyl, C2.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituent» independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, C1-3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Ci.4 alkyl or cycloalkyl; or

22 ⁷0 22 when R and R are attached to a common nitrogen atom R and R may join to fonn a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyioxy, acylamino, -NO?. -SfOJ^R²⁶, -CN, C μ alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF3;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof;

provided that when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which they arc attached form a piperazîne which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)2-, X is -O-, R² is benzyl, each R³is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R^! is aryl or heteroaryl, then both R⁴are hydrogen. ^4 [0006] In certain embodiments, the disclosure provides compounds of Formula IA:

wherein:

Cy is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

Q is a covalent bond, -O-C0-2 alkylene, -NR¹ ’-Co.₂ alkylene, C₂ alkylene,

C₂ alkenylene or C₂ alkynylene;

m is 0, 1,2 or 3;

is 0, 1,2, 3, 4 or 5;

each R¹⁰ is independently selected Irom the group consisting of halo, -NO?, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2<’)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C|.6 alkyl, C₂_4 alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|_6 alkyl, C₂-4 alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected front the group consisting of halo, -NO?, aryl, heterocyclyl, heteroaryl, Ci,₆ alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is alkylene-R⁵, -L-R⁵, -L-C|.(, alkylene-R⁵, -C|.(, alkylene-L-R⁵ or -Ο|.₆ alkyiene-L-Ci-6 alkylene-R⁵;

wherein each -Ci._f) alkylene is optionally substituted by one substituent independently selected front the group consisting of C₂^ alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|_6 alkyl, C2-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L îs -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or-NHC(O)-; provided that when R² is -L-R⁵ or -L-C|.6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2- or -NHC(O)-; and each R³ is independently hydrogen, deuterium, C|.₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci_û alkyl is optionally substituted wîth one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, C|_6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C1-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -NiR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

or R and one of R can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionaliy substituted with one, two or three substitueras independently selected from the group consisting of C].6 alkyl, -O-R²⁰, -N(R^2O)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C|_6 alkyl is optionally substituted with one, two or three substituents independently selected from lhe group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deutérium, C i -6 alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|.6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, Ci_6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰; and wherein said C|.₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2,

-N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R^s is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|._(t alkyl, C24 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-

wherein said C|.& alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|_6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|_g alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected front the group consisting of halo, aryl, -NO,, -CF3, -NfR^’XR²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹⁷ is halo, -O-R²⁰ or C|.6 alkyl;

R²⁰ and R²² are in each instance independently selected front the group consisting of hydrogen, C|.₆ alkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C|^ alkyl, C₂._f, alkenyl, C₂._ô alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected front the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂, -S(O)₂R²⁶, -CN, C1.3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R and R are attached to a coinmon nitrogen atom R and R ntay join to form a heterocyclic or heteroaryl ring whicli is then optionally substituted with one, two or three substituents independently selected front the group consisting of hydroxyl, halo, Cjm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C1.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected front the group consisting of hydrogen, C'1.4 alkyl, aryl and cycloalkyl; cX whereîn the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substitueras independently selected from the group consisting of hydroxyl, halo, Ci.4 alkoxy, -CFj and -OCF3;

or a phannaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof;

provided that when each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached fonn a piperazine which is optionally substituted with tert-butoxycarbonyl, Q is a bond and Cy is phenyl or morpholinyl, then n is I, 2, 3, 4 or 5.

[0007| Sonie embodiments provide a mcthod of using the compounds of Formula I, IA, IB, 11, IIA, IIB, III, IIIA, IV, V, VI, VI! I, VIIΙΑ, IX, X, XII or XIII, or additional Formula(s) described throughout, in the treatment of a disease or condition in a mainmal that is amenable to treatment by a late sodium channel blocker. Such diseases include cardiovascular diseases such as atrial and ventricular anhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal’s (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, récurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease and intermittent claudication. Such diseases may also include diabctes and conditions related to diabètes, e.g. diabetic peripheral neuropathy. Such diseases may also include conditions affecting the neuromuscular system resulting in pain, seizures or paralysis. Therefore, it is contemplated that the compounds of the disclosure and their phannaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers and/or tautomer forms are potentially of use as médicaments for the treatment of the albrementioned diseases.

|0008| In certain embodiments, the disclosure provides pharmaceutical compositions comprisîng a therapeutically effective amount of a compound of the disclosure (e.g. a coinpound of Formula I or additional Formulas described throughout), and at least one phannaceutically acceptable excipient.

[0009] In certain embodiments, the compound is: 4-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoiOmcthoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-1);

4-(2-(pyrroIidin-l-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one ( 11-3 );

4-((5-cyclobutyl-l,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (H-4);

4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-7-(4-(trifluoroniethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (ll-5);

4-(quinolin-2-y!methyl)-7-(4-(trilluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-7);

(R) -2-(pyrimidin-2-ylniethyl)-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (II-8);

4-(cyclopropylniethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepîn-5(2H)-one (II-10);

(S) -3-methyl-4-(pynmidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (ll-12);

(R)-3-methyl-4-(pyriniidin-2-ylniethyl)-7-(4-(trifluorometliyl)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-13);

6- ((5-oxo-7-(4-(ti‘iiluoiOnietlioxy)phcnyl)-2,3-diliydiObenzo[f][l,4]oxazepin-4(5H)yl)methyl)picolinonitrile (Π-14);

7- (4-( trifluoromethoxy)phenyl)-4-((6-( tri fluoroinethyl)pyridin-2-yl)methyi )-3,4dihydrobenzo[fJ[l,4]oxazepin-5(2H)-one (Il-l5);

7-(4-(trifluoroinethoxy)plieiiyl)-4-((6-(trifluoromcthyl)pyndin-3-yl)niethyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (II-16);

4-((6-niethylpyridin-2-yl)inethyl)-7-(4-(trifluoroiiicthoxy)phenyl)-3,4dihydrobenzo[ f][ l ,4]oxazepin-5(2l!)-one (l I-17);

(2R, l laS)-2-amino-7-(4-(lritluoromethyl)phenyl)-2,3,11,1 latetrahydrobenzo[f]pyrrolo[2,1-c][ 1,4]oxazepin-5( 1 H)-one (11-21 );

(R)-2-(2,2-difluoroethy])-8-(4-(tritluoromethyl)plienyl)-3,4,12,12a-tetfahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (11-22);

(R) -2-ethyI-8-(4-(tritluorometliyl)phenyl)-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2,1 -c][ 1,4]oxazepin-6(2H)-one (11-23);

(S) -2-(2,2-difluoroethyl)-8-(4-(trifluoiOmethyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazcpin-6(2H)-one (11-24);

(S)-2-etliyl-8-(4-(tri fluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (11-25);

4-(pyrazin-2-ylmethyl)-7-(4-(trifluoroinethoxy)phenyl)-3,4dihydrobenzo[fJ[l,4]oxazepin-5(2II)-oiie (11-31);

4-((5-inethyloxazol-2-yl)methy))-7-(4-(trifluoroinethoxy)phenyl)-3,4dîhydiObcnzo[f][ l,4]oxazepin-5(2H)-one (11-33);

7-(4-(trifluoroniethoxy)phenyl)-4-(2-(2,5,5-tnmethyl-l,3-dioxan-2-yl)ethyl)-3,4diliydrobenzo[f][1,4]oxazepi n-5(2H)-one ( 11 -3 5) ;

tert-butyl (2R, 1 laR)-5-oxo-7-(4-(trifluoiOmethyl)phenyl)-l,2,3,5,l 1,11ahexahydrobenzo[f]pyrrolo[2, l -c][ 1,4]oxazepin-2-ylcarbaniate (11-39);

4-((5-(pyridin-2-yl)isoxazol-3-yl)niethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f] [ I,4]oxazepin-5(2H)-one ( 11-41 );

4-((4,6-diniethoxypyrimidin-2-yl)metliyl)-7-(4-(trifluoroinethoxy)phenyl)-3,4di hyd robenzo[ f][ 1,4]ox azepi n-5 (2 I I )-one ( 11 -42 ) ;

ethyl 3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepiii-4(51-I)yl)methyl)benzoate (11-43);

4-(2-(pyrimidin-2-yl)etliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2I-l)-one (11-44);

4-(3,4-difluoiObenzyl)-7-(4-(trifluoiOinethoxy)phenyl)-3,4-dihydiObenzo[l][l,4]oxazepin5(2H)-one (11-45);

4-(2-chlorobenzyl)-7-(4-(trifluoiOinethoxy)plienyl)-3,4-dihydiObenzo[n[*»41oxazepin5(2H)-one (11-47);

4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)pheiiyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-48); <Z

4-(2,6-ditluorobenzyl)-7-(4-(trilluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-49);

4-(2-( l H-pyrazol-l -yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one ( 11-50);

(2S, 11 aS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,11,11atetrahydrobenzo[f]pyrrolo[2,1 -c][ 1,4]oxazepin-5( 1 H)-one (11-51 );

4-(2-(pyridin-2-yl)etliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[ 1,4]oxazepin-5(2H)-one (11-54);

4-(2-fluorobeiizyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepÎn10 5(2H)-one (11-57);

(R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11 a-tetrahydrobenzo[f]pynOlo[2,1 c][ 1,4]oxazepin-5( 1 H)-one (11-59);

4-(pyrimidin-2-ylmethyl)-7-(4-(ln 11 uoromethyOphenyl )-3,4dihydrobenzo[f|[ ! ,4]oxazepîn-5(2H)-one (11-61 );

4-(4-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyi)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-62);

4-(( 1 -metliyl-1 H-pyrazol-3-yl)niethyl)-7-(4-(trifluoroinethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-64);

4-((5-chloropyrimidin-2-yl)rnethyl)-7-(4-(trifluorometlioxy)phenyl)-3,420 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-65);

4-(pyridin-4-ylmetliyl)-7-(4-(lritluoromethoxy)phcnyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-67);

4-((5-cyclopropyl-l,3,4-oxadiazol-2-yl)metliyl)-7-(4-(trifluoromcthoxy)pbenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-68);

4-(2-(pyriinidin-2-yloxy)ethyl)-7-(4-(trilluoiOmetlioxy)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (11-69);

4-(pyridin-3-ylmethyl)-7-(4-(trilluoroinethoxy)phenyl)-3,4diliydiObenzo[f][l,4]oxazepin-5(2H)-one (11-70);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-72);

4-(pyrimidin-2-yhnethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[fj[l,4]oxazepin-5(2H)-one (I1-73);

4-((3-niethylpyridin-2-yl)methyl)-7-(4-(trifluoromcthoxy)phenyl)-3,4dihydrobenzo[l][ l,4]oxazepin-5(2H)-one ( 11-75);

(R)-2-(2,2,2-trifluoroethyl)-8-(4(trifluoromethyl)phenyl)-3,4,l2,l2a-tetrahydro-lHbenzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (I1-83);

4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-87);

7-(4-clilorophciiyl)-4-(pynniidin-2-ylmethyl)-3,4-dihydrobenzo[fJ[l ,4]oxazcpin-5(2H)one (11-88);

7-(4-isopiOpylphenyl)-4-(pyriniidin-2-ylmcthyl)-3,4-dihydrobenzo[f][l,4]oxazepiri5(2H)-one (11-89);

7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-91);

7-(4-cyclopropylphe!iyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-92);

(R)-4-(l-(pyriinidin-2-yl)cthyl)-7-(4-(trifluoromethyl)phcnyl)-3,4dihydrobenzo[t][ 1,4]oxazepin-5(2H)-one (11-95);

7-(4-isobutoxyphenyl)-4-(pyriinidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-97);

7-(4-tert-butylphenyl)-4-(pyriniidin-2-ylmethyl)-3,4-dihydiObenzo[f][l,4]oxazepin5(2H)-one (11-98);

7-(4-cyclopiOpoxyplienyl)-4-(pyrimidin-2-ylniethyl)-3,4-diliydrobenzo[f]| 1,4]oxazepin5(2H)-one(II-l02);

7-(4-fluoiOphenyl)-4-(pyriniidin-2-ylmetliyl)-3,4-diliydrobcnzo[f|[ l,4]oxazepin-5(2H)one (II-104);

7-(2-fluoiO-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-105); X

7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylrnethyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (II-l 06);

4-(pyrimidin-2-y]rnethyl)-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-107);

7-(2-chloro-4-(trifluoromethyl)plienyl)-4-(pyriinidin-2-ylmethyl)-3,4dihydrobenzo[f][i,4]oxazepin-5(2H)-one (II-110);

7-(4-( tri fluoromethoxy)phenyl)-4-((4-(trifluoroinethyl)pyriiTiidin-2-yl)methyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (II-l 13);

7-(4-(trifluoroinethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2IO yl)methyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (ll-l 15);

7-(4-chloiO-2-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobeiizo[f][l,4]oxazepin5(2H)-one (Π-l I7);

l-(4-(5-oxo-4-(pyrimidin-2-ylmetliyl)-2,3,4,5-tetrahydiObenzo[f][ 1,4]oxazepin-7yl)phenyl)cyclopcntanecarbonitrile (II-l 22);

7-(4-etlioxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (II-123);

7-(4-(difluoiOinethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzof f][1,4]oxazcpin-5(2H)-one (II-l24);

4-(iniidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromcthyl)phenyl)-3,420 dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-129);

4-((4-morpholinopyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4diliydrobenzo[f][l,4]oxazepiti’5(2II)-one (11-133);

4-benzyl-7-(4-(tiïfluoroniethoxy)phenyl)-3,4-dihydrobenzo[f][i,4]oxazepin-5(2H)-one (II-134);

4-(imidazo[ 1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoroinethyl)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepîn-5(2H)-one (11-135);

7-(3-11 uoro-4-(lriiluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzof f][ 1,4|oxazepin-5(2H)-onc (II-136);

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-137);

4-((4-methylpyriniidin-2-yl)niethyl)-7-(4-(trifluorotnethoxy)phenyl)-3,4dîhydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-138);

4-((4-(piperidin-1 -y l )pyri mid i ti-2-y l )methy I )-7-(4-(tri fluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-139);

4-((4-(dimethylamino)pyriinidiii-2-yl)methyl)-7-(4-(trifluoroinethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-140);

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (III4l);

4-((3-jnethoxypyridin-2-yl)niethyl)-7-(4-(trifluoroincthoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazcpiii-5(2H)-one (II-143);

7-(4-(cyclobutylmethoxy)phenyl)-4-(pyrirnidin-2-ylrnethyl)-3,4dihydrobenzo[f][ 1,4]oxazepiii-5(2ll)-onc (H-144);

7-(2-inethyl-4-(trifluoromethyl)phenyl)-4-(pyriinidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepîn-5(2H)-one (II-145);

7-(2-methyI-4-(trifluoromcthoxy)phenyl)-4-(pyriinidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-146);

4-(( l -(difluoromcthyl)-1 H-pyrazo!-3-yl)methyl)-7-(4-(trifluoromethoxy)pbenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-147);

7-(4-( trifluoromethoxy)phenyl)-4-((3-(trifluoromethyl)-lH-pyrazol-l-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazcpin-5(2H)-one (11-148);

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoiOethyl)phenyl)-3,4dihydrobenzo [ f] [ 1,4] oxazepin-5(2 H)-one ( 11-150) ;

4-(pyridin-2-ylmethyl )-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-151);

4-(( l -cyclopentyl-1 H-pyrazol-3-yl)methyl)-7-(4-(tri fluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-152); J

4-((l-ethyl-lH-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-153);

4-(( l-methyl-1 H-imidazol-4-yl )methyl )-7-(4-(tri fl uoromethoxy)phcn yl)-3,4diliydiobenzo[f][ l ,4]oxazepin-5(2H)-one (II-154);

4-((4-methyl-1 H-pyrazol-1 -yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobcnzo[f][ l ,4]oxazepin-5(2H)-one (II-155);

4-((4-chloro-1 H-pyrazol- l-yl)metliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-l 56);

7-(4-(difluorornethyl)pheiiyl)-4-(pyridin-2-ylrnethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-157);

7-(4-chloro-3-fluorophenyl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-158);

7-(4-(difluororncdioxy)phenyl)-4-(pyridin-2-ylrnethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (H-159);

4-(( l-methyl-1 H-pyrazol-4-yl)methyl)-7-(4-(trifluoromethoxy)phenyl )-3,4dihydrobenzo[f|[1,4]oxazepin-5(2H)-one (11-160);

4-(pyrimidin-2-ylmethyl )-7-(2,3,4-trifluorophenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-162);

7-(3,4-difluorophenyl)-4-(pyrirnidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-163);

4-((3-iluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-164);

4-benzyl-9-fluoro-7-(4-(trifluorometlioxy)plienyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-165);

4-benzyl-9-fluoiO-7-(4-(tnfluoromethyl)phcnyl)-3,4-dihydiObeiizo[f][l,4]oxazepin5(2H)-one (11-166);

4-benzyl-8-fluoro-7-(4-(trifluoroinethoxy)phenyl)-3,4-dihydiObenzo[f][l,4]oxazepin5(2H)-one (11-167); /

4-benzyl-8-tluoro-7-(4-(trifluoroniethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-168);

7-(4-chloro-3-fluorophenyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-169);

7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-((3-fluoropyridin-2-yl)rnethyl)-3,4dihydrobenzo[f][ I,4]oxazepin-5(2H)-one (II-170);

4-(5-oxo-4-(pyrimidin-2-ylniethyl )-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-7-yl)phenyl tri fl uorometlianesul fonatc (11-171);

4-((5-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-172);

2,2,3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trÎfluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-174);

4-((6-methylpyrazin-2-yl)methyl)-7-(4-(triiluoromethoxy)phenyl)-3,4dihydrobenzo[fj[l,4]oxazepin-5(2H)-one (II-l75);

4-((3-11 uoropyridin-2-yl)metliyl)-7-(4-(trilluoiOmethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Il-l 76);

N-(2-(5-oxo-7-(4-(trifluoiOtnethoxy)phenyl)-2,3-dihydrobenzo[f)[l,4]oxazepin-4(5H)yl)ethyl)benzenesulfonamide ( II-177);

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)cyclopropanesulfonamide (II-179);

4-((1-ιΐΊ6^1-1Η-ΐιι^3ζοΙ-2^1)Γη6ΐΙψΙ)-7-(4-(ίπ11ιιοΓοηΊ£ΐ1κ)χγ)ρΗεηγ1)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-186);

4-((l-bcnzyl-lH-iniidazol-2-yl)inetiiyl)-7-(4-(trifluoiOrnethoxy)phenyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-187);

4-(iniidazo[ 1,2-a] pyrid i n-2-yl met hyl )-7-(4-( tri fluoromethoxy)phenyl)-3,4dihydrobenzo[fj[ l,4]oxazepin-5(2H)-one (II-189);

N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)propane-l-sulfbnamide (11-190); X

N-(2-(5-oxo-7-(4-(trifluorotnethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)pyrimidine-2-carboxamide (Π-192);

7-(4-(4-fluorophenoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-193);

7-(4-phenoxyphenyi)-4-(pyrimidin-2-ylmethyl)-3,4-dihydiObenzo[f][l,4]oxazepin-5(2I-I)one (II-194);

7-(3-pbenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydiObenzo[f][l,4]oxazepin-5(2H)one (II-195);

7-(4-tcrt-butylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydiObenzo[f][1,4]oxazepin-5(2H)-one (V-l );

7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydiObenzo[f][l,4]oxazepin-5(2H)-one (V-3);

7-(4-niethylcyclohex-l-enyl)-4-(pyriniidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (V-5);

7-(2-tert-butoxypyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (VI-4);

7-( I -niethyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-yhnethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (VI-12);

4-(pyridin-2-ylinethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-26);

7-(2-isopropylthiazol-4-yl)-4-(pyridin-2-yhnethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (VI-30);

4-(pyridin-2-ylmethyl)-7-(5-(tritluoroinethyl)thiophen-2-yl)-3,4diliydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-31);

7-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylinethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (VI-32);

7-(5-cyclopropylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4diliydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-36); and

4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoiOniethyl)thiophen-2-yl)-3,4dihydrobenzo[f][I,4]oxazepin-5(2H)-one (VI-37);

4-(pyrimidin-2-yimethyl)-7-((4-(tri fluoromethoxy)phenyi)ethynyl )-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (VlII-4);

7-(phenylethynyl)-4-(pyriniidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VilI-5);

4-(pyrimidin-2-yImethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VHI-6);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoiOinethyl)phenethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-7);

4-(pyriinidin-2-ylinethyl)-7-(4-(trifluoroniethyl)phenethyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2I-I)-oiie (VlH-8);

4-((3-0 uoropyridin-2-yl)methyl )-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][1,4]oxazepin-5(2H)-one (VlIl-9);

(E)-4-benzyl-7-(4-(trifluoromethyl)styryl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIll-lO); and

4-benzyl-7-(4-(trifluoroinethyl)phenethyl)-3,4-dihydrobenzo[f)[l,4]oxazepin-5(2H)-one (Vlll-ll);

2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)pbenyl)-3,4-dihydro-2H- benzo[b][ l,4,5]oxathiazepîn-sulfone (IX-2);

2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][ 1,4,5 loxathiazepin-snlfone (IX-3);

4-(2-(benzyloxy)ethyl)-l-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (X-7);

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1 H-benzo[e][ 1,4]diazepine-2,5-dione (X-8);

4-benzyl-l-methyl-7-(4-( trifluoromethyl)phenyl)-3,4-dihydro-l H-benzo[e][l,4]diazepine2,5-dione (X-l I);

5-benzyl-8-(4-(trifIuoromethyl)phenyl)-4H-benzo[f]imidazo[l,2-a][l,4]diazepin-6(5H)one (X-12);

4-benzyl-7-(4-(trifluorometlioxy)phenyl)-3,4-dihydropyrido[4,3-f][l,4]oxazepin-5(2H)one (XII-1);

4-benzyl-7-(4-(tritluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][ l ,4]oxazepin-5(2H)one (XII-2);

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][l,4]oxazepin-5(2H)-one (XII-3);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XII-5);

4-((4-methylpyriinidin-2-yl)metbyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][ l,4]oxazepin-5(2H)-one (XII-8);

4-(cyclopropylmethyl)-7-(4-(triHuoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XII-9);

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][ l ,4]oxazepin-5(2H)-one (ΧΠ-10);

4-((3 -fl uoropyridi n-2-yl)methyl )-7-(4-( tri fluoromethoxy)phenyl)-3,4-di hydropyrido [4,3 f][ 1,4]oxazepin-5(2H)-one (XII-11 );

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3₎4dihydropyrido[4,3-f][l,4]oxazepin-5(2H)-one (XII-14);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylainino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (XIΠ-1);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4dihydrobenzo| f][l ,4]oxazcpin-5(2H)-one (XII1-2);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoiOmetliyl)phenylamino)-3,4diliydrobenzo[F][l,4]oxazepin-5(2H)-one (XI11-3);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (XII1-4);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyiamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (XIll-6); or

7-(methyl(4-(trifluoromethoxy)phenyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (XIII-10);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

|00101 In other embodiments, the compound is: 4-(2,2-difluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l ,4]oxazepin5(2H)-one (II-6);

4-(2-methoxyethyI)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-1 l);

(R) -3-methyl-7-(4-(trifluoiOmethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-19);

4-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (H-46);

(S) -3-isopiOpyl-7-(4-(trifluoromethyl)phcnyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (11-77);

3- (pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4- dihydrobenzo[fj[l ,4]oxazepin-5(2H)-one (II-142);

N-(2-(5-oxo-7-(4-(trifluoromelhoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)ethanesulfonamide (11-178); or

4- (3-( azetidin-l-ylsulfonyl)propyl )-7-(4-( trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-191);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof [0011 ) ln other embodiments, the compound is:

pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methanone (III-1 );

phenyl(7-(4-(tritluoromethoxy)plienyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methanone (II1-4);

( l -methylcyclopropyl)(7-(4-(lrifluoromethoxy)phenyl)-2,3dihydrobenzo[f][ l ,4]oxazepin-4(5H)-yl)methanone (lll-10);

(3,3-ditluorocyclobutyl)(7-(4-(tritluoromethoxy)phenyl)-2,3dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methanone (ΠΙ-l l);

( l -methyl-1 H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (III-12);

(lH-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)methanone (III-15);

pyrazin-2-yl(7-(4-(trifluoromethoxy)phenyI)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methanone (III-23);

pyridazin-3-yl(7-(4-(triiluoiOmethoxy)phenyl)-2,3-dihydrobenzo[lj[l,4]oxazepin-4(5II)yl)methanone (III-24);

2-(pyridin-2-yl)-1-(7-(4-( tri fluoromethyl)phenyl)-2,3-dihydrobenzo[f][l,4]oxazcpin4(5H)-yl)ethanone (III-29);

2-(pyrimidin-2-yl)- l-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][ 1,4]oxazepin4(5H)-yl)ethanone (111-30);

( 1 -methyl-1H-im idazol-5-yl )( 7-(4-(tri lluoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (111-32);

( 11-l-imidazol-2-yl)(7-(4-(trinuoromethyl)phenyl)-2,3-dihydrobenzo[i][ 1,4]oxazepin4(5H)-yl)methanone (III-33);

( 1 -methyl-lH-imidazol-2-yl)(7-(4-(tii lluoromethyl )phenyl )-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (111-37);

(R)-(2-methyl-7-(4-(trifluoroinethoxy)phenyl)-2,3-dihydrobenzo[t][I,4]oxazepin-4(5H)yl)(pyrimidiii-2-yl)methanone (111-38);

tert-butyl 2-(7-(4-(trifIuoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepinc-4carbonyl)-5,6-dihydroimidazo[ l,2-a]pyrazine-7(8H)-carboxylate (111-40);

( l H-l ,2,4-triazol-3-yl)(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[ fj[ l ,4]oxazepin4(5H)-yl)methanone (III-50); or ( l ,5-dimethyl-1 H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (Hl-58);

or a pharmaccutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

100121 The inventions of this disclosure are described throughout. In addition, spécifie embodiments of the invention are as disclosed herein.

Dctailcd Description

7. Définitions and General Parameters |0013] As used in the présent spécification, the following words and phrases are generally intended to bave the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

|0014| The tcrm “alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms, or from I to 15 carbon atoms, or from I to 10 carbon atoms, or from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. This term is exemplified by groups such as melhyl, cthyl, npropyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

|0015| The tcrm “substituted alkyl” refers to:

I ) an alkyl group as defined above, having 1,2, 3, 4 or 5 substituents, (in some embodiments, l, 2 or 3 substituents) selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyatio, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl,-S(O)-heteroaryl. -S(O)j-alkyl, -S(O)2-cycloalkyl, -S(O)2-heterocyelyl, -S(O)2-aryl and -S(O)2-hetcroaryl. Unless cZ otherwise constrained by the définition, ail substituents may optionally be further substituted by l, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR“, in which R^ais alkyl, aryl or heteroaryl and n is 0, l or 2; or

2) an alkyl group as defined above that is interrupted by l - l 0 atoms (e.g. 1,2, 3, 4 or 5 atoms) independently chosen from oxygen, sulfur and NR^a, where R^a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. Ail substituents may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFj, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)„R^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, l or 2; or

3) an alkyl group as defined above that lias both 1,2,3,4 or 5 substituents as defined above and is also interrupted by 1-10 atoms (e.g. I, 2, 3, 4 or 5 atoms) as defincd above.

10016] The terni “lower alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1,2, 3, 4, 5 or 6 carbon atoms. This tenu is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tbutyl, n-hexyl, and the like.

|<)017| The term “substituted lower alkyl” refers to lower alkyl as deflned above having to 5 substituents (in some embodiments, 1,2 or 3 substituents), as defincd for substituted alkyl or a lower alkyl group as defined above that is interrupted by 1,2, 3, 4 or 5 atoms as deflned for substituted alkyl or a lower alkyl group as defincd above that lias both 1,2, 3, 4 or 5 substituents as deflned above and is also interrupted by 1,2, 3, 4 or 5 atoms as deflned above.

|0018| T lie term “alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, in some embodiments, having from I to 20 carbon atoms (e.g. 1-10 carbon atoms or 1,2, 3, 4, 5 or 6 carbon atoms). This tenu is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2and -CH(CH₃)CH₂-), and the like. X |(K)19] The term “lower alkylene” refers to a diradîcal of a branched or unbranched saturated hydrocarbon chain, in some embodiments, having 1,2, 3,4, 5 or 6 carbon atoms.

[0020] The term “substituted alkylene” refers to an alkylene group as defined above having l to 5 substituents (in some embodiments, 1,2 or 3 substituents) as defined for substituted alkyl.

|002l| The term “aralkyl” refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined hercîn. “Optionally substituted aralkyl” refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4methoxyphenyl)propyl, and the like.

10022] The term “aralkyloxy” refers to the group -O-aralkyl. “Optionally substituted aralkyloxy” refers to an optionally substituted aralkyl group covalently linked to an optionally substituted alkylene group. Sucli aralkyl groups are exemplified by benzyloxy, phenylethyloxy, and the like.

|0023| The term “alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from l to 6 carboncarbon double bonds, e.g. I, 2 or 3 carbon-carbon double bonds. In some embodiments, alkenyl groups include ethenyl (or vinyl, i.e. -CH=CIl₂), l-propylcne (or allyl, i.e. -CH₂CH=CH₂), isopropylene (-C(CH₃)=CH₂), and the like.

10024] The tenu “lower alkenyl” refers to alkenyl as defined above having from 2 to 6 carbon atoms.

|0025] The term “substituted alkenyl” refers to an alkenyl group as defined above having l to 5 substituents (in some embodiments, l, 2 or 3 substituents) as defined for substituted alkyl.

|0026| The tenu “alkenylene” refers to a diradîcal of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms (in some embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from l to 6 carboncarbon double bonds, e.g. I, 2 or 3 carbon-carbon double bonds.

J0027J The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbon, in some embodiments, having front 2 to 20 carbon atoms (in sonie embodiments, from 2 to 10 carbon atoms, e.g, 2 to 6 carbon atoms) and having front l to 6 carbon-carbon triple bonds e.g. I, 2 or 3 carbon-carbon triple bonds. In sonie embodiments, alkynyl groups include ethynyl (-OCH), propargyl (or propynyl, i.e. -CsCCII₃), and the like.

|0028[ The term “substituted alkynyl” refers to an alkynyl group as defined above having l to 5 substituents (in some embodiments, 1,2 or 3 substituents) as defined for substituted alkyl.

|(IO29| The term “alkynylene” refers to a diradical of an unsaturated hydrocarbon, in some embodiments, having front 2 to 20 carbon atoms (in some embodiments, from 2 to carbon atoms, e.g. 2 to 6 carbon atoms) and having from l to 6 carbon-carbon triple bonds e.g. I, 2 or 3 carbon-carbon triple bonds.

10030] The term “hydroxy” or “hydroxyl” refers to a group -OU.

|00311 The term “alkoxy” refers to the group R-O-, where R is alkyl or -Y-Z, in which

Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyl and alkynyl are as defined herein. In some embodiments, alkoxy groups are alkyl-O- and includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, l,2-dimethyIbutoxy, and the like.

[0032) The tenu “lower alkoxy” refers to the group R-O- in which R is optionally substituted lower alkyl. Thts tenu is exemplified by groups suclt as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, n-hexyloxy, and the like.

[0033] The term “substituted alkoxy” refera to the group R-O-, where R is substituted alkyl or -Y-Z, in which Y is substituted alkylene and Z is substituted alkenyl or substituted alkynyl, where substituted alkyl, substituted alkenyl and substituted alkynyl 25 are as defined herein.

100341 The term “C].₃ haloalkyl” refers to an alkyl group having from I to 3 carbon atoms covalently bondcd to from l to 7, or from I to 6, or from l to 3, halogen(s), where alkyl and halogen are defined herein. In some embodiments, Cj.₃ haloalkyl includes, by way of example, trilluoromethyl, difiuoromethyl, fiuoromethyl, 2,2,2-trifluoroethyl, 2,230 dilluoroethyl, 2-fiuoroethyl, 3,3,3-trifluoropropyl, 3,3-difluoropropyl, 3-fluoropropyl.

10035] The term “cycioalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ring or multiple condensed rings. Such cycioalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like or multiple ring structures such as adamantanyl and bicyclo[2.2.l]heptanyl or cyclic alkyl groups to which is fused an aryl group, for example indanyl, and the like, provided tliat the point of attachaient is through the cyclic alkyl group.

10036] The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings and having at least one double bond and in some embodiments, from l to 2 double bonds.

[00371 The terms “substituted cycioalkyl” and “susbstituted cycloalkenyl” refer to cycioalkyl or cycloalkenyl groups having l, 2, 3, 4 or 5 substituents (in some embodiments, l, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycioalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylainino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthîo, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(0)-cycloalkyl, -S(O)-hctcrocyclyl, -S(O)-aryl,-S(O)heteroaryl, -S(O)2-alkyl, -S(0)2-cycloalkyl, -S(O)2-heterocyclyl, -S(O)2-aryl and -SfO)?heteroaryl. The term “substituted cycioalkyl” also includes cycioalkyl groups wherein one or more of the annular carbon atoms of the cycioalkyl group has an oxo group bonded thereto. In addition, a substituent on the cycioalkyl or cycloalkenyl may be attached to the same carbon atom as, or is geminal to, the attachment of the substituted cycioalkyl or cycloalkenyl to the 6,7-ring system. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by l, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFj, amino, substituted amino, cyano, cycioalkyl, heterocyclyl, aryl, heteroaryl, and -SfO^R¹¹, in which R^!l is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

10038] The term “cycloalkoxy” refers to the group cycloalkyl-O-.

|0039| The term “substituted cycloalkoxy” refers to the group substituted cycloalkyl-O-. [00401 The term “cycloalkenyloxy” refers to the group cycloalkcnyl-O-, (/ [0041| The terin “substituted cycloalkenyloxy” refers to the group substituted cycloalkenyl-O-, [0042] The tenu “aryl” refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl, fluorcnyl and anthryl). In some embodiments, aryls include phenyl, fluorenyl, naphthyl, anthryl, and the like.

[0043| Unless otherwise constrained by the définition for the aryl substituent, such aryl groups can optionally bc substituted with I, 2, 3, 4 or 5 substiluents (in some embodiments, l, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthîo, h etero arylthîo, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, hetcroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(0)-cycloalkyl, -S(O)-heterocyclyl, -S(O)-aryl,-S(O)heteroaryl, -S(O)2-alkyl, -S(0)₂-cycloalkyl, -S(O)2-heterocyclyl, -S(O)₂-aryl and -S(O)2heteroaryl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by l, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)„R^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, I or 2.

|0044| The terni “aryloxy” refers to the group aryl-O- whereîn the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term “arylthio” refers to the group R-S-, where R is as defined for aryl.

[0045| The term “heterocyclyl,” “heterocycle,” or “helerocyclic” refers to a monoradical saturated group having a single ring or multiple condensed rings, having from I to 40 carbon atoms and from I to 10 hetero atoms, and from I to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. In some embodiments, the heterocyclyl,” “heterocycle,” or “helerocyclic group is linked to the remainder of the molécule through one of the heteroatoms within the ring.

|0046J Unless otherwise constrained by the définition for the helerocyclic substituent, such heterocyclic groups can be optionally substituted with l to 5 substituents (in some 1½ embodiments, i, 2 or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-hetcrocyclyl, -S(O)-aryl,-S(O)heteroaryl, -S(O)₂-alkyl, -S(0)2~cycloalkyl, -S(0)2-heterocyclyl, -S(O)₂-aryl and -S(O)2heteroaryl. In addition, a substituent on the heterocyclîc group may be attached to the same carbon atom as, or is geminal to, the attachaient of the substituted heterocyclîc group to the 6,7-ring System. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by l, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nRⁿ, in which R is alkyl, aryl or heteroaryl and n is 0, l or 2. Examples of heterocyclics include tetrahydrofuranyl, morpholino, pipcridinyl, and the like.

|00471 The term “heterocyclooxy” refers to the group -O-heterocyclyl.

10048| The tenu “heteroaryl refers to a group comprising single or multiple rings comprising l to 15 carbon atoms and I to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. The term “heteroaryl” is generic to the terms “aromatic heteroaryl” and “partially saturated heteroaryl”. The term “aromatic heteroaryl” refers to a heteroaryl in which at least one ring is aromatic, regardless of the point of attachment. Examples of aromatic heteroaryls include pyrrole, thiophene, pyridine, quînoline, pteridine.

[0049] The tenu “partially saturated heteroaryl” refers to a heteroaryl having a structure équivalent to an underlying aromatic heteroaryl which lias had one or more double bonds in an aromatic ring of the underlying aromatic heteroaryl saturated. Examples of partially saturated heteroaryls include dihydropyrrole, dihydropyridine, chroman, 2-oxo-l,2dihydropyridin-4-yl, and the like.

[0050| Unless otherwise constrained by the définition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with I to 5 substituents (in some embodiments, l, 2 or 3 substituents) selected from the group consisting alkyl, alkenyl, X

3I alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkyl thio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylainino, hetcroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -S(O)-alkyl, -S(O)-cycloalkyl, -S(O)-hetcrocyclyl, -S(O)-aryl,-S(O)heteroaryl, -S(O)₂-alkyl, -S(O)₂-cycloalkyl, -S(0)₂-heterocyclyl, -S(O)₂-aryl and -S(O)₂heteroaryl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by l, 2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -SfO^R”, in which R^a is alkyl, aryl or heteroaryl and n is 0, l or 2. Sueh heteroaryl groups can hâve a single ring (e.g,, pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, bcnzothiazole or benzothienyl). Examples of nitrogen heterocyclyls and hcteroaryls include, but are not limited to, pyrrolc, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phcnanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenolhiazinc, imidazolidine, imidazoline, and the like as well as N-alkoxynitrogen containing heteroaryl compounds.

100511 The tenu “heteroaryloxy refers to the group heteroaryl-O-.

|0052| The term “amino” refers to the group -NH₂.

|00531 The term “substituted amino” refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen or a group -YZ, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)|,R‘', in which R‘‘ is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

|00541 The tenu “alkyl amine” refers to R-NIl₂ in which R is optionally substituted alkyl.

[0055] The tenu “dialkyl amine” refers to R-NHR in which each R is independently an optionally substituted alkyl.

[0056| The term “trialkyl amine” refers to NR₃ in which each R is independently an optionally substituted alkyl.

[0057| The term “cyano” refers to the group -CN.

[0059J The term “keto” or “oxo” refers to a group =0.

|0060[ The term “carboxy” refers to a group -C(O)-Ol·!.

|0061) The terni “ester” or carboxyester” refers to the group -C(O)OR, where R is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may be optionally further substituted by alkyl, alkoxy, halogen, CF₃, amino, substituted amino, cyano or-S(O)_nR^a, in which R¹¹ is alkyl, aryl or heteroaryl and n is 0, I or 2.

|00621 The term “acyl” dénotés the group -C(O)R, in which R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -SÎOJJV, in which R“ is alkyl, aryl or heteroaryl and n is 0, I or 2.

[0063] The term “carboxyalkyl” refers to the groups -C(O)O-alkyl or -C(O)Ocycloalkyl, where alkyl and cycloalkyl arc as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -8(0),^', in which R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

|0064] The term “aminocarbonyl” refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1,2 X or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFj, amino, substituted amino, cyano, cycioalkyl, heterocyclyl, aryl, heteroaryl, and -SfOJnR¹¹, in which R“ is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

|0065] The tenu “acyloxy” refers to the group -OC(O)-R, in which R is alkyl, cycioalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CFj, amino, substituted amino, cyano, cycioalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nRⁿ, in which R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

(0066] The term “acylamino” refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, cycioalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycioalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^:i, in which R“ is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

|00671 The tenu “alkoxycarbonylamino” refers to the group -N(R^d)C(O)OR in which R is alkyl and R^d is hydrogen or alkyl. Unless otherwise constrained by the définition, each alkyl may optionally be further substituted by 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycioalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[0068] The tenu “aminocarbonylamino” refers to the group -NR^cC(O)NRR, wherein R^cis hydrogen or alkyl and each R is hydrogen, alkyl, cycioalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwise constrained by the définition, ail substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycioalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R^a is alkyl, aryl or heteroaryl and n is 0, I or 2.

|(H)69| The term “thiol” refers to the group-SH. / f0070] The tenn “thiocarbonyl” refers to a group =S.

[00711 The tenn “alkylthio” refers to the group -S-alkyl.

100721 The term “substituted alkylthio” refers to the group -S-substituted alkyl,

10073} The term “heterocyclylthio” refers to the group -S-heterocyclyl.

[00741 The term “arylthio” refers to the group -S-aryl.

[0075] The term “heteroarylthiol” refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.

101)76] The tenn “sulfoxide” refers to a group -S(O)R, in which R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide” refers to a group -S(O)R, in which R is substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl or substituted heteroaryl, as defined herein.

]0077| The term “sulfone” refers to a group -S(O)?R, in which R is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfone” refers to a group -S(O)2R, in which R îs substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl or substituted heteroaryl, as defined herein.

100781 The term “aminosulfonyl” refers to the group -S(O)2NRR, wherein each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwise constraincd by the définition, ail substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O)_nR^a, in which R” is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

[(1079] The term hydroxyamino” refers to the group -NHOH.

[0080] The tcrm “alkoxyamino” refers to the group -NI IOR in which R is optionally substituted alkyl.

100811 The tenn “halogen” or “halo” refers to fluoro, bromo, chloro and iodo, |0082| “Optional” or “optionally” means thaï the subscquently descrîbcd event or circumstance may or may not occur, and that the description includes instances wliere said event or circumstance occurs and instances in which it does not. (X [00831 A “substituted” group includes embodiments in which a monoradicai substituent is bound to a single atom of the substituted group (e.g, fonning a branch), and also includes embodiments in which the substituent may be a diradical bridging group bound to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituted group.

|0084| Where a given group (moiety) is described hercin as being attached to a second group and the site of attachment is not explîcit, the given group may be attached at any availabié site of the given group to any available site of the second group. For example, a “lower alkyl-substituted phenyl”, where the attachment sites are not explîcit, may bave any available site of the lower alkyl group attached to any available site of the phenyl group. In this regard, an “available site” is a site of the group at which a hydrogen of the group may be replaced with a substituent.

10085] It is understood that in ali substituted groups defined above, polymers arrived at by defining substituents with lurther substitueras to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion hereîn. Also not includcd are infinité numbers of substituents, whether the substituents are the same or different. In such cases, the maximum number of such substituents is three. Each of the above définitions is thus constraîned by a limitation that, for example, substituted aryl groups are limited to -substituted aryl-(substituted aryl)-substituted aryl.

[00861 A compound of a given formula (e.g. the compound of Formula l, which also includes Formula IA, IB, II, IIA, III, ΠΙΑ, IV, V, VI, VIII, VIIIA, IX, X, XI and XIII) is intended to encompass the compounds of the disclosure, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, isomers, tautomers, solvatés, isotopes, hydrates, polymorphs, and prodrugs of such compounds. Additionally, the compounds of the disclosure may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers présent in any given compound of a given formula dépends upon the number of asymmetric centers présent (therc arc 2'¹ stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis or by résolution of the compound by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the présent disclosure, ail of which are intended to be depicted by the structures of this spécification unless otherwise specifically indicated.

[0087J “Isomers” are different compounds that hâve the same molccular formula. Isomers inciude stereoisomers, enantiomers aiid diastereomers.

10088| “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.

|0089| “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A I : l mixture of a pair of enantiomers is a “racemic” mixture. The terni (±) is used to designate a racornie mixture where appropriate.

[0090J “Diastereoisomers” are stereoisomers that hâve at least two asymmetrîc atoms, but which are not mirror-images of each other.

10091 ] The absolute stereochemistry is specified according to the Câlin Ingold Prelog R S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designatcd (+) or (-) depending on the direction (dextro- or laevorotary) that they rotate the plane of polarized light at the wavelength of the sodium D line.

[00921 Some of the compounds exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to inciude their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to inciude their amide tautomers. Non-limiting examples of amide-comprising and imidic acid-comprising tautomers arc shown below:

[0093] The term “therapeutically effective amount” refers to an amount that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and âge of the subject, the severity of the dîsease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

[0094] The term “polymorph” refers to different crystal structures of a crystalline compound. The different polymorphs may resuit from différences in crystal packing (packing polymorphism) or différences in packing between different conformers of the saine molécule (confonnational polymorphism).

|0095| The term “solvaté” refers to a complex formed by the combining of a compound of Formula I, IA, IB, II, Il A, IIB, III, ΠΙΑ, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII and a solvent.

|0096] The tenu “hydrate” refers to the complex formed by the combining of a compound of Formula l, IA, IB, II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII and water.

|0097| The term “prodrug” refers to compounds of Formula I, IA, IB, II, ΠΑ, IIB, III, 111A, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII that include chemical groups which, in vivo, can be converted and/or can be split off from the remainder of the molécule to provide for the active drug, a pharmaceutically acceptable sait thereof or a biologically active métabolite thereof.

]0098| Any formula or structure given herein, including Formula I, IA, IB, II, IIA, IIB, III, ΠΙΑ, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII compounds, is also intended to represent unlabeled fonns as well as îsotopically labeled forms of the compounds. Isotopically labeled compounds bave structures dcpicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass numbcr. Examples of isotopes that can be incorporatcd into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to ²I l (deutérium, D), ³U (tritium), ^HC, ^l3C, ^l4C, ^l5N, ^lBF, ³ⁱP, ³²P, ³⁵S, ³⁶Cl and ^l25l. Various îsotopically labeled compounds of the présent disclosure, for example those into which radioactive isotopes such as ³I-I, ^l3C and ^l4C are incorporatcd. Such îsotopically labelled compounds may be useful in metabolic studies, X reaction kinetic studies, détection or imaging techniques, such as positron émission tomography (PET) or single-photon émission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0099] The disclosure also included compounds of Formula I, IA, IB, II, IIA, IIB, III, IIIA, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII in which from l to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molécule. Such compounds exhibit increased résistance to metabolism and are thus useful for increasing the half life of any compound of Formula I when administered to a mammal. Sce, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Phannacol. Sci. 5(12):524-527 (1984). Such compounds are synthesîzed by means well known in the art, for example by employing starting materials in which one or more hydrogens hâve bcen replaced by deuterium.

[0100] Deuterium labelled or substituted therapeutic compounds of the disclosure may hâve improvcd DMPK. (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excrétion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo liaif-life, reduccd dosage requirements and/or an improvemcnt in therapeutic index. An ^lKF labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and préparations described below by substituting a readîly available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.

[0101] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as H or ''hydrogen, the position is understood to bave hydrogen at its naturel abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[01021 The term “treatment” or “treating” means administration of a compound of the invention, by or at the direction of a competent caregiver, to a mammal having a disease for purposes including:

(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;

(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relicving the disease, that is, causing the régression of clinical symptoms.

|01031 In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

|()104| The term “pharmaceutically acceptable sait” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnésium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substitutcd alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, hcterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and arc selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group. Amines are of general structure

N(R^3O)(R^3I)(R³²), wherein mono-substîtuted amines bave 2 of the three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substituted amines hâve 1 of the three substituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen, whereas tri-substituted amines hâve none of the three substituents on nitrogen (R , R and R ) as hydrogen. R , R and R are selected from a variety of substituents such as hydrogen, optionally substituted alkyl, aryi, heteroayl, cycloalkyl, cycloalkenyi, heterocyclyl and the like. The above-nientioned amines refer to the compounds wherein either one, two or three substituents on the nitrogen are as listed in the name. For example, the terni “cycloalkenyi amine” refers to cycloalkenyl-NFh, wherein “cycloalkenyi” is as defined herein. The terni “diheteroarylamine” refers to NH(heteroaryl)2, wherein “heteroaryl” is as defined herein and so on.

[0105| Spécifie examples of suitable amines include, by way of example only, isopropylamine, trimcthyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, Nalkylglucamines, theobromine, purines, piperazine, piperidîne, morpholine, Nethylpiperidinc, and the like.

[01061 Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartane acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-tolucne-sulfonic acid, salicylic acid, and the like.

[0107| As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and ail solvents, dispersion media, coatings, antibactcrial and antilungal agents, isotonie and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any convcntional media or agent is incompatible wilh the active ingrédient, its use in the therapeutic compositions is contemplated. Supplementary active ingrédients can also be încorporated into the compositions.

10108] “Coronary diseases” or “cardiovascular diseases” refer to diseases of the cardiovasculature arising froin any one or more than one of, for example, heart failure (includîng congestive heart failure, diastolic heart failure and systolic heart failure), acute heart failure, ischemia, récurrent ischemia, myocardial infarction, arrhythmias, angina (includîng exercise-induced angina, variant angina, stable angina, unstable angina), acute coronary syndrome, diabètes and intermittent claudication.

|0109| “ Intermittent claudication” means the pain associated with peripheral artery disease. “Peripheral artery disease” or PAD is a type of occlusive peripheral vascular disease (PVD). PAD affects the arteries outside the heart and brain. The most common symptom of PAD is a painful cramping in the bips, tlrighs or calves when walking, climbing stairs or exercising. The pain is called intermittent claudication. When listing the symptom intermittent claudication, it is inlended to include both PAD and PVD.

|0110] Arrhythmia refers to any abnormal heart rate. Bradycardia refers to abnormally slow heart rate whereas tachycardia refers to an abnormally rapid heart rate. As used herein, the treatment of arrhythmia is intendcd to include the treatment of supra ventricular tachycardias such as atrial fibrillation, atrial llutler, AV nodal reentrant tachycardia, atrial tachycardia and the ventricular tachycardias (VTs), includîng idiopathic ventricular tachycardia, ventricular fibrillation, pre-excitation syndrome and Torsade de Pointes (TdP).

2. Nomenclature [0111| Naines of compounds of the présent disclosurc are provided using ACD/Name software for naming chemical compounds (Advanced Chemistry Development, Inc., Toronto, Canada). Other compounds or radicals may be natned with common names or systematic or non-systematic names. The naming and numbering of the compounds of the disclosure is illustrated with a représentative compound of Formula 1:

which is named 4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobcnzo[f][ l,4]oxazepin-5(2Il)-one.

3. Compounds |0l 121 Accordingly, typical embodiments the présent disclosure provide novel compounds that fonction as late sodium channel blockers. In one embodiment, the disclosure provides compounds of Formula I:

wherein:

Z¹ and Z² are each independently selected from the group consisting of CR⁷ and

N;

X is -O- or -NR⁶-;

Y is -C(O)-, -C'(R)₂- or -S(O)₂-;

Q is a covalent bond, -0-Co.₂ alkylene, -NR^l!-Co-₂ alkylene, C₂ alkylene,

C₂ alkenylene or C₂ alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CN, -SF$, -Si(Cl 13)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-0R²⁰, -N(R²⁽')(R²²), -C(O)-N(R²⁰)(R²²), -N(R²ⁿ)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R², -OS(O)2-R^2ü, -S(O)2-N(R²⁰)(R²²), C|_6 alkyl, C₂_4 alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cj.t, alkyl, C₂^ alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two 5^ or three substituents independently selected from the group consisting of halo, -NO2, aryl, heterocyclyl, heteroaryl, Ci-6 alkyl,

Cj.jhaloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C].6 alkylene-R⁵, -L-R⁵, -L-C].f, alkylene-R⁵, -C|_6 alkylene-L-R⁵or -C|,6 alkyIene-L-C|-₆ alkylene-R⁵;

wherein each -Ci_₆ alkylcnc is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R^2ü, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted witli one, two or three substituents independently selected from the group consisting of Cu, alkyl, C2-4 alkynyl, halo, -NOi, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH-, or -NHC(O)-; provided that when Y is -C(R^H)2-, then R² is -L-R⁵, -L-Cr, alkylene-R⁵, -Cj-è alkyleneL-R⁵ or -Ci-6 alkylene-L-C|.(, alkylene-R⁵ and L is not -C(O)-; and when R² is -L-R⁵ or -L-Ct-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2or -NHC(O)-;

each R³ is independently hydrogen, deuterium, C].₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|.& alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, C|-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2<’)(R²²), -CN and -O-R²⁰; and wherein said C|.(, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo,-NO?,-N(R )(R ), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

3 or when Y is -C(O)-, then R and one of R can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C|._f, alkyl, -O-R²⁰, -NfR^’XR²²), -N(R^2,,)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deutérium, Ci.6 alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²°XR²²), -CN and -O-R²⁰; and / wherein said C|.& alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionaliy further substituted with one, two or three substituents independently selected front the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR^2ü, -C(0)-N(R^2ü)(R²²), -CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atoni to which they are attachcd form an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaliy substituted with one, two or three substituents independently selected front the group consisting of Ci-& alkyl, C2-4 alkynyl, halo, -NOi, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said C|.₍, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected front the group consisting of halo, -NOi, Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2,’)(R²²), -CN and -O-R²⁰; and wherein said C|.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected front the group consisting of halo, aryl, -NO₂, -CF₃, -N(R^2O)(R²²), -C(O)R²⁰, -C(O)-OR^2ü, -C(O)-N(R^2<i)(R²²), -CN, -S(O)₂-R^2Ü and -O-R²⁰;

Z

R is hydrogen, C].₆ alkyl or cycloalkyl;

wherein said C|.(, alkyl is optionaliy substituted with one, two or three substituents independently selected front the group consisting of halo, -ΝΟ2, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁷ is hydrogen, halo, -O-R²⁰ or C|.6 alkyl;

R¹¹ is hydrogen or Cm alkyl;

R and R are in each instance independently selectcd from the group consisting of hydrogen, Cm alkyl, C2.6 alkenyl, C2.6 alkynyl, cycloalkyl, helerocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C2.6 alkenyl, C2.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting ofhydroxyl, halo, Cj-4 alkyl, acylamino, oxo, -NO2. -S(O)2R²⁶, -CN, Cm alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

2D 2^ ^0 22 when R and R are attached to a common nitrogen atom R‘ and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2. -S(O)2R²⁶, -CN, C|_3 alkoxy, -CFj, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selectcd from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting ofhydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

provided that when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)2-, X is -O-, R² is benzyl, each R³is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴are hydrogen. c/

10113] In another embodiment, the disclosure provides compounds of Formula I:

wherein:

Xis -O- or -N R⁶-;

Y is -C(O)-;

Q is a covalent bond, -O-C0.2 alkylene, -NR^{1 l}-C₀.2 alkylene, C₂ alkylene,

C₂ alkenylene or C₂ alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two, three, four or five substituents independently selected lïom tlie group consisting of halo, -NO₂, -CN, -SF5, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -NiR^’XR²²), -C(O)N(R^2O)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -O-S(O)2-R^2ü, -S(O)2-N(R²⁰)(R²²), C|,₆ alkyl, C₂^ alkenyl, C₂.i alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.(, alkyl, C₂_î alkenyl, C₂-i alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, C|.₆ alkyl, C 1.3 haloalkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2o)(R²²), -CN and -O-R²⁰; X

R² îs -Ci-6 alkylene-R^s, -L-R^s, -L-Cm alkylene-R^s, -Cialkylene-L-R⁵ or -C|.6 alkylene-L-Cj-ô alkylcne-R^s;

wherein each -C_t.₆ alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-1 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2O)(R²²), -N(R²⁰)-S(O)2-R²⁰, cycioalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycioalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cu, alkyl, C2-1 alkynyl, halo, -NO2, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

L is -O-, -S-, -C(O)-, -NHS{0)₂-, -S(O)₂NH-, -C(O)NI I- or -NHC(O)-; provided that when R² is -L-R⁵ or -L-C14, alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂-or-NHC(O)-; and each R³ is independently hydrogen, deutérium, Ci.#, alkyl, cycioalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cialkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -ΝΟί, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycioalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NOi, C|._f, alkyl, aralkyl, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²)(R), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

wherein said C|.6 alkyl, aralkyl, cycioalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected <

from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR^2ü;

or R² and one of R³ can join together with the atom to which they arc attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C i_6 alkyl, -O-R²⁰, -N(R^2o)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C|.(, alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, C|._ft alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|._fl alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁽')(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C,.₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.₍, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atom to which they are attached form an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cj.6 alkyl, C₂4 alkynyl, halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said C i.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂,

C|.(, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cj.û alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R^2O)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁽ⁱ)(R“), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, C|.6 alkyl or cycloalkyl;

wherein said C talkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -CiOJ-NiR²⁰)^²²), -CN and -O-R²⁰;

R⁷ is hydrogen, halo, -O-R²⁰ or C|.₆ alkyl;

R^fl is hydrogen or C1-4 alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|._f, alkyl, C₂.₍₁ alkenyl, C₂._f, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C|.₍, alkyl, C₂._f, alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, νζ

5!

halo, Ci-4 alkyl, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, Cm alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, C|_3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo. Cm alkoxy, -CF3 and -OCF3;

provided that wlien X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which lhey are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl.

[01141 In another embodiment, the disclosure provides compounds of Formula I:

wherein Z¹, Z², Z³, Z⁴, X, R³ and R⁴ are as defined herein;

Y is-C(R)₂-;

R² is -L-R⁵, -L-C|.ô alkylene-R^s, -C|.(, alkylcne-L-R⁵or -C|.₆ alkylene-L-Ci-c alkylcne-R⁵; J wherein each -C|_6 alkylene is optionally substituted by one substituent independently selected from the group consisting of C2-4 alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|.ô alkyl, C₂.₄alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-NiR²⁰)^²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and

-O-R²⁰;

L is -O-, -S-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or-NHC(O)-; and

Rⁿ is hydrogen or Cm alkyl.

|0l 15] In yct another embodiment, the disclosure provides compounds of Formula I:

wherein Z¹, Z², Z³, Z⁴, X, R², R³ and R⁴ are as defincd herein; and

Y is -S(O)₂-;

•j 1 41 provided that when X is -O-, R“ is benzyl, each R is hydrogen, Z is C-Q-R , Q is a bond and R¹ is aryl or heteroaryl, then both R⁴ are hydrogen.

|0116| In somc embodiments, R¹ is aryl, cycloalkyl, cycloalkenyl or heteroaryl;

wherein said aryl, cycloalkenyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -O-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -N(R^2ü)-C(O)-R²², -N(R²⁰)-C(O)25 OR²², -S(O)2-R²⁰, -O-S(O)2-R²⁰, C|.(, alkyl, cycloalkyl and heterocyclyl; and wherein said Cm alkyl or cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -CN and -O-R²⁰.

» |0117| In sonie embodiments, each R is independently hydrogen, deuterium or Cm alkyl.

[0118] In sonie embodiments, each R⁴ is independently hydrogen, deuterium or Cm alkyl.

101191 In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting oî’Cm alkyl, halo, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl arc optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, Cm alkyl, aryl, heterocyclyl and heteroaryl; and wherein said Cm alkyl is optionally further substituted with one, two or three halo.

101201 In some embodiments, R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, -OR²⁰, -N(R²⁰)(R²²) and -C(O)-0R²⁰; and wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.

101211 In certain embodiments of each of the formulas disclosed Iwrein, each -Cmo alkylene of R² is unsubstituted -Cm, alkylene.

[01221 In certain embodiments, the compound is not tert-butyl ό-οχο-8-phenyl3,4,l2,12a-tetrahydro-lH-benzo[f|pyrazino[2.1-c|| l,4]oxazcpine-2(6H)-carboxylate, tert- <7^ butyl 6-oxo-9-phenyl-3,4,12,12a-tetrahydro-1 H-benzo[f]pyrazino[2,1 -c][ 1,4]oxazepine2(6H)-carboxylate, 8-phenyl-3,4,12,12a-tetrahydro-1 H-benzo[flpyrazino[2,1 c][ 1,4]oxazcpin-6(2H)-one, 9-phenyl-3,4,12,12a-tetrahydro-1 H-benzo[f]pyrazino[2,1 c][ 1,4]oxazepin-6(2H)-one, 8-morpholino-l ,2,3,4,12,12ahexahydrobenzo[e]pyrazino[ 1,2-a]azepin-6( 11 H)-one, tert-butyl 8-morpholino-6-oxo3,4,6,11,12,12a-hexahydrobenzo[e]pyrazino[ 1,2-a]azepine-2( 1 H)-carboxylate, tert-butyl 2-morpholino-l 2-oxo-5,6,6a,7,9,l 0-hexahydropyrazino[ 1,2-a]pyrido[3,2-e]azepine8( 12H)-carboxylate, 2-morpholino-6,6a,7,8,9,1()-hexahydropyrazino[ 1,2-a]pyrido[3,2e]azepin-12(5H)-one, 2-morpholino-8,9,10,10a, 11,12-hexahydropyrazino[ 1,2a]pyrido[2,3-e]azepin-5(7H)-one or tert-butyl 2-morpholino-5-oxo-7,8,10,10a,l 1,12hexahydropyrazino[ l,2-a]pyrido[2,3-e]azepine-9(5H)-carboxylate.

|01231 In alternative embodiments, the disclosure provides compounds of Formula i:

wherein:

» ₄ , , 7

Z and Z“ are each independently selected from the group consisting of CR and N;

J 7

Z and Z are each independently selected from the group consisting of CR , C-QR¹ and N, provided that one of Z³ and Z⁴ is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further provided that only one of Z¹, Z² and Z⁴ is N;

X is -O- or -NR⁶-;

Y is -C(O)-, -C(R^{] l})₂- or -S(O)₂-;

Q is a covalent bond, -O-C₀-2 alkylene, -NR^{1 l}-C₀.₂ alkylene or C₂ alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NCb, -CN, -SF5, -Si(Cl 13)3, -O-R²”, -S-R²”, -C(O)-R²”, -C(O)-OR²⁰, -N(R^21I)(R²²), -C(O)-N(R²⁰)(R²²),

-N(R²⁰)-C(O)-R²², -N(R²ⁿ)-C(O)-OR²², -N(R²⁰)-S(O)3-R²⁶, -S(O)2-R²⁰, -oS(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, Gm alkenyl, C₂₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and whereîn said Cm alkyl, C₂.<i alkenyl, C₂_4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R^s, -L-C|_ô alkylene-R⁵, -Cm alkylene-L-R⁵or-C|._ôalkylene-L-CM alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-; provided that when Y is -CfR’’^-, then R² is -L-R⁵, -L-C|_6 alkylene-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylene-L-CM alkylene-R⁵;

each R³ is independently hydrogen, deuterium, C|_j5 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

whereîn said Cm5 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2Ü)(R²²), -CN and -O-R²⁰;

whereîn said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R^2O)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

*5 1 or when Y is -C(O)-, then R and one of R can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cru alkyl, -O-R²⁰, -NiR²⁰)^²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Cris alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, Cris alkyl, Cm alkoxy, -C(O)OR²⁶, -C(O)-N(R²⁶)(R²⁶), -N(R²ⁿ)-S(O)₃-R²⁰, cycioalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci.15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycioalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C|._f, alkyl, aralkyl, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.₆ alkyl, aralkyl, cycioalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO2, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R^J or two R⁴ together with the carbon atom to which they are attached form an oxo; rZ

R^s is cycloalkyl, aryl, heteroaryl or hcterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cj.è alkyl, C₂^ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C|.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|,6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, Cms alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cj.15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2Ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cu, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -NiR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰XR²²), -CN and -OR²⁰;

T

R is hydrogen, halo or Cm alkyl;

R^u is hydrogen or Cm alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|-i 5 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C]-]5 alkyl, C₂-is alkenyl, C₂-1 s alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂, -S(O)₂R^2Û, -CN, Ci.3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R and R“ arc attached to a common nitrogen atom R and R may jointe form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂.

-S(O)2R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof;

provided thaï when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted ¢/ with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)₂-, X is -O-, R is benzyl, each R is hydrogen, Z is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴ are hydrogen.

10124] In some embodiments, R¹ is aryl, cycloalkyl, cycloalkenyl or heteroaryl;

wherein said aryl, cycloalkenyl or heteroaryl are optionaliy substituted with one, two or three substituents independently selected front the group consisting of halo, -O-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -N(R²⁰)-C(O)-R²², -N(R²°)-C(O)OR²², -S(O)2-R²⁰, -O-S(O)2-R²⁽⁾, C|.₆ alkyl, cycloalkyl and heterocyclyl; and wherein said C|.6 alkyl or cycloalkyl are optionaliy substituted with one, two or three substituents independently selected front the group consisting ofhalo, -CN and -O-R²⁰.

[0125] In sonie embodiments, each R³ is independently hydrogen, deutérium or Cms alkyl.

|0126) In sonie embodiments, each R⁴ is independently hydrogen, deuterium or C|.|5 alkyl.

[0127] In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaliy substituted with one, two or three substituents independently selected front the group consisting of C|.6 alkyl, halo, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Ci_₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl arc optionaliy further substituted with one, two or three substituents independently selected front the group consisting ofhalo, Cialkyl, aryl, heterocyclyl and heteroaryl; and wherein said C].6 alkyl is optionaliy further substituted with one, two or three halo.

[0128| In some embodiments, Y is -C(O)- and R and one of R can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionaliy substituted with one, two or three substituents independently selected from the group consisting of C_t.|5 alkyl, -O-R²⁰, -N(R^2t,)(R²²) and -C(O)-OR²⁰; and wherein said Cms alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.

|0129] In some embodiments, the disclosure provides compounds of Formula IA:

wherein:

Cy is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

Q is a covalent bond, -O-Co-2 alkylene, -NR¹ '-Co-2 alkylene, C2 alkylene,

C2 alkenylene or C2 alkynylene;

m is 0, 1,2 or 3;

n is 0, 1,2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2-4 alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C m alkyl, C2.4 alkenyl, C2^t alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R^s, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵or -Cm alkylene-L-C i-6 alkylene-R⁵;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting 0I C2.4 alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)- /

N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected front the group consisting of C|.₆ alkyl, C₂-4 alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L îs -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-; provided that when R² is -L-R⁵ or -L-Ci-6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-; and each R³ is independently hydrogen, deutérium, C|.₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C14, alkyl is optionally substituted with one, two or three substituents independently selected front the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected front the group consisting of halo, -NO₂, C|_6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected front the group consisting of halo, -NO₂, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²¹’;

or R² and one of R³ can join together with the atom to which they are attached to fornt a heterocyclyl; ¢/ wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Ci.6 alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C|.f, alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, Ci.& alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C i.6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2t1)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cj.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.& alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO?,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C^ alkyl, C2.4 alkynyl, halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)?-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-

	wherein said Cm, alkyi, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NCh, Ci-6 alkyi, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),
5	-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyi, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO?, -CF₃, -N(R²⁰)(R²²), -C(O)-
ΙΟ	R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)?-R²⁰ and -O-R²⁰; R¹⁷ is halo, -O-R²⁰ or C ialkyi; R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogcn, C\|.6 alkyi, C2.6 alkenyl, C2.6 alkynyl, cycloalkyl, heterocyclyl, aryl
15	and heteroaryl; wherein the C).6 alkyi, C?-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyi, acylamino, oxo, -NO2, -S(O)2R²⁶, -CN, Cj-3 alkoxy, -CF3,
20	-OCF3, -OCH2CF3, -C(O)-NH?, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyi or cycloalkyl; or when R and R are attached to a common nitrogen atom R and R may join to fonn a heterocyclic or heteroaryl ring which is then optionally substituted with
25	one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyi, aralkyl, aryloxy, aralkyloxy, acylamino, -NCh. -S(O)?R²⁶, -CN, C1 -3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyi, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycioalkyl may be nirther substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

provided that when each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl, Q is a bond and Cy is phcnyl or inorpholinyl, then n is l, 2, 3, 4 or 5.

[0130] In certain embodiments, the disclosure provides compounds of Formula 11:

wherein:

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3,4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -C(O)N(R^2o)(R²²), -N(R²⁰)-C(O)-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R^2ü)(R²²), Cm alkyl, Cm alkenyl, C2.₄ alkynyl, cycioalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, Cm alkynyl, cycioalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|,₃ haloalkyl, cycioalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm> alkylene-L-R⁵ or-Cm alkylene-L-C|.6 alkylene-R⁵;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of C2.4 alkynyl, halo

-NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2o)(R²²), -N(R^2ü)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of C|„6 alkyl, C₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R^2ü, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NI ÎC(O)-, provided that when R² is -L-R⁵ or -L-C|.6 alkylcne-R⁵, then L is not -O-, -S-, -NI IS(O)₂- or -NHC(O)-;

each R³ is independently hydrogen, deuterium, C|._f, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|.₍₁ alkyl is optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰,

-C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|_6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰; and wherein said C;alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm, alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C|.₆ alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, C|_t» alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C',.6 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cialkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^’XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²°XR²²), -CN and -O-R²⁰; and wherein said Ch, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2üXR²²), -CN and -O-R²⁰;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm, alkyl, C’₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²°XR²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)- lZ

C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said C|.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected lrom the group consisting of halo, -NO?, C|.û alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO?, -CFj, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -CfOJ-NfR^fR²²), -CN, -S(O)?-R²⁰ and -O-R²⁰;

R¹⁷ is halo, -O-R²⁰ or C_I4, alkyl;

R and R “ are in each instance independently selected frotn the group consisting of hydrogen, C|._f, alkyl, C?.₆ alkenyl, C?._ft alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C|.6 alkyl, C?.6 alkenyl, C?.₍, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C;_4 alkyl, acylamino, oxo, -NO?. -S(O)₂R²⁶, -CN, Cι.3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(O)-NH?, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or •jq 22 20 22 when R“ and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO?, -S(O)₂R^2î’, -CN, C1.3 alkoxy, -CF₃, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; X wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stéréo isomer, mixture of stercoisomers or tautomer thereof;

provided that when m is 0, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then n is l, 2 or 3.

|Ül3I| In some embodiments, R is -Cm alkylene-R or -Cm alkylene-L-R .

|(II32| ln some embodiments, each -Cm alkylcne of R“ is optionally substituted by one substituent independently selected from the group consisting ofC_2j) alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R^2,1)(R²²), -C(O)-R²⁰, -C(O)-OR^2û, -C(O)-N(R²⁰)(R²²), -N(R²⁰)-S(O)₂R²”, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂m alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)N(R^2O)(R²²), -CN and -O-R²'¹.

[0133] ln some embodiments, each -Cm alkylene of R is unsubstituted.

[0134] In some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, halo, cycloalkyl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-OR²⁰, -CN and -O-R²⁰;

wherein said C|.(, alkyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, Cm alkyl and aryl; and wherein said Cm> alkyl is optionally further substituted with one, two or three halo.

10135] ln some embodiments, R² and one of R³ can join together with the atom to which they are attached to lorm a heterocyclyl; X wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cj.6 alkyl, -O-R²⁰, -N(R²⁰)(R²²) and -C(O)-OR²⁰; and wherein said C|._f, alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.

»

» [0136| In some embodiments, R² is

Ο [0137] In some embodiments, n is I, 2 or 3; and each R¹⁰ is independently selected from the group consisting of halo, -O-R²¹¹, -OS(O)2-R²⁰, Cm alkyl and cycloalkyl; and wherein said alkyl and cycloalkyl arc optionally substituted with one, two or three halo or -CN; and 'X

R²⁰ is independently selected from the group consisting of Cm alkyl, cycloalkyl and aryl; and wherein the alkyl and aryl are optionally substituted with one, two or three halo or cycloalkyl.

|0138) ln some embodiments, n is 1,2 or 3; and each R¹⁰ is independently 2-fluoro, 3lluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-difluoromcthyl, 4-trifluoromethyl, 4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4trifluoromethoxy, 4-(2,2,2-trifluoroethoxy), 4-trifluoromethylsulfoxyl, 4-(2,2,2trifluorocthyl), 4-cyclopropoxy, 4-cyclobutylmethoxy, 4-fluorophcnoxy, 4-phenoxy or 3phenoxy.

|01391 In some embodiments, each R³ is independently hydrogen, deuterium or Cm alkyl optionally substituted with heteroaryl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, -N(R^2I1)(R²²) and -N(R²⁽’)-C(O)-OR²⁰; and wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; and

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ct__fl alkyl and heteroaryl.

)0140) In some embodiments, each R³ is independently hydrogen, deuterium or Cm alkyl optionally substituted with heteroaryl; and each R⁴ is independently hydrogen, deuterium or Cm, alkyl optionally substituted with heteroaryl.

[014l| ln some embodiments, each R³ is independently hydrogen, deuterium or Cm alkyl optionally substituted with heteroaryl;

m is 0 or I ; and

R¹⁷ishalo.

|(> 142| In some embodiments, eacli R³ is independently hydrogen, deuterium, methyl, isopropyl or pyiïdin-2-ylmcthyl;

m is 0 or l ; and

R is iluoro.

(0143] In some embodiments, each R⁴ is independently hydrogen, deuterium or C|.6 alkyl.

|0144| lu some embodiments, each R³ is independently hydrogen, deuterium or Ci_6 alkyl optionally substituted with heteroaryl;

or R“ and one of R can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting ofC|.6 alkyl, -N(R^2O)(R²²) and -N(R²⁰)-C(O)-OR²⁰; and wherein said C]._ft alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; and each R⁴ is independently hydrogen, deuterium or C i_& alkyl optionally substituted with heteroaryl.

10145| In certain embodiments, the disclosure provides compounds of Formula 11A:

wherein:

n is 0, 1,2 or 3;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CI I3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2Ü)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(0)2-N(R²⁰)(R²²), Cm, alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C].6 alkyl, C₂_4 alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, C|.6 alkyl, C|.₃ haloalkyl, cycloalkyl, -NiR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R² is -C,.₆ alkylene-R⁵, -L-R⁵, -L-Cj.6 alkylene-R⁵, -Ci.6 alkylene-L-R⁵ or -C|.6 alkylene-L-C[.ù alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-C|.6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2- or -NHC(O)-;

each R³ is independently hydrogen or C|.₆ alkyl;

each R⁴ is independently hydrogen or C|.₆ alkyl;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm, alkyl, C₂.₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-

wherein said C|.(, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.₍, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰; 7

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C| alkyl, C?.6 alkenyl, C2.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C[.4 alkyl, acylantino, oxo, -NO2, -S(O)2R²⁶, -CN, C1.3 alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NI-h, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R and R mayjointo form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ch alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R^2f‘, -CN, C 1.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and

A?

each R is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl inay be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, stereoisoiner, mixture of stereoisomers or tautomer thereof.

[0146| In certain embodiments, the disclosure provides compounds of Formula IIB:

wherein:

n is 0, l, 2 or 3;

each R^lü is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(Cl l3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR^2ü, -N(R^2O)(R²²), -C(O)NiR^XR²²), -N(R^2,l)-C(O)-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)-S(O)2-R^2ft, -S(O)₂

R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C_w alkenyl, C₂₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said Cm alkyl, Cm alkenyl, C’₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NOi, aryl, heterocyclyl, heteroaryl, Cm alkyl, Cm haloalkyl, cycloalkyl, -N(R^2o)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C|.(, alkylene-R⁵;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R^2ü, -N(R²⁰)-C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)N(R^2O)(R²²), -CN, oxo and -O-R²⁰; and wherein said Cm alkyl is optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R~ and R are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂-6 alkenyl, C₂.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.6 alkenyl, C₂.<, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting ofhydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R^2ft, -CN, Cm alkoxy, -CF₃, -OCF₃, -OCH₂CF₃ and -C(O)-NH₂; or

7il 77 70 77 when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂. -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃ and -OCF₃; and / each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

whereîn the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, C m alkoxy, -CF3 and -OCFj;

or a phannaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

10147| In some embodiments, n is 1,2 or 3; and each R^lü is independently selected from the group consisting of halo, -O-R²⁰, -OS(O)2-R²⁰, Cm alkyl and cycloalkyl; and whereîn said alkyl and cycloalkyl are optionally substituted with one, two or three halo or -CN; and

R²⁰ is C|.(, alkyl, cycloalkyl or aryl; and whereîn the alkyl and aryl are optionally substituted with one, two or three halo or cycloalkyl.

10!48] In some embodiments, n is l, 2 or 3; and each R^ll) is independently 2-fluoro, 3fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-mcthyl, 4-ethyl, 4-isopropyl, 4-tcrt-butyl, 4-difluoromethyl, 4-trifluoromethyl, 4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4tritluoromcthoxy, 4-(2,2,2-trifluorocthoxy), 4-trifluoromethylsulfoxyl, 4-(2,2,2trifluoroethyi), 4-cyclopropoxy, 4-cyclobutylmethoxy, 4-fluorophenoxy, 4-phenoxy or 3phenoxy.

|<) 149] In some embodiments, the compound is selected from the group consisting of:

4-((3-methyloxetan-3-yl)mcthyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (ll-l);

4-(2-(pyrrolidin-l-yl)ethyl)-7-(4-(trilluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (H-3);

4-((5-cyclobutyl-l,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phcnyl)-3,4dihydrobenzo[f][ l,4]oxazcpin-5(2H)-one (l l-4);

4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-7-(4-(tri fl uoromethoxy)phenyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2l I)-one (II-5);

4-(i|uinolin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4diliydrobenzo[f][ I ,4]oxazepin-5(2H)-one (II-7);

(R) -2-(pyrimidin-2-yhnethyl)-8-(4-(trifluoromethyI)phenyl)-3,4,12,12a-tetrahydro-1H benzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (Π-8);

4-(cyclopropylniethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-10);

(S) -3-methyl-4-(pyrimidin-2-ylrnethy])-7-(4-(trifluoiOinethyl)plienyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-12);

(R)-3-nietliyl-4-(pyriniidin-2-ylmethyl)-7-(4-(trÎfluoromethyl)phenyl)-3,4dihydrobenzo[f|[ l ,4]oxazepin-5(2H)-one (I l-13);

6- ((5-oxo-7-(4-(tnfluoromethoxy)phenyl)-2,3-dihydiObcnzo[f|[l,4]oxazepin-4(5H)- yl)methyl)picolinonitrile (II-14);

7- (4-( tri fluoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-2-yl)methyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (I I-l 5);

7-(4-(trifluoromethoxy)phenyl)-4-((6-(trifluoroinethyl)pyridin-3-yl)methyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-16);

4-((6-methylpyridin-2-yl)inethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-17);

(2R,l laS)-2-amino-7-(4-(trifluoromethyl)phenyl)-2,3,l l,l iatetrahydrobenzo[f]pyrrolo[2, l -c][ l ,4]oxazepin-5( l H)-one (II-21 );

(R)-2-(2,2-difluoiOethyl)-8-(4-(triiluorornetliyl)phenyl )-3,4,12,12a-tetrahydro-l Hbenzo[f]pyrazino[2,1 -c][ l ,4]oxazepin-6(2H)-one (I l-22 ) ;

(R) -2-ethyl-8-(4-(triiluoiOmethyl)phenyl)-3,4,l2,l2a-tetrahydro-II-lbenzo[f]pyrazino[2,!-c][l,4]oxazcpin-6(2H)-one (II-23);

(S) -2-(2,2-difluoroetliyl)-8-(4-(trifluoiOmcthyl)phenyl)-3,4,12,12a-tctrahydiO-1Hbenzo[l']pyrazino[2,1 -c][ l ,4 |oxazepin-6(2H)-one ( 11-24);

(S)-2-ethyl-8-(4-(tiifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-l IIbcnzo[f]pyrazino[2, l-c][ 1,4]oxazcpin-6(2H)-one (I1-25); X

4-(pyrazin-2-yhnethyl)-7-(4-(trilluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-31);

4-((5-methyloxazol-2-yl)methyl)-7-(4-(trifluoromethoxy)plienyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (II-33 );

7-(4-(trifluorornethoxy)phenyl)-4-(2-(2,5,5-trimethyl-l,3-dioxan-2-yl)cthyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-35);

tert-butyl (2R,l laR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11ahexahydrobenzo[f]pyrrolo[2,l-c][l,4]oxazepin-2-ylcarbarnate (11-39);

4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trilluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-41);

4-((4,6-dimethoxypyrimidiii-2-yl)metliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (11-42);

ethyl 3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][ l,4|oxazepin-4(5H)yl)mcthyi)benzoate (11-43);

4-(2-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoiOinethoxy)pheny])-3,4dihydrobenzo[t][l,4]oxazepin-5(2H)-one (11-44);

4-(3,4-ditluorobenzyl)-7-(4-(trifluoiOmethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-45);

4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (11-47);

4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (11-48);

4-(2,6-ditluoiObenzyl)-7-(4-(trifluoiOniethoxy)phenyl)-3,4-dihydrobenzo[f'][l,4]oxazcpin5(21-1 )-one (11-49);

4-(2-( I H-pyrazol-1 -yl)cthyl)-7-(4-(trifluoromethoxy)phcnyl)-3,4dihydrobenzo[f|[ 1,4]oxazepin-5(2H)-one (11-50);

(2S, 1 laS)-2-amino-7-(4-(trifluoromethyl)phenyi)-2,3,l 1,1 latetrahydrobenzo[f]pyrrolo[2,1 -c][ 1,4]oxazepin-5( 1 H)-one (11-51 ); (X

4-(2-(pyndin-2-yi)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (I1-54);

4-(2-Huorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-57);

(R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11 a-tetrahydrobenzo[FJpyrrolo[2, l c][l,4]oxazepin-5( lH)-one (11-59);

4-(pyrimidin-2-ylmcthyl)-7-(4-(trifluoromethyl)plienyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (H-61);

4-(4-lluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[fJ[l,4]oxazepin5(2H)-one (11-62);

4-((1-mcthyl-lH-pyrazol-3-yl)inethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-64);

4-((5-cliloiOpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydiObenzo[fJ[ 1,4]oxazepîn-5(2H)-one (11-65);

4-(pyridin-4-ylmethyl)-7-(4-(trif]uoromethoxy)phenyl)-3,4dihydiObenzo[f][l,4]oxazepin-5(2H)-one (11-67);

4-((5-cyclopropyl-l,3,4-oxadiazoI-2-yl)niethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-68);

4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[fj[ 1,4]oxazepin-5(2H)-one (11-69);

4-(pyridin-3-ylmethyi)-7-(4-(trifluoromcthoxy)pheriyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-70);

4-(pyridio-2-ylmethyl)-7-(4-(trilluoromethoxy)plienyl )-3,4dihydrobenzo[f]| 1,4]oxazepin-5(2H)-one (11-72);

4-(pyrimidin-2-ylmetliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-73);

4-((3-inethylpyridin-2-yl)methyl)-7-(4-(tri fluoiOmethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2I-l)-one (11-75); çZ (R)-2-(2,2,2-tri fluoroethy I )-8-(4-( tri fluoromethy l )phenyl)-3,4,12,12a-tetrahydro-1Hbenzo[t]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one (II-83);

4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (I1-87);

7-(4-chlorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][ l,4]oxazcpin-5(2H)one (II-88);

7-(4-isopropylphenyl)-4-(pyrnnidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2ll)-one (II-89);

7-(4-ethylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[fj[l,4]oxazepin-5(2H)-one (II-9Î);

7-(4-cyclopiOpylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (I1-92);

(R)-4-(l-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (II-95);

7-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-97);

7-(4-tert-butylphenyl)-4-(pyriinidin-2-ylinethyl)-3,4-dihydrobenzo[f][l,4]oxazepiii5(2H)-one (H-98);

7-(4-cyclopropoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l_}4]oxazepin5(2H)-one (II-102);

7-(4-fluorophenyl)-4-(pyrirnidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one (II-104);

7-(2-fluoro-4-(trifluoroinethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dîhydrobenzo[f|[ I _t4]oxazepin-5(2H)-one (II-105);

7-(3-fluoiO-4-(2,2,2-trilluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-I06);

4-(pyrimidin-2-ylinctliyl)-7-(4-(2,2,2-trifluoroethoxy)plicnyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (II-107);

7-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyriinidin-2-ybnethyl)-3,4diliydrobenzo[f][ l ,4]oxazepin-5(2H)-one (11-110); (Z

7-(4-(trifluoromethoxy)phenyl)-4-((4-(trifluoromethyl)pyrimidin-2-yl)rnethyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Il-113);

7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2yl)rnethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-115);

7-(4-chloro-2-fluoroplienyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-Il 7);

I-(4-(5-oxo-4-(pyrimidin-2-yImethyl)-2,3,4,5-tetrahydrobenzo[l][l,4]oxazepin-7yl)phenyl)cyclopentanecarbonitrile (II-122);

7-(4-ethoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydiObenzo[f][l,4]oxazcpiii-5(2I-l)one (II-123);

7-(4-(diiluoromethyl)phenyl)-4-(pyrimidin-2-ylinethyl )-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (II-124);

4-(iinidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(triiliioiOmethyl)plicnyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-129);

4-((4-morpholinopyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-133);

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-diliydiObenzo[f][ 1,4]oxazepin-5(2H)-one (II-I34);

4-(iniidazo[l,2-a]pyi‘idin-2-yimethyl)-7-(4-(trifluoromethyl)plienyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-135);

7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyriinidin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-136);

4-((4-inethoxypyriniidin-2-yl)methyl)-7-(4-(tritluoronicthoxy)phenyl)-3,4dîhydrobenzo[f][1,4]oxazepin-5(2H)-one (II-137);

4-((4-methylpyrimidin-2-yl)mcthyl)-7-(4-(trifluoroinethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (IM38);

4-((4-(piperidin-l-yl)pyrimidin-2-yl)methyl)-7-(4-(trifluoiOinethoxy)phcny!)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-139); c/

4-((4-(di]nethylamino)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[fj[ l ,4]oxazepin-5(2H)-one (II-140);

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydiObenzo[f][l,4]oxazepin-5(2H)-one (III4I);

4-((3-mcthoxypyridin-2-yl)rnethyl)-7-(4-(trilluoroinethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-143);

7-(4-(cyclobutylmethoxy)phenyi)-4-(pyrimidin-2-ylmethyl)-3,4d ihydrobenzof f] [ 1,4]oxazepi π-5 (2H )-one ( 11 -144) ;

7-(2-inethyl-4-(trifluoroniethyl)phenyl)-4-(pyrimidin-2-ylmelhyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-145);

7-(2-methyl-4-(trifluoiOinethoxy)phenyl)-4-(pyrimidin-2-yhnethyI)-3,4dibydrobenzo[f][l,4]oxazepin-5(2H)-one (11-146);

4-((l-(difluoromethyl)-lH-pyrazol-3-yl)niethyl)-7-(4-(trifluorometlioxy)phenyl)-3,4dihydrobcnzo[f][ 1,4]oxazepin-5(2H)-one (11-147);

7-(4-(trifluorometlioxy)phenyl)-4-((3-(trifluoromethyl)-1 H-pyrazol-1 -yl)metliyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-148);

4-(pyrimidin-2-yimethyl)-7-(4-(2,2,2-trifluoiOethyl)phenyl)-3,4dihydrobenzo[f|[ 1,4]oxazepin-5(2H)-one (11-150);

4-(pyridin-2-ylmethyl)-7-(4-(2,2,2-trifluorocthyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-151);

4-((1-cyclopentyl-lH-pyrazol-3-yI)methyl)-7-(4-(trifluoromethoxy)phenyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-152);

4-((1-etliyl-l H-pyrazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobcnzo[f][ l,4]oxazepin-5(2H)-one (11-153);

4-((l-inethyl-lH-imidazol-4-yl)niethyl)-7-(4-(trifluoromethoxy)pbcnyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-154);

4-((4-mcthyl-l H-pyrazol-l-yl)methyl )-7-(4-(tri iluoromethoxy)plienyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-155);

4-((4-chloro-1 H-pyrazol-1 -yl)methyl)-7-(4-(trilluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-156);

7-(4-(difluoromethyl)phenyi)-4-(pyridtn-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-157);

7-(4-(difluoromethoxy)phenyl)-4-(pyridin-2-ylmethyl)-3,4-diliydrobenzo[f][t_t4]oxazepin5(2H)-one (II-159);

4-(( l -methyl-1 H-pyrazol-4-yl)methyI)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-otie (11-160);

4-(pyrimidin-2-ylmethyl)-7-(2,3,4-trifluoroplienyl)-3,4-dihydrobcnzo[f|[l,4]oxazepiii5(2H)-one (II-162);

7-(3,4-difiuorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepÎn5(2H)-one (II-163);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ I ,4]oxazepin-5(2H)-one ( II-164);

4-benzyl-9-tluoro-7-(4-(tritluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-165);

4-benzyl-9-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-diliydrobenzo[f][l,4]oxazepin5(2H)-one (II-I66);

4-benzyl-8-fluoro-7-(4-(trifluoronietboxy)phenyl)-3,4-dihydrobcnzo[fj[l,4]oxazepin5(2H)-one (II-167);

4-benzyl-8-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-I68);

7-(4-chloro-3-fluorophenyl)-4-((3-fluoropyridin-2-yl)nictliyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-onc (II-169);

7-(2-11 uoro-4-(trifluoromethyl)phenyi)-4-((3-fluoropyndin-2-yl)methyI )-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-170); ¢/

4-(5-oxo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-7-yl)phenyl trifluoromethanesulfonate (II-171 );

4-((5-methylpyrazin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-l72);

2,2,3,3-tetradeutero-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-174);

4-((6-methylpyrazin-2-yl)methyl)-7-(4-(trifluoiOmethoxy)phcnyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-175);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(ti‘ifluoiOinethyl)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2II)-onc (ll-l 76);

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)benzenesulfonamide (Π-177);

N-(2-(5-oxo-7-(4-(tri(luoiOmethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)ethyl)cyclopropanesulfonarnide (II-179);

4-(( l -methyl-1 H-imidazol-2-yl)methyl )-7-(4-(tiï tluoromethoxyjphenyl )-3,4dihydrobenzoff][ l ,4]oxazepin-5(2H )-one (l I-186);

4-((I-benzyl-lH-imidazoi-2-yl)methyl )-7-(4-(tri Il uoiOmethoxyJphenyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-187);

4-(imidazo[l,2-a]pyridin-2-yImethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2II)-one (II-189);

N-cyclopropyl-3-(5-oxo-7-(4-(tiïfluorç>methoxy)phenyl)-2,3dihydrobenzo[f][ l ,4]oxazepin-4(5H)-yl)propane-1 -sulfonamide (11-190);

N-(2-(5-oxo-7-(4-(trilluoromethoxy)phenyl)-2,3-dihydiObenzo| f|[ l ,4]oxazepin-4(5H)yl)ethyl)pyrimidine-2-carboxamide (II-l 92);

7-(4-(4-fluorophenoxy)phenyl )-4-(pyrimidin-2-yl methyl )-3,4dihydrobenzo[f][1,4]oxazepin-5(2H)-onc (II-193);

7-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][ l,4]oxazepin-5(2H)one (ll-l94); and ,7/

7-(3-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one(II-l95);

|0150| In other embodiments, the disclosure provides compounds of Formula II:

wherein:

m is 0 or l ;

n is 0, l, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO?, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)?R²⁰, -O-S(O)?-R²⁰, -S(O)2-N(R^2ü)(R²²), Cm alkyl, C?.4 alkenyl, C_M alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C m alkyl, C₂^ alkenyl, C?^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R^2ü, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R² is -C’m alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵or-Cj.₆alkylene-L-CM alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)?-, -S(O)?NH-, -C(O)N11- or -NHC(O)-;

each R³ is independently hydrogen, deuterium, Cms alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cms alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, ç/

-NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -CfCO-NfR^XR²³), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NiR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.(, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R )(R ), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰XR²²), -CN and -OR²⁰;

or R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C i.js alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C|_js alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, Cms alkyl, Cm alkoxy, -C(O)OR²⁶, -C(O)-N(R²⁶XR²⁶), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cms alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰XR²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents X independently selected from the group consisting of halo, -NO₂, C|.f, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|_6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atom to which they are attached forni an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|.(, alkyl, C₂^ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C|.(, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci_<, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -NfR^’XR²²), -C(O)R²⁰, -C(O)-OR²⁰, -CfOi-NfR^’XR²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹⁷ is halo or Cj.f, alkyl; X

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|-is alkyl, C₂-is alkenyl, C₂-i5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C|-|5 alkyl, C2-15 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NOi. -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(O)-NI 1₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a conunon nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with 011c, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -SfOJiR²⁶, -CN, C|.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

provided the eompound is not tert-butyl 6-oxo-8-phenyl-3,4,12,12a-tetrahydro1 H-benzo[f]pyrazino[2,l-c][ 1,4]oxazepine-2(6H)-carboxylate, tert-butyl 6-oxo-9phenyl-3,4,12,12a-tetrahydro-1 H-benzo[f]pyrazino[2,1 -c][ 1,4]oxazepîne-2(6H)carboxylate, 8-phenyl-3,4,12,12a-tetrahydro-1 H-benzo[f]pyrazino[2,1 c|[ 1,4|oxazepin-6(2H)-one, or 9-phenyl-3,4,12,12a-tetrahydro-111benzo[t]pyrazino[2,1 -c][ 1,4]oxazepin-6(2H)-one.

|(I15I | In some embodiments, R² is -Cm alkylene-R⁵ or -Cm alkylene-L-R⁵.

|01521 ln some embodiments, R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl; X wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of C|.û alkyl, halo, cycloalkyl, heterocyclyl, heteroaryl, -N(R“ )(R ), -C(O)-OR²⁰, -CN and -O-R²⁰;

wherein said C|.(, alkyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, C]._& alkyl and aryl; and wherein said C|.6 alkyl is optionaily further substituted with one, two or three halo.

[01531 In some embodiments, R² and onc of R³ can joîn together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionaily substituted with one, two or three substituents independently selected from the group consisting of C|. 15 alkyl, -O-R²⁰, -N(R^2O)(R²²) and -C(O)-OR²⁰; and wherein said Ci_i5 alkyl is optionaily substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.

In some embodiments, R is

|0154|

οι

[0155| In some embodiments, n is 1, 2 or 3; and each R¹⁰ is independently selected from the group consisting of halo, -O-R²⁰, -OS(O)₂-R²⁰, Cr alkyl and cycloalkyl; and wherein said alkyl is optionally substituted with one, two or three halo; and R²⁰ is independently selected from the group consisting of Ci-Cis alkyl and cycloalkyl; and wherein the alkyl is optionally substituted with one, two or three halo or cycloalkyl.

|(H56| In some embodiments, n is 1,2 or 3; and each R¹⁰ is independently 2-iluoro, 3fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-diiluoromethyl, 4-trifluoromethyI, 4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4trifluoromethoxy, 4-(2,2,2-trifluoroethoxy), 4-trifluoromethylsuifoxyl, 4-(2,2,2trifluorocthyl), 4-cyclopropoxy or 4-cyclobutylmethoxy.

|01571 ln some embodiments, each R³ is independently hydrogen, deuterium or Cms alkyl optionally substituted with heteroaryl;

or R² and one of R³ can join together with the atom to which they are attached to fonn a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C|.15 alkyl, -N(R²⁰)(R²²) and -N(R²⁰)-C(O)-OR²⁰; and wherein said C|.|j alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; and

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|-Cjs alkyl and heteroaryl.

|0158] In some embodiments, each R³ is independently hydrogen, deutérium or Ci-|5 alkyl optionally substituted with heteroaryl.

|01591 In some embodiments, each R³ is independently hydrogen, deuterium, methyl, isopropyl or pyridin-2-ylmethyl.

|(>160] ln some embodiments, each R⁴ is independently hydrogen, deuterium or Cj.j5 alkyl.

|0l6I| In some embodiments, each R⁴ is independently hydrogen, deuterium or methyl, |01621 In some embodiments, m is 0.

|01631 ln some embodiments, m is l; and R¹⁷ is halo.

[01641 In some embodiments, m is 1; and R is fluoro.

[0165] I11 certain embodiments, the disclosure provides compounds of Formula III:

wherein:

n is 0, I, 2, 3, 4 or 5:

each R¹⁰ is independently selected from the group consisting of halo, -NO?, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R^2l’)(R²²), -N(R²⁰)-C(O)-R²², -N(R^2g)-C(0)-0R²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2^ alkenyl, C_M alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, phenyl, heterocyclyl, heteroaryl, Cm alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -L-R⁵, -L-C|.6 alkylene-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylene-L-C|_6 alkylene-R⁵;

wherein each -Cialkylene is optionally substituted by one substituent independently selected from the group consisting of C₂_4 alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R^2ll)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2o)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂m alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NiR^’XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰XR²²), -CN and -O-R²⁰;

L is -O-, -S-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or-NHC(O)-, provided thaï when R² is -L-R⁵ or -L-C,.6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)2- or -NHC(O)-;

•1 each R is independently hydrogen, deuterium, C145 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰XR²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R^2O)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

each R⁴ is independently hydrogen, deuterium, C|.|5 alkyl, Cm alkoxy, -C(O)OR²⁶, -C(O)-N(R^2ft)(R²⁶), -N(R^2Ü)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cms alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR^2ü, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰; and wherein said C|.₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -qoî-nîr^xr²²), -CN and -O-R²⁰;

4 or two R or two R together with the carbon atom to which they are attached form an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C'2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²°, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents X independently selected from the group consisting of halo, -NO₂, Cj-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|_6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

22

R and R are in each instance independently selected from the group consisting of hydrogen, Cj-is alkyl, C₂-is alkenyl, C₂-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C₂-is alkenyl, C₂-i5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO_2i -S(O)₂R‘ , -CN, Cm alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R“ and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃; X or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

10166| In other embodiments, the disclosure provides compounds of Formula III:

wherein:

n is 0, 1,2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R^2O)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C,.(, alkyl, CM alkenyl, C₂-i alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.6 alkyl, C₂_4 alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, C|_6 alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -L-R⁵, -L-C|.6 alkylene-R⁵, -Cj.6 alkylene-L-R⁵ or -C[.& alkylene-L-Ci.f, alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

each R is independently hydrogen, deuterium, C’i_i5 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C^s alkyl is optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, -NOi, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, 5/

Cj.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, -NiR^fR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

each R⁴ is independently hydrogen, deuterium, Cms alkyl, Cm alkoxy, -C(O)OR²⁶, -C(O)-N(R²⁶)(R²⁶), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci.15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Ci-6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2o)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cialkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO?, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atom to which they are attached fonn an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C ialkyl, C₂^i alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C|^ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cj.6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R^2O)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁽’ and -O-R²⁰;

011 77

R~ and R‘ are in each instance independently selected from the group consisting of hydrogen, Cj-i 5 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cn5 alkyl, C₂-is alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C^ alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, C|.₃alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² arc attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclîc or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C_H alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂.

-S(O)2R²⁶, -CN, Ci_3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and X each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

|0167] In some embodiments, R² is -C(O)-R⁵ or -C(O)-C].₆ alkylcne-R⁵; and

R⁵ is cycloalkyl, aryl or heteroaryl;

wherein said cycloalkyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, halo and -C(O)-OR²⁰.

10168] In some embodiments, R⁵ is cycloalkyl, aryl or heteroaryl;

|0169] In some embodiments, each -Cm alkylene of R is unsubstituted.

|0170]

O

In some embodiments, R² is

O

|0171 ] In some embodiments, n is 1; and

R¹⁰ is -O-R²⁰ or C_M alkyl;

100 wherein said alkyl is optionally substituted with one, two or three halo; and

R²⁰ isCi-Cis alkyl;

wherein the alkyl is optionally substituted with one, two or three halo.

[01721 ln some embodiments, n is 1 ; and R¹⁰ is 4-trifluoromethyl or

4-tri fluoromethoxy.

[0173) In some embodiments, the compound is selected from the group consisting of: pyrimidin-2-yl(7-(4-(trifIuoromethoxy)phenyl)-2,3-dihydiObenzo[f][l,4]oxazepin-4(5H)yl)methanone (III-1 );

phenyl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)yl)methanone (111-4);

(l-methylcyclopropyl)(7-(4-(trifluoromethoxy)phcnyl )-2,3dihydrobenzof 1][ 1,4]oxazepin-4(5H)-yl)methanone (111-10);

(3,3-difluorocyclobutyl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (II1-11);

( 1 -methyl-1 H-pyrazol-4-yl)(7-(4-(tri fluoromethoxy)phenyl)-2,3dihydrobenzo[f][ 1,4]oxazepin-4(5H)-yl)mcthanone (III-12);

( 1 H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][ 1,4]oxazepin4(5H)-yl)methanone (III-15);

pyrazin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methanone (111-23);

pyridazin-3-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl)methanone (111-24);

2-(pyridin-2-yl)-l-(7-(4-(trilluoiOmethyl)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(511)-yl)ethanone (III-29);

2-(pyrimidin-2-yl )-1-(7-( 4-(lrifluoromethyl)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)ethanone (III-30);

(1 -methyl-IH-imidazol-5-yI)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (II1-32); Λ

101 ( l H-imidazol -2-yl )(7-(4-(tri fluoromethyl )plieny l)-2,3-d ihydrobenzo[f] [ l ,4]oxazepin4(5H)-yl)methanone (III-33);

( l -methyl-1 H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3d ihydrobenzo[ f] [ l ,4]oxazepi n-4(5 H )-yl )mcthanone ( 111-3 7) ;

(R)-(2-methyl-7-(4-(trif]uoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin-4(5H)yl )(pyrimidin-2-yl)methanone ( 111-3 8) ;

tert-butyl 2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepine-4carbonyl)-5,6-dihydroimidazo[ l ,2-a]pyrazine-7(8H)-carboxylate (III-40);

(lH-l,2,4-triazol-3-yl)(7-(4-(trifluoromcthyl)phenyl)-2,3-dihydiObenzo[t][l,4]oxazepin4(5H)-yl)methanone (III-50); and (l ,5-dimethyl-1 H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo[f][ l ,4]oxazepin-4(5H)-yl)methanone (111-58);

or a pharmaceutically acceptable sait, ester, stereoisomcr, mixture of stereoisomers or tautomer thereof.

|0174| In certain embodiments, the disclosure provides compounds of Formula IV:

wherein:

n is 0, l, 2, 3, 4 or 5:

each R^lü is independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CI I₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR², -N(R²⁰)(R²²), -C(O)N(R^2O)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)₂-N(R²⁰)(R²²), Ci-6 alkyl, C₂.₄ alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm, alkyl, C₂.₄ alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, C|._f, alkyl, Cu haloalkyl, X

I02 cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Ci-6 alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -C].& a!kylene-L-R⁵ or -Cm e

alkylene-L-C|.6 alkylene-R ;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂_4 alkynyl, halo, -NO?, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(0)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂.₄alkynyl, halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(0)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)?-, -S(O)?NH-, -C(O)NH- or -NIIC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)?- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C?,₄ alkynyl, halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^î0)(R²²), -CN and -O-R²⁰; and wherein said Ci_c, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two (X

103 or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cj-is alkyl, C₂-is alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cri? alkyl, C₂-is alkenyl, C₂-ts alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|.₄ alkyl, acylamino, oxo, -NO₂. -S(O)₂R^2f’, -CN, C|.₃alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

22 ^0 2** when R and R are attached to a common nitrogen atom R“ and R “ may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, araikyloxy, acylamino, -NO₂. -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

10175] In other embodiments, the disclosure provides compounds of Formula IV: X

104

n is 0, l, 2 or 3 :

each R¹⁰ is independently selected l'rom the group consisting of halo, -NO?, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, Cw alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl arc optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R^ÎO)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-C|.₍, alkylene-R⁵, -Cri, alkylene-L-R⁵ or -Cm alkylene-L-C|.(, alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

S(O)R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting ofhalo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two <

105 or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R^2Ü)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -CjOj-NfR^XR²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-15 alkyl, C₂-|₃ alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cns alkyl, C₂-|₃ alkenyl, C₂-i₃ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl arc optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO_2i -S(O)₂R²⁶, -CN, C|.₃alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cj.₄alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to f’orm a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2i -S(O)2R²⁶, -CN, Cm alkoxy, -CF3, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting ofhydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stéréo isomers, tautomer, polymorph and/or prodrug thereof.

|()176| In some embodiments, each -Cm alkylene of R is unsubstituted.

[01771 In certain embodiments, the disclosure provides compounds of Formula V:

106

V wherein:

A is cycloalkenyl;

n is 0, I, 2, 3, 4 or 5;

each R^lü is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Sî(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -C(O)N(R^2O)(R²²), -N(R^2ü)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -0-S(O)2-R²°, -S(O)2-N(R²⁰)(R²²), C|.6 alkyl, C₂_4 alkenyl, C₂_; alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Ci.₍, alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, C|.(, alkyl, C;.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein each -Ci-6 alkylene is optionaily substituted by one substituent independently selected from the group consisting of C₂.₄ alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2o)(R²²), -N(R^2ü)-S(O)₂-R^2ü, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of C|.(, alkyl, C’₂-i alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

107

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)?NH-, -C(O)NH- or -NHC(O)-, provided tliat when R² is -L-R⁵ or -L-C|_6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NIIC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂.4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)?-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting ofhydrogcn, Cns alkyl, C?-is alkenyl, C₂-|5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cj-j5 alkyl, C?-is alkenyl, C₂-u alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO?. -S(O)₂R²⁶, -CN, Ci.3 alkoxy, -CF₃, -OCF3, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or X

108

2(1 22 20 22 · when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂. -S(O)2R²⁶, -CN, Ci_3 alkoxy, -CFj, -OCF3, aryl, heteroaryl and cycloalkyl; and each R^2fi is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and whereîn the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

|0178] In other embodiments, the disclosure provides compounds of Fonnula V:

whereîn:

A is cycloalkenyl;

n is 0, 1, 2 or 3:

cach R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R², -S-R²⁰, -C(O)-R²⁰, -C(0)-OR², -N(R²⁰)(R²²), -C(O)N(R^2O)(R²²), -N(R²⁰)-C(O)-R²², -N(R²)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R², -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm, alkyl, C2^ alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and whereîn said Cm, alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -NfR^’XR²²), -C(O)-R^2ü, -C(O)-OR², -C(O)-N(R²)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R^sor -Cm alkylene-L-C Μ, alkylcne-R⁵:

109

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected lrom the group consisting of C[._f, alkyl, C₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C|.₍, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci.6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci.₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CFj, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² arc in each instance independently selected from the group consisting of hydrogen, Cj-is alkyl, C₂-is alkenyl, C₂-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cj-ts alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, C’1.3 alkoxy, -CF₃, -OCF₃, -OCH₂CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² arc attachcd to a common nitrogen atom R²⁰ and R²² may join to form a hetcrocyclic or heteroaryl ring which is then optionally substituted with X

110 one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2j-S(O)₂R²⁶, -CN, Cj_3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stcreoisomer, mixture of stereoisomers, tautoiner, polymorph and/or prodrug thereof.

|0179] ln some embodiments, R² is -Cm a)kylene-R⁵.

|()180] ln some embodiments, R⁵ is heteroaryl.

·) |0l81 ] ln some embodiments, each -Cm alkylene of R is unsubstituted.

|OI82| In some embodiments, R² is |0183] In some embodiments, A is cyclohex-l-enyl.

|01841 In some embodiments, A is cyclohex-l-enyl; n is 0 or 1 ; and R^lü is 4-methyl or 4-re/7-butyl.

[0185] In some embodiments, the compound is selected from the group consisting of:

7-(4-tert-butylcyclohex-1 -enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (V-l );

7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (V-3); and

7-(4-methylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl )-3,4d i hydrobenzo [ 1] [ 1,4] oxazepi n-5(2 H )-one ( V-5 ) ;

or a pharmaceutically acceptable sait, ester, stcreoisomer, mixture of stereoisomers or tautomer thereof.

10186] ln certain embodiments, the disclosure provides compounds of Formula VI:

I 1 I

wherein:

B is heterocyclyl or heteroaryl;

n is 0, 1, 2, 3, 4 or 5:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C24 alkenyl, C₂₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, C|,₆ alkyl, Ci.₃ haloalkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-C|._b alkylene-R⁵, -Cm alkylene-L-R⁵or -Cm alkylene- L-C m alkylene-R⁵;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂₄ alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|._b alkyl, C₂_j alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^MR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; X

112

	L is -0-, -S-, -C(0)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -0-, -S-, -NHS(O)₂- or -NHC(O)-; R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;
5	wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂.4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²ⁿ)(R²²), -CN and -O-R²⁰;
10	wherein said C].₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C\|.₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2Ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and
I5	wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -NfR^JfR²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN, -S(O)₂-R²⁰ and
20	-O-R²⁰; R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cj-is alkyl, C₂-is alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the Cns alkyl, C2-15 alkenyl, C₂-\|₃ alkynyl, cycloalkyl,
25	heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO_2i -S(O)₂R^2f>, -CN, Cj.₃alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and
30	wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or ρζ

J

9Π 79 9Π 99 when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

[0187] In other einbodiments, the disclosure provides compounds of Formula VI:

wherein:

B is heterocyclyl or heteroaryl;

n is 0, 1,2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)j, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(Q).-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R^2ü, -S(O)2-N(R²⁰)(R²²), C|.₆ alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂h alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR^2q, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R^s, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵or -C|.₆alkylene-L-C|.6 alkylene-R⁵; X

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂m alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cru alkyl, C₂-u alkenyl, C₂-u alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cris alkyl, C₂-u alkenyl, C₂-u alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|_i alkyl, acylamino, oxo, -NO₂, -S(O)₂R , -CN, Cm alkoxy, -CFj, -OCF3, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with ll5 one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2t-S(O)₂R²⁶, -CN, Ci-3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvatc, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

101881 In some embodiments, B is heteroaryl.

|0189| In some embodiments, B is 2-oxo-l,2-dihydropyridin-4-yl, pyridin-4-yl, pyridin2-yl, thiazol-4-yl or thiophen-2-yl.

\|0190]	In some embodiments, each -Cm alkylene of R² is unsubstituted.
\|0191\|	In some embodiments, R² is -Cm alkylene-R⁵.
\|0192\|	In some embodiments, R⁵ is heteroaryl.
\|0193\|	„ «O In some embodiments, R” is N ^/ .
10194]	In some embodiments, n is 1;

R¹⁰ is cycloalkyl, -O-R²⁰ or C|.₄ alkyl;

wherein said alkyl is optionally substituted with one, two or three halo; and R²⁰ is Ci-C15 alkyl.

|0195| In some embodiments, n is 1;

R^l0is-O-R²⁰ or C_M alkyl;

wherein said alkyl is optionally substituted with one, two or three halo; and

R²⁰ is C|-C|₅ alkyl.

116 |0196] In some embodiments, B is 2-oxo-l,2-dihydropyridin-4-yl, pyridin-4-yl, 5(trifluoromethyl)pyridin-2-yl, 2-isopropyltliiazol-4-yl, 5-(trifluoromethyl)thiophen-2-yl or 5-cyclopropylthiophen-2-yl.

[0197| In some embodiments, the compound is selected from the group consisting of:

7-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (VI-12);

4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-26);

7-(2-isopropylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (VI-30);

4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4dihydrobenzo[f][ I,4]oxazepin-5(2H)-one (VI-31 );

7-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (VI-32);

7-(5-cyclopropylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VI-36); and

4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (VI-37);

or a pharmaccutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tau to mer thereof.

|0l98| In certain embodiments, the disclosure provides compounds of Formula VIII:

wherein:

n is 0, l, 2, 3, 4 or 5;

II7 =-=-= represents a single, double or triple bond;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -C(O)NiR^’jtR²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(0)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R^2ü)(R²²), Cm alkyl, C2-4 alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and whereîn said Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, Ci-jhaloalkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-Cm alkylcne-R^s, -Cm alkylene-L-R⁵ or -Cm alkylene-L-CM alkylene-R^s;

whereîn each -Cm alkylcne is optionally substituted by one substituent independently selected from the group consisting of Cm alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R^2ü, cycloalkyl, aryl, heteroaryl or heterocyclyl; and whereîn said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NIIC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

whereîn said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl,

118 aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci.& alkyl, C₂.6 alkenyl, C₂.6 alkynyl, cycloalkyl, heterocyclyl, aryl an'd heteroaryl;

wherein the Cj.6 alkyl, C₂_6 alkenyl, C₂.& alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionaily substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionaily further substituted with Cm alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionaily substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2<-S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

119 wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

[0199] In some embodiments, each -C|.6 alkylene of R² is unsubstituted.

[0200]

In some embodiments, R² is [0201] In some embodiments, n is 0 or 1 ; and R¹⁰ is 4-trifluoromethyl or

- tri fl uoromethoxy.

10202] In some embodiments, the compound is selected from the group consisting of:

4-(pyrimidin-2-ylmethyl)-7-((4-(triiluoromethoxy)phcnyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-4);

7-(phenylcthynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VII1-5);

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)phenyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-6);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (VIII-7);

4-(pyri m i d i n-2-yl methyl )-7-(4-(tri fl uoromet hyl )phenethyl )-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (VII1-8);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromcthyl)phcnethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (V111-9);

(E)-4-benzyl-7-(4-(trifluoromethyl)styryl)-3,4-dihydrobenzo[f][l,4]oxazcpin-5(2H)-one (VIII-10); and

4-benzyl-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-II);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof. ’X

120 [0203] In other embodiments, the disclosure provides compounds of Formula VIIIA:

wherein:

n is 0, l, 2 or 3:

each R.¹⁰ is independently selected from the group consisting ofhalo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)r R²⁰, -O-S(O)₂-R²⁰, -S(O)2-N(R²⁰)(R²²), C|.6 alkyl, C₂₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.₆ alkyl, C_w alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaliy substituted with one, two or three substituents independently selected from the group consisting ofhalo, _NO₂, phenyl, heterocyclyl, heteroaryl, C|_6 alkyl, cycloalkyl, -NiR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Ci-6 alkylene-R⁵, -L-R⁵, -L-Cialkylene-R⁵, -C|.f, alkylene-L-R⁵ or -C].₆ c

alkylcnc-L-Ci-6 alkylene-R ;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or-NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaliy substituted with one, two or three substituents independently selected from the group consisting of Ci-6 alkyl, C₂.₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C u, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected from the group consisting ofhalo, -NO₂, Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-0R²°, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and

121 wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cj-|₅ alkyl, C₂-is alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C|-u alkyl, C₂-is alkenyl, C₂-|5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO_2i -S(O)₂R^2ft, -CN, C,.₃alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|.4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2i -S(O)2R²⁶, -CN, C|.3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

|(I2O4| In some embodiments, R² is -Cm alkylene-R⁵.

|(!205| In some embodiments, R⁵ is heteroaryl. iX

122

[ 0207| In some embodiments, n is 0 or 1 ;

R^l0is -O-R²⁰ or Cm alkyl;

wherein the alkyl is optionally substituted with three halo; and

R²⁰ is C1-C15 alkyl; and wherein the alkyl is optionally substituted with one, two or three halo.

[0208| In some embodiments, n is 0 or I; and R¹⁰ is 4-trifluoiOmethyl or

4-trîfluoromethoxy.

[02091 In some embodiments, the compound is selected from the group consisting of: 4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VIII-4);

7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Vil 1-5); and

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethyl)pheiiyl)ethynyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (VII1-6);

|0210| In certain embodiments, the disclosure provides compounds of Formula IX:

‘0

IX wherein:

n is 0, 1,2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -C(O)N(R^2O)(R²²), -N(R^2ü)-C(O)-R²², -N(R^2t,)-C(O)-OR²². -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, CL, alkenyl, C2.₄ alkynyl, cycioalkyl, aryl, heteroaryl and heterocyclyl; and

123 wherein said Cm alkyl, C₂.4 alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.j haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R^s, -L-R^s, -L-C'm alkylene-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylene-L-CM alkylene-R^s;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂m alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2o)(R²²), -N(R²⁰)-S(O)₂-R^2ü, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂m alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, ¢/

124

Ci-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO?, -CF3, -N(R^2ü)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)2-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂_6 alkenyl, C₂_6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C|_6 alkyl, C?^ alkenyl, C?.(, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selectcd from the group consisting ofhydroxyl, halo, C]-4 alkyl, acylamino, oxo, -NO?, -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO?, -S(O)?R²⁶, -CN, Ci.₃ alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cι-a alkyl, aryl and cycloalkyl may bc further substituted with from I to 3 substituents independently selected from the group consisting ofhydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

102111 ln other embodiments, the disclosure provides compounds of Formula IX:

I25

wherein:

n is 0, l, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R^2ü)-C(O)-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, Cm alkenyl, C2.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R^s, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵or -Cm alkylene-L-Ci-6 alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NI1-, -C(O)NH- or -NI IC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂.₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and ¢/

126 wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R²⁰)(R²²), -C(O)5 R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and

-O-R²⁰;

wherein the C|-u alkyl, C₂-i5 alkenyl, C₂-u alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R^2f’, -CN, C|.₃alkoxy, -CF₃, -OCF₃, -OCII₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is thon optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂.

-S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stéréo isomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

[02121 In sonie embodiments, each -C m alkylene of R² is unsubstituted.

[02 L 3] In some embodiments, R² is -Cm alkylene-R⁵.

I27 [0214] In some embodiments, R is not benzyl.

|0215| In some embodiments, R is heteroaryl;

wherein said heteroaryl is optionally further substituted with halo.

Λ

In some embodiments, R is selected from the group consisting of

[0216)

[0217| In some embodiments, R¹⁰ is 4-trifluoromethyl.

[0218] In some embodiments, the compound is selected from the group consisting of:

2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (IX-2); and

2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone (IX-3);

[0219] In certain embodiments, the disclosure provides compounds of Formula X:

wherein:

n is 0, 1,2, 3, 4 or 5;

R¹⁰ is independently selected from the group consisting of halo, -NCh, -CN, -SF5, -Si(ClI3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁽’)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci.6 alkyl, C2_t alkenyl, Cm alkynyl, cycioalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.₆ alkyl, Cm alkenyl, Cm alkynyl, cycioalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three

Vit substituents independently selected from the group consisting of halo, -NCh, plienyl, heterocyclyl, heteroaryl, Cm alkyl, Ci^haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2Ü)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylcne-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -C|.& alkylene-L-R⁵or -Cm alkylene-L-CM alkylene-R⁵;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂-<i alkynyl, halo, -NO₂₎ -CN, -O-R²⁰, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2ü)(R²²), -N(R^2<’)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl arc optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂.4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R“), -CN and -O-R²⁰;

each R⁴ is independently hydrogen, deuterium, Ci_is alkyl, Cm alkoxy, -C(O)OR²⁶, -C(O)-N(R²⁶)(R²⁶), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cj.|5 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^'XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

V19

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

-O-R²⁰; and wherein said Cm alkyi, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO?, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

or two R⁴ together with the carbon atom to which they are attached form an oxo; R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyi, C'?.4 alkynyl, halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyi, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, C[.& alkyi, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyi, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO?, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)?-R²⁰ and

R⁶ is hydrogen, Cm alkyi or cycloalkyl;

wherein said Cm alkyi is optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

-NO2, -NfR^’XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²°XR²²), -CN and X

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|-_l5 alkyl, C₂-|₅ alkenyl, C₂-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Ci-15 alkyl, C₂-is alkenyl, C₂-i5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionaily substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C m alkyl, acylamino, oxo, -NO_2i -S(O)₂R²⁶, -CN, C|.₃alkoxy, -CF₃, -OCF3, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionaily further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²” and R²² may join to form a heterocyclic or heteroaryl ring which is then optionaily substituted with one, two or three substituents independently selected from the group consisting of I5 hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂.

-S(O)₂R²⁶, -CN, Ci-3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R^2û is independently selected from the group consisting of hydrogen, C m alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

10220] ln other embodiments, the disclosure provides compounds of Formula X:

wherein:

n is 0, I, 2 or 3;

13’

R¹⁰ is independently selected from the group consisting of halo, -NO?, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C|.6 alkyl, C_M alkenyl, C-m alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C[.6 alkyl, C₂..| alkenyl, C₂_4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, C|.6 alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R² is -C|.6 alky!ene-R^s, -L-R⁵, -L-Cm alkylene-R⁵, -Cj.6 alkylene-L-R⁵or-Ci-6 alkylene-L-Ci-6 alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NI1-, -C(O)NI1- or -NHC(O)-;

each R⁴ is independently hydrogen, deuterium, Ct-is alkyl. Cm alkoxy, -C(O)OR²⁶, -C(O)-N(R²⁶)(R²⁶), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci_js alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cj.(, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, Z

or two R⁴ together with the carbon atom to which they are attached form an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|.6 alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

wherein said C|._fl alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected liom the group consisting of halo, -NO₂, C|.₍, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Ci-_ft alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CFj, -N(R^2O)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²)(R“), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, C|.|₅ alkyl, -C(O)-R²⁰, -C(O)-OR^2<1, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cms alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

12>3>

-N(R^2ü)(R²³)_t -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and whereîn said Ci_₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -NfR^’XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰XR²²), -CN and -ΟΧ²⁰;

R²⁰ and R²² are in each instance independently selected liom the group consisting of hydrogen, Ci-jj alkyl, C₂-|₅ alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

whereîn the Cj-15 alkyl, C2-15 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, C|.₃alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and whereîn said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or *^0 22 when R and R are attached to a common nitrogen atom R and R mayjointo fonn a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C[.₃ alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and whereîn the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a phannaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof. X l? Il (0221] |0222| |()223|

In some embodiments, each -Cm alkylene of R² is unsubstituted.

S

In some embodiments, R is -Cm alkylene-R .

In some embodiments, R⁵ is aryl.

|0224]

> X \\ /> s In some embodiments, R“ is '— or

10225| In some embodiments, R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

|0226| In some embodiments, each R⁴ is independently hydrogen, deuterium or Cm alkyl optionally substituted with heteroaryl, or two R⁴ together with the carbon atom to which they are attached form an oxo.

10227] In some embodiments, two R⁴ together with the carbon atom to which they are attached form an oxo.

(02281 In some embodiments, R^(J is hydrogen or Cm alkyl.

(0229] ln some embodiments, R^û is hydrogen or methyl.

[0230] In some embodiments, the compound is selected from the group consisting of:

4-(2-(benzyloxy)ethyl)-1 -methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-1Hbenzo[e][ 1,4]diazepine-2,5-dione (X-7);

4- benzyl-1-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1 H-benzo[e] [ 1,4]diazepine-

2,5-dione (X-l 1); and

5- benzyl-8-(4-(trifluoromethyl)phenyl)-4H-benzo[f]imidazo[1,2-a][ 1,4]diazepin-6(5H)one (X-l2);

10231 ] In certain embodiments, the disclosure provides compounds of Formula XII:

wherein:

Z⁴ is CR⁷ or N; provided that only one of Z¹, Z² and Z⁴ is N;

n is 0, 1,2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R^2ü)-C(O)-R²², -NtR^-CiOJ-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2^ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂.₄ alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, C].₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylene-L-Ci-6 alkylene-R⁵;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂₄ alkynyl, halo, -NO2, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2o)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm, alkyl, C’2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, X

VU,

L îs -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-C|.6 alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaliy substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C_t^ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected from the group consisting ofhalo, -NO₂, C|.₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2<’)(R²²), -CN and -O-R²⁰; and wherein said C|.<, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected from the group consisting ofhalo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁷ is hydrogen, halo or Cm alkyl;

R²⁰ and R²² arc in each instance independently selected from the group consisting of hydrogen, Cn₅ alkyl, C₂-_J5 alkenyl, C₂-_]5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cn5 alkyl, C2-15 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionaliy substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, Ci_₃

Μ'⁷* alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a coinmon nitrogen atom R²⁰ and R²² may join to form a lieterocyclic or heteroaryl ring which is lhen optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF₃;

[0232] In other embodiments, the disclosure provides compounds of Formula XII :

XII wherein:

Z⁴ is CR⁷ or N; provided that only one of Z¹, Z² and Z⁴ is N;

n is 0, 1,2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R^2ü, -C(O)-OR²⁰, -N(R^2ü)(R²²), -C(O)N(R²°)(R²²), -N(R²⁰)-C(O)-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C,.6 alkyl, Cm alkcnyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and X

138 wherein said Cr_<> alkyl, C₂^ alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C|.f, alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylene-L-Ci-û alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-;

c

R is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2ü)(R²²), -N(R^2,,)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R )(R “), -C(O)-R²⁰, -C(O)-OR²⁰, -CfOJ-NfR^’jfR²²), -CN and -O-R²⁰; and wherein said Cm, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R is hydrogen, halo or Cj._f, alkyl;

R and R are in each instance independently selected from the group consisting of hydrogen, C|-|5 alkyl, C₂-is alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cj-j5 alkyl, C?-is alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or

139 three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂, -S(O)₂R²⁶, -CN, C|.₃alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

7A 77 7ίΊ 77 when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2>-S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting ** ofhydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a phannaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stéréo isomers, tautomer, polymorph and/or prodrug thereof.

|(I233| In some embodiments, R² is -Cm alkylene-R⁵ or -Cm alkylene-L-CM alkylene102341 In some embodiments, each -C m alkylene of R² is unsubstituted.

10235| In some embodiments, R⁵ is cycloalkyl, aryl or heteroaryl;

wherein said heteroaryl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, halo and -O-R²⁰.

|<)236| In some embodiments, R“ is

140 |02371 In some embodiments, n is 0 or l ;

R¹⁰ is -O-R²⁰ or Cm alkyi;

wherein the alkyi is optionally substituted with three halo; and

R²⁰ is C|-Cis alkyi; and wherein the alkyi is optionally substituted with one, two or three halo.

10238] In some embodiments, n is 0 or 1; and R¹⁰ is 4-triiluoromethyl or 4-trifluoromethoxy.

|02391 In some embodiments, the compound is selected from the group consisting of:

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3-f][l,4]oxazepin-5(2H)one (XII-1);

4-benzyl-7-(4-(trifluoromcthoxy)phenyl)-3,4-dihydropyrido[2,3-f][l,4]oxazepin-5(2H)one (XII-2);

4-benzyl-7-(4-(triiluoiOmethyl)phenyl)-3,4-dÎhydropyrido[2,3-f][l,4]oxazepin-5(2H)-one (X1I-3);

4-(pyrimidin-2-ylmethyl)-7-(4-(triiluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XI1-5);

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trit]uoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][ l,4]oxazepin-5(2H)-one (X11-8);

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][ 1,4]oxazepin-5(2II)-one (X11-9);

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][l,4]oxazepin-5(2H)-one (XII-10);

4-((3-fluoropyridin-2-y])methyl)-7-(4-(triiluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XII-11); and

4-((4-methoxypyrimidin-2-yl)methyl)-7-(4-(trinuoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][l,4]oxazepin-5(2H)-one (XI1-14);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof. À

141 |0240| In certain embodiments, the disclosure provides compounds of Formula XIII:

O

XIII wherein:

Q is a -O-Co-2 alkylene- or -NR^ll-C₀.₂ alkylene-;

n is 1, 2, 3, 4 or 5;

R^IÜ is halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -NîR^-CO-OR²², -N(R²⁰)S(O)2-R²⁶, -S(O)2-R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2m alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C m alkyl, C₂-4 alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is-Ci.₍, alkylcne-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵ or -C|.6 alkylene-L-C|_6 alkylcne-R⁵;

wherein each -Cm, alkylene is optionaily substituted by one substituent independently selected from the group consisting of C₂.₄ alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

142

L is -O-, -S-, -C(O)-, -NFIS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NIIC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R^2ü)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-ÛR²⁰, -C(O)-N(R^2t))(R²²), -CN, oxo and -OR²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci*6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2Ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R^2O)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(ü)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹¹ is hydrogen or Cm alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, Cm alkenyl, C₂.₍, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂._f, alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂, -S(O)₂R^2il, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and 'Z

143 wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

9Λ 99 9Λ 99 when R and R arc attached to a common nitrogen atom R and R may joîn to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Ci.4 alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof,

J02411 In other embodiments, the disclosure provides compounds of Formula XIII:

wherein:

Q is a -0-Co.₂ alkylene- or -NR¹ '-Co.₂ alkylene-;

n is 1,2 or 3;

R¹⁰ is halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2o)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)S(O)2-R²⁶, -S(O)2-R²⁰, -O-S(0)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C|-6 alkyl, Cm alkenyl, C2-4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.6 alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl,

-N(R^2t,)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2,j)(R²²), -CN and -O-R²⁰; /

144

R² is -Ci.6 alkylene-R^s, -L-R⁵, -L-CY_(| alkylene-R⁵, -Cm alkylene-L-R^s or -Cm alkylene-L-C|.6 alkylcne-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NII- or -NHC(O)-;

R⁵ is cycioalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycioalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C2-4 alkynyl, halo, -NO₃, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C|.6 alkyl, cycioalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|._f, alkyl, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycioalkyl, aryl, heterocyclyl or heteroaryl arc optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹¹ is hydrogen or Cm alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-15 alkyl, C₂-|₃ alkenyl, C₂-|5 alkynyl, cycioalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C₂-is alkenyl, C2-15 alkynyl, cycioalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted wîtli one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, Cj.₃alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycioalkyl and heteroaryl; and

145 wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Ci.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C_Nalkyl, aryl and cycloalkyl; and wherein the C_H alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomcr, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

|(1242| In some embodiments, Q is a -O-, -NH- or-NR¹¹-.

|(1243) In some embodiments, R¹¹ is methyl |Ü244| In some embodiments, each -Cm alkylene of R is unsubstituted.

|0245| In some embodiments, R is -Cm alkylene-R .

|0246| In some embodiments, R⁵ is heteroaryl.

|0247|

In some embodiments, R² is or |()248|

In some embodiments, n is 1 ;

R²⁰ is C|-C₁₅ alkyl; and wherein the alkyl is optionally substituted with one, two or three halo.

[0249| In some embodiments, R¹⁰ is 4-lrifluoromethoxy.

[02501 In some embodiments, the compound is selected from the group consisting of;

4-(pyrimidin-2-ylmethyl)-7-(4-(triiluoromethoxy)phenylamino)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (XIII-1 );

146

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenoxy)-3,4diliydrobenzo[f][ 1,4]oxazepin-5(2H)-one (XIII-2);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4dîhydrobenzo[f][l,4]oxazepin-5(2H)-one (XllI-3);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4dihydrobenzo[f|[ l ,4]oxazepin-5(2H)-one (XIH-4);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenylamino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Xlll-6); and

7-(methyl(4-(trifluoromcthoxy)phcnyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)~one (XIII-10);

or a pharmaceutically acceptable sait, ester, stereoisonier, mixture of stereoisomers or tautomer thereof.

102511 In certain alternative embodiments, the disclosure provides compounds of

Formula IB:

wherein:

R¹ is aryl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CN, -SF₅, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2o)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R^2ü)-C(O)OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C24 alkenyl, Cm alkynyl, cycioalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.<, alkyl, Cm alkenyl, C₂.₄ alkynyl, cycioalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

147

-NO₂, phenyl, heterocyclyl, heteroaryl, C|_6 alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, C_M5 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁸),

-N(R )-S(O)₂-R~ , cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|_ts alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C’m alkyl, C2.4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cj. <, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -0R²⁰;

Q is a covalent bond or C₂ alkynylene;

Y is -C(O)-, -CH₂-, -C(NR⁵)- or-S(O)₂-;

X is -O- or -NR⁶-;

each R³ is independently hydrogen, C|_i5 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1.15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents i

148 independently selected from the group consisting of halo, -NO₂, Ci.₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²),-CN and -O-R²⁰; and wherein said C|.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cι_|s alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C]_js alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, Cms alkyl, Cm alkoxy, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R^2S), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ct-is alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C[.t, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R^2Z), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and

149 whereîn said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R^J or two R⁴ together with the carbon atom to which they are attached form an oxo;

R⁵ is hydrogen, C|.j5 alkyl, Cm alkoxy, -C(O)-O-R²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

whereîn said Ci_i5 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

whereîn said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and whereîn said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or R² and R⁵ can join together with the atom to which they are attached to fonn a heterocyclyl or heteroaryl;

whereîn said heterocyclyl or heteroaryl is optionally substituted with one, two or three substituents independently selected from the group consisting

150 of C i-is alkyl, cycloalkyl, heteroaryl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Cms alkyl is optionally substituted with one, two or thi ee substituents independently selected from the group consisting of halo and heteroaryl;

wherein said Cι_15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.(, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C m alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-15 alkyl, C₂-is alkenyl, C₂-i5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C₂-15 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF3, -OCF3, -OCH₂CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and ¢4.

I5l wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C|_3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof, [02521 ln certain alternative embodiments, when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)₂-, X is -O-, R² is benzyl, each R³ is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴are hydrogen.

[02531 In certain alternative embodiments, the disclosure provides compounds of Formula ΠΑ:

11A

wherein:

n is 0, 1,2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO₂, -CN,

-SF_s, -Si(CH₃)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-0R²°, -N(R²⁰)(R²²),

-C(O)-N(R^2ü)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²)-S(O)₂-R²⁶,

152

-S(O)₂-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, C-m alkenyl, C2_i alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C2-4 alkenyl, C₂_4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -NfR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, CM5 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm5 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C’₂.4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2Ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C m alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^:<’)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2Ü)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -N(R^2Ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R^2Ü and -OR²⁰;

each R³ is independently hydrogen, Ci_is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|._l5 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; tZ

153 wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C].₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁽’)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R )(R““), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²),-CN and-O-

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C[_is alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said C|_js alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, Cm5 alkyl, Cm alkoxy, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C1.15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, X

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R and R are in each instance independently selected from the group consisting of hydrogen, Cru alkyl, C₂-ts alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cru alkyl, C₂-u alkenyl, C₂-!5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C1.4 alkyl, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C|.j alkoxy, -CF3, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO_2>-S(O)₂R²⁶, -CN, C|_3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stéréoisomers, tautomer, polymorph and/or prodrug lhereof,

102541 In some embodîments, R² is hydrogen or C,.15 alkyl; X

155 wherein said alkyl is optionaliy substituted with one, two or three substituents independently selected from the group consisting ofhalo, aryl, 20 heterocyclyl, heteroaryl, cycloalkyl and -O-R ;

wherein said aryl, heterocyclyl or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected from the group consisting ofhalo, Cm alkyl, heterocyclyl, heteroaryl, cycloalkyl, -C(O)-OR²⁰, -CN and -O-R²⁰; and wherein said Cm alkyl,or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected from the group consisting ofhalo and -CF₃;

wherein said heterocyclyl is optionaliy substituted with one, two or three substituents independently selected from the group consisting of Cm5 alkyl, -N(R²⁰)(R²²) and -N(R²⁰)-C(O)-OR²⁰; and wherein said Ci-is alkyl is optionaliy substituted with one, two or three substituents independently selected from the group consisting ofhalo and heteroaryl; and

R and R are in each instance independently selected from the group consisting of hydrogen, Cj-Cis alkyl and heteroaryl.

yC~<l * ?

|0255]

In some embodiments, R² is hydrogen,

F

156

/-Ο'-Ύγ ίο S or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

10256| ln some embodiments, n is l or 2; and X

157 each R¹⁰ is independently selected from the group consisting of halo, -O-R²⁰, Ομ alkyl and cycloalkyl; and wherein said alkyl is optionally substituted with one, two or three halo; and R²⁰ is independently selected from the group consisting ofC|-Cu alkyl and cycloalkyl; and wherein the alkyl is optionally substituted with one, two or three halo. |0257| In some embodiments, n is 1 or 2; and each R¹⁰ is independently selected from the group consisting of 2-lluoro, 3-fluoro, 4-fluoro, 2-chloro, 4-chloro, 4-ethyl, 4isopropyl, 4-tert-butyl, 4-trifluoromethyl, 4-cyclopropyl, 4-isobutoxy, 4-trifluoromethoxy, 4-(2,2,2-trifluoroethoxy) and 4-cyclopropoxy.

[0258| In some embodiments, each R³ is independently hydrogen or C|.u alkyl;

1 or R and one of R can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C i_ts alkyl, -N(R²⁰)(R²²) and -N(R²⁰)-C(O)-OR²⁰; and wherein said C|.u alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; and

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Ci-Cu alkyl and heteroaryl.

|0259| In some embodiments, each R³ is independently hydrogen or Ci.15 alkyl.

10260| In some embodiments, each R³ is independently hydrogen, methyl or isopropyl.

102611 In some embodiments, the compound is selected from the group consisting of

4-((3-methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[l][ 1,4]oxazepin-5(2H)-one;

4-(2-(pynolidin-l-yl)ethyl)-7-(4-(tri nuoromethoxy)phenyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(211)-one; X

158

4-((5-cyclobutyl-l,3,4-oxadiazol-2-yl)mcthyl)-7-(4-(trifluorornethoxy)phenyi)-3,4diliydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)niethyl )-7-(4-( trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

4-(2,2-difluoroethyl)-7-(4-(trifluoromcthoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

4-(quinolin-2-ylinethyl)-7-(4-(trifluoromelhoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

( R)-2-(pyri m i d i n-2-yl methyl )-8-(4-( tri fluorometliyljplienyl )-3,4,12,12a-tetrahydro-1Hb enzo [ f] pyrazino[2 , I -c] [ l ,4 ] ox azepi n -6 (2 H ) -o n e;

4-(cyclopiOpylmethyl)-7-(4-(tritluoromethoxy)plienyl)-3,4dihydrobenzo[fj[ l ,4]oxazepin-5(2H)-one;

4-(2-methoxyethyl)-7-(4-(trifluoromctlioxy)phenyl)-3,4-dihydiObenzo[f][l ,4]oxazcpin5(2H)-one;

(S)-3-methyl-4-(pyriinidin-2-yimethyl)-7-(4-(trifluorometliyl)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

(R)-3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoroinethyl)plienyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

6- ((5-oxo-7-(4-(trilluoiOmethoxy)pbenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)- y l )methyl )pico l i non i tri I e;

7- (4-(trifluoromethoxy)phenyl)-4-((6-(trifluoiOmethyl)pyridin-2-yl)inethyl)-3,4- dî hydrobenzof f] [ l ,4] oxazepi n-5 ( 2 H )-one;

7-(4-(trifluoromethoxy)pbenyl)-4-((6-(tri lluoromethyl)pyridin-3-yl)methyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)plicnyl)-3,4diliydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

(R)-3-methyl-7-(4-(trifluoiOmethyl)pheny!)-3,4-dihydrobenzo| f][l,4]oxazepin-5(2H)-one;

(2R,I laS)-2-amino-7-(4-(triiluoiOinethyl)phenyl)-2,3,l 1,1 latetrahydrobenzo[flpynOio[2,1 -c | [ 1,4]oxazepin-5( 1 H)-one; Z

159 (R)-2-(2,2-ditluoroethyl)-8-(4-(tritluoromethyl)phenyl)-3,4,l2,l2a-tetrahydro-lHbenzo[f]pyrazino[2, l -c][ l ,4]oxazepin-6(2H)-one;

(R) -2-ethyl-8-(4-(trifluorornethyi)phenyl )-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2, l -c][ l ,4]oxazepin-6(2H)-one;

(S) -2-(2,2-difluorocthyl)-8-(4-(trifluoroniethyl)phenyl)-3,4,l2,l2a-tetrahydro-l Hbenzo[f|pyrazino[2,l-c][ l ,4]oxazepin-6(2H)-one;

(S)-2-etbyl-8-(4-(tritluoromethyl)phenyl)-3,4,12,12a-tetrahydro- i Hbenzo[f]pyrazino[2,l-c|[l,4]oxazepin-6(2H)-one;

4-(pyrazin-2-ylmcthyI)-7-(4-(tri lluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazcpin-5(2H)-one;

4-((5-nictliyloxazol-2-yl)inethyl)-7-(4-(tritluoroinethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

7-(4-(trilluoroinethoxy)phenyl)-4-(2-(2,5,5-tnmethyl-l,3-dioxan-2-yl)ethyl)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-onc;

tert-butyl (2R,l laR)-5-oxo-7-(4-(trifluoromethyl)phenyl)-1,2,3,5,11,11ahexahydrobcnzof f]pyrrolo[2,1 -c | [ 1,4]oxazepin-2-ylcarbamate;

4-((5-(pyridin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(211)-one;

4-((4,6-dimethoxypyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

cthyl 3-((5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[t][l,4]oxazepÎii-4(5H)yl)methyl)benzoate;

4-(2-(pyriniidin-2-yl)ethyl)-7-(4-(triiluoiOmethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

4-(3,4-dinuoiObenzyl)-7-(4-(trinuoroiiicthoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(211 )-one;

4-niethyl-7-(4-(tiifluoromethoxy)phenyl)-3,4-diliydrobcnzo[f][l,4]oxazepin-5(2H)-one;

4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f|[l,4]oxazepin5(2H)-one;

160

4-(2,6-dichlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[ l ,4]oxazepin-5(2H)-one;

4-(2,6-difluoiObenzyl)-7-(4-(trifluoroniethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

4-(2-( l H-pyrazol-1 -yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

(2S,l laS)-2-amino-7-(4-(triiluoiOinethyl)phenyl)-2,3,l l,llatetrahydrobenzo[f]pyrrolo[2,l -c][ l,4]oxazepin-5( l H)-one;

4-(2-(pyridin-2-yl)etliyl)-7-(4-(triiluorotnethoxy)phenyl)-3,4d ihydrobenzo[ f] [ 1,4] ox azepi n-5(2 H )-one;

4-(2-fluorobenzyl)-7-(4-(trifluoromethoxy)plienyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

(R)-7-(4-(trifluoromethyl)phenyl)-2,3,11,11 a-tetrahydrobenzo[flpyrrolo[2,l c][ l ,4]oxazepin-5( I H)-one;

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepiii-5(2I l)-one;

4-(4-fluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

4-(( l-methyl-1 H-pyrazol-3-yl)methyl )-7-(4-( tri tluoromethoxy)phenyl )-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

4-((5-chloropyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl )-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

4-(pyridin-4-ylmcthyl)-7-(4-(trifluoromcthoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2ll)-one;

4-((5-cyclopropyl-l,3,4-oxadiazol-2-yl)nicthyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-onc;

4-(2-(pyrimidin-2-yloxy)etliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one; pt

I6I

4-(pyridin-3-ylmetbyl)-7-(4-(trifluoromethoxy)phenyl)-3,4diliydrobenzo[f][l,4]oxazepin-5(2H)-one;

4-(pyridin-2-ylniethyl)-7-(4-(trifiuoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

4-(pyrimidin-2-ylrnethyl)-7-(4-(trifluoroinethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

4-((3-methylpyridin-2-yl)metliyl)-7-(4-(tnfluoromethoxy)phenyl)-3,4dibydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

(S)-3-isopiOpyl-7-(4-(trifluoiOmethyl)phenyl)-3,4-dihydrobeiizo[i][l,4]oxazepin-5(2H)one;

(R)-2-(2,2,2-tii fluoroethyl)-8-(4-(tnfluoroinethyl)phenyl )-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2,1 -c|[ 1,4]oxazepin-6(2H)-one;

4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydiObenzo[f][ l,4]oxazepin-5(2H)-one;

7-(4-chlorophcnyl)-4-(pyrimidin-2-yltnethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one;

7-(4-isopiOpylphenyl)-4-(pynmidin-2-ylmcthy1)-3,4-dihydrobenzo[t][l,4]oxazepin5(2H)-one;

7-(4-cthylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-diliyd!Obenzo[f][l,4]oxazepin-5(2H)one;

7-(4-cyciopropylphenyl)-4-(pyriinidin-2-ylmethyl)-3,4-dihydrobcnzo[fj[l,4]oxazepin5(2H)-one;

(R)-4-(l-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)plienyl)-3,4dihydrobcnzof f][ 1,4]oxazepin-5(2H)-one;

7-(4-isobutoxyphenyl)-4-(pyrimidin-2-ylmetliyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one;

7-(4-tert-butylphenyl)-4-(pyrimidin-2-yhnethyl)-3,4-dihydrobenzo[f][l,4]oxazcpin5(2H)-one;

7-(4-cyclopiOpoxyphenyl)-4-(pyrimidin-2-ylinethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one; X

162

7-(4-fiuoropheny])-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one;

7-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f)[ l ,4]oxazepin-5(2H)-one;

7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f]| l ,4]oxazepin-5(2H)-one;

4-(pyrimidin-2-ylmethyI )-7-(4-(2,2,2-trifluoroethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

7-(2-chloro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[fj[ 1,4]oxazepin-5(2H)-one;

7-(4-(trifluoromethoxy)phcnyl)-4-((4-(tritluoromethyl)pyrimidin-2-yl)methyl)-3,4dîhydrobenzo[t][ l ,4]oxazepin-5(2H)-one;

7-(4-( tritluoromethoxy)phcnyl)-4-((5-(6-(trifluoiOmethyl)pyridin-3-yl)pyrimidin-2yl)methyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-(4-chloro-2-fluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one; and

4-(imidazo[l,2-a]pyridin-2-ylmethyI)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautoiner, polymorph and/or prodrug thereof.

[02621 In certain alternative embodiments, the disclosure provides compounds of

Formula IIIA:

wherein:

n is 0, l, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs. -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), X

163

-C(O)-N(R^2<’)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R^2û, -S(O)2-N(R²⁰)(R²²), C|.6 alkyl, C₂.₄ alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂m alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, CN5 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²ⁱ’)(R²⁸), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|.,5 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting oFCm alkyl, C₂m alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -N(R^2Ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

1(1 11

R and R are in each instance independently selected from the group consisting of hydrogen, C1-15 alkyl, C2-15 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cj-15 alkyl, C₂-is alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionaily substituted with one, two or

164 three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF3, -OCH₂CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may joîn to form a heterocyclîc or heteroaryl ring which is lhen optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)2R²⁶, -CN, Ci.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and

R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Ci.4 alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF3;

|0263| In some embodiments, R² is -C(O)-R²⁰; and

R²⁰ is heteroaryl.

[0264|

In some embodiments, R² is

[0265] In some embodiments, n is l ; and

R^luis -O-R²⁰; and

|0266| In some embodiments, n is I ; and R^lü is 4-trifluoromethoxy.

10267] ln some embodiments, the compound is pyrimidin-2-yl(7-(4-(trif]uoiOmethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)melhanonc tZ

165 or a phannaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thercof, |0268| In certain alternative embodiments, the disclosure provides compounds of Formula IV:

wherein:

n is 0, l, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci-6 alkyl, Cm alkenyl, C₂-t alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.₆ alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Ci.6 alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -CWNtR^’XR²²), -CN and -O-R²⁰;

R² is hydrogen, C|.,5 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁽¹)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C_t.|₅ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cu alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said C|._ft alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂,

166

C|-6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C |.₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

R' and R are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂-is alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cj-js alkyl, C₂-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C1.3 alkoxy, -CF3, -OCF3, -OCH₂CF3, -C(O)-NH_2î aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

Of) 77 7il 77 when R and R are attached to a common nitrogen atom R and R may jointe form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof. 'X

167 [0269] In certain alternative embodiments, the disclosure provides compounds of

Formula V:

wherein:

A is cycloalkenyl;

n isO, l, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO?, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)?-R²⁶, -S(O)?-R²⁰, -S(O)?-N(R²⁰)(R²²), Cm alkyl, C2.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂.₄ alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, C|.₁₅ alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R^2S), -N(R²⁰)-S(O)?-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cï_is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or tliree substituents independently selected from the group consisting of Cm alkyl, C₂^ alkynyl, halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said C|.₍, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and

168 wherein said C m alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CFj, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²ⁿ)(R²²), -CN, -S(O)₂-R^2Ü and -OR²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|-i5 alkyl, C2-15 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1 -15 alkyl, C2-15 alkenyl, C₂-u alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO_2> -S(O)₂R²⁶, -CN, C 1.3 alkoxy, -CF₃, -OCF3, -OCH2CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a .common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C 1.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, C 1.4 alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

[0270| ln some embodiments, A is cyclohex-l-enyl.

[02711 ln some embodiments, R² is Ci-15 alkyl;

wherein said alkyl is optionally substituted with heteroaryl. X

169

ο [0272] In some embodiments, R is [0273| In some embodiments, n is 0 or I ; and

R¹⁰ is Cm alkyl.

10274] In some embodiments, A is cyclohex-l-enyl;

n is 0 or 1 ; and

R¹⁰ is 4-methyl or 4-te/7-butyl.

[02751 In some embodiments, the compound is selected from the group consisting of

7-(4-tert-butylcycIohex- 1-enyl )-4-(pyrimidin-2-ylmethyl )-3,4dihydrobenzo[f|[ 1,4]oxazepin-5(2H)-one;

7-cyclohcxenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydiObenzo[f][l,4]oxazcpin-5(2H)-onc; and

7-(4-methylcyclohex-1-enyl )-4-(pyrimidin-2-y!methyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

10276] In certain alternative embodiments, the disclosure provides compounds of

Formula VI:

wherein:

B is heterocyclyl or heteroaryl;

n is 0, 1,2 or 3:

-SF_s, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR^2ü, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)₂-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci.₆ alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and

170 wherein said Cm alkyl, C₂..i alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaliy substituted with one, two or three substituents independently selected from the group consisting ofhalo, -NO₂, phenyl, heterocyclyl, heteroaryl, C m alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R² is hydrogen, C|.l5 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R^2S), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|.is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaliy substituted with one, two or three substituents independently selected from the group consisting of C|_6 alkyl, C2-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected from the group consisting ofhalo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl. or heteroaryl are optionaliy further substituted with one, two or three substituents independently selected from the group consisting ofhalo, -NO₂, -CF3, -NtR²⁰)^²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cru alkyl, C₂-is alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and wherein the C|-i5 alkyl, C₂-is alkenyl, C₂-i5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionaliy substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO₂. -S(O)₂R²⁶, -CN, C|.j alkoxy, -CF₃, -OCF3, -OCl l₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; cZ

I7l wherein said heteroaryl is optionally lùrther substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a conunon nitrogen atoin R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamîno, -NO?, -S(O)₂R²⁶, -CN, C i-3 alkoxy, -CFj, -OCF3, aryl, heteroaryl and cycloalkyl; and

R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF₃;

10277] In some embodiments, B is heterocyclyl.

|0278| In some embodiments, B is 2-oxo-l,2-dihydropyridin-4-yl.

|0279| In some embodiments, B is heteroaryl.

|0280| In some embodiments, B is pyridin-4-yl.

[02811 In some embodiments, R² is C1.15 alkyl;

wherein said alkyl is optionally substituted with heteroaryl.

N.

•y [0282] In some embodiments, R is [0283] I11 some embodiments, n is I ;

R¹⁽¹ is -O-R²⁰ or C 1.4 alkyl; and

R²⁰ isCj-Cis alkyl.

|02841 In some embodiments, B is 2-tert-butoxypyridin-4-yl.

|0285| In some embodiments, B is 1 -methyl-2-oxo-l ,2-dihydropyridin-4-yl.

[0286| In some embodiments, the compound is selected from the group consisting of

172

7-(2-tert-butoxypyridin-4-yl)-4-(pyiidin-2-ylmethyl)-3,4-dihydrobenzo[i][ l ,4]oxazepin5(2H)-one; and

7-( l -methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one;

[02871 In certain alternative embodiments, the disclosure provides compounds of

Formula VIIIA:

wherein:

n is 0, l, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO?, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2t’)(R²²), -C(O)-N(R²⁰)(R²²), -NiR^-CiOj-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)₂-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2.4 alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -NfR^’XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, CM5 alkyl, -C(O)-R²⁰, -C(0)-OR²⁶, -C(O)-N(R²⁽’)(R^2S), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci.15 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selectcd from the group consisting of Cm alkyl, C₂m alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

173 wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected l'roni the group consisting of halo, -NO₂, C|.6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR²⁰)^²²), -C(O)-R²⁰, -C(O)-OR²⁰, -CiOJ-NiR^JfR²²), -CN and -O-R²⁰; and wherein said C|.6 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|-u alkyl, C₂-u alkenyl, C₂-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cj-u alkyl, C₂-u alkenyl, C₂-u alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO₂. -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO2. -S(O)2R²⁶, -CN, Ci_3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; and wherein the Cjm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OC’F₃; d.

174

n |(I288] In some embodiments, R. is Ci_i5 alkyl;

wherein said alkyl is optionally substituted with heteroaryl.

[0289| In some embodiments, R² is [0290] In some embodiments, n is 0 or l ;

R^lois -O-R²⁰ or C_M alkyl;

wherein the alkyl is optionally substituted with three halo; and

R²⁰ is C|-Cis alkyl; and

ÎO wherein the alkyl is optionally substituted with one, two or three halo.

|0291| In some embodiments, n is 0 or l ; and R¹⁰ is 4-trifluoromethyl or 4trifluoromethoxy.

[0292] In some embodiments, the compound is selected from the group consisting of

4-(pyrimidin-2-ylmethyl)-7-((4-(tri fl uoromethoxy)phcnyl)cthynyl )-3,415 dihydrobenzo[f][l,4]oxazepin-5(2H)-one;

7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|[l,4]oxazepin-5(2H)one; and

4-(pyrimidin-2-yhnethyl)-7-((4-(trilluoromcthyl)phenyl)etliynyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one;

10293] In certain alternative embodiments, the disclosure provides compounds of

Formula IX:	'^r2
25	IX
wherein:

175 n is 0, l, 2 or 3:

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CII3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, C'm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm, alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, CM5 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R^2S), -N(R^2U)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cms alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -N0₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -CfOJ-NtR^XR²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

176

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|-|5 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO₂. -S(O)₂R²⁶, -CN, C1.3 alkoxy, -CF₃, -OCF3, -OCH₂CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C|.₄alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cj.₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Ci-3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and

R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, C|.₄ alkyl, aryl and cycloalkyl; and wherein the C|.₄ alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stercoîsomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.

|0294| In some embodiments, R² is Cj.is alkyl;

wherein said alkyl is optionally substituted with heteroaryl; and wherein said heteroaryl is optionally further substituted with halo.

·)

In some embodiments, R“ is selected from the group consisting of

|0295]

[0296| I11 some embodiments, R¹⁰ is 4-trilluoromethyl.

177 |0297| In some embodiments, the compound is selected from the group consisting of: 2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][ l,4,5]oxathiazepin-sulfone; and

2-((5-ch!oropyrimidin-2-y1)methyl)-8-(4-(trifluoiOmethyl)phenyl)-3,4-dihydro-2Hbenzo[b][ 1,4,5]oxathiazepin-sulfone;

[0298] In certain alternative embodiments, the disclosure provides compounds of Formula X:

X

wherein:

n is 0, 1,2 or 3;

R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R^2O)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)₂R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2.₄ alkenyl, C₂__t alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl,

R² is hydrogen, C,.t5 alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R^2S), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm5 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO_:

178 cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O-R²⁰;

wherein said C^ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NtR²⁰)^²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.(, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -NiR²⁰)^²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R^2ü and -OR²⁰;

each R⁴ is independently hydrogen, Ci.15 alkyl, Cm alkoxy, -C(O)-OR²⁶, -C(O)-N(R^2î,)(R^2s), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci.15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰; X

179 or two R⁴ together with the carbon atom to which they are attachée! form an oxo;

R⁶ is hydrogen, Ci_is alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|.;5 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

R²⁰ and R²² arc in each instance independently selected from the group consisting of hydrogen, C|-|₅ alkyl, C₂-is alkenyl, C₂-|5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C1-15 alkyl, C2-15 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO₂. -S(O)₂R²⁶, -CN, C|_j alkoxy, -CF3, -OCF3, -OCH₂CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cj.j alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a hcterocyclic or heteroaryl ring which is then optionally substituted with X.

180 one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|.₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO₂. -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and

R and R“ are in each instance independently selected from the group consisting of hydrogen, C|.₄ alkyl, aryl and cycloalkyl; and wherein the C|.₄ alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, C|₄ alkoxy, -CF₃ and -OCF₃;

|0299| In some embodiments, R² is Ci.jg alkyl;

wherein the alkyl is optionaily substituted with aryl or -O-R²⁰; and wherein the alkyl is optionaily substituted with aryl.

[03001

In some embodiments, R² is

[03011 In some embodiments, R¹⁰ is 4-trifluoromethyl or 4-trifluoromethoxy.

[03021 In some embodiments, two R⁴ together with the carbon atom to which they are attached form an oxo.

[03031 In some embodiments, R⁶ is hydrogen or C|_j5 alkyl.

[0304| In some embodiments, R^û is hydrogen or methyl.

[0305| In some embodiments, the compound is selected from the group consisting of

4-(2-(benzyloxy)ethyl)-l-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-IHbenzo[c][ 1,4]diazepine-2,5-dione; and

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-l H-benzo[e][l,4]diazepine-2,5dione;

181 |(>306| In some embodiments of Formula I and each of the other formulas disclosed hereîn, R and R are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂-6 alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.6 alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionaliy substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, -NO₂. -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)NI I2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionaliy further substituted with Cm alkyl or cycloalkyl; or

7() 22 ^0 22 when R and R are attached to a common nitrogen atom R“ and R may join to form a heterocyclic or heteroaryl ring which is then optionaliy substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO₂. -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl.

|0307| In certain embodiments, R²⁰ is hydrogen or Cm alkyl; wherein the Cm alkyl is optionaliy substituted with one, two or three halo.

7Ω 7Π |0308} In certain embodiments, R“ is hydrogen. In other embodiments, R is-CF₃. ^{4 * * * * * * * * * *}

4. Further Embodiments

10309| In some embodiments, the compounds provided by the présent disclosure are effective in the treatment of conditions or diseases known to respond to administration of late sodium channel blockers, including but not limited to cardiovascular diseases such as atrial and vcntricular arrhythmias, including atrial fibrillation, Prinzmetars (variant) angina, stable angina, unstabic angina, îschemia and reperfusion injury in cardiac, kidney, liver and the brain, exercise induccd angina, puhnonary hypertension, congestive heart disease including diastolic and systolic heart failure, and myocardial infarction. In some embodiments, compounds provided by the présent disclosure which functîon as late sodium channel blockers may be used in the treatment of diseases affecting the neuromuscular system resulting in pain, itching, seizures, or paralysis, or in the treatment

182 of diabètes or reduced insulin sensitivity, and disease states related to diabètes, such as diabetic peripheral neuropathy.

[0310| Certain compounds of the disclosure may also possess a sufficient activity in modulating neuronal sodium channels, i.e., Na_v 1.1., 1.2, 1.3, 1.5, 1.7, and/or 1.8, and may hâve appropriate pharmacokinetic properties such that they may be active with regard to the central and/or peripheral nervous System. Consequently, some compounds of the disclosure may also be of use in the treatment of epilepsy or pain or itching or heachache of a neuropathie origin.

[03111 In one embodiment, this disclosure provides a method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of reducing late sodium current, comprising administering to a mammal in necd thereof a therapeutically effective dose of a compound of Formula I, IA, IB, II, IIA, IIB, III, II1 A, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII or other formulas or compounds disclosed herein. In another embodiment, the disease state is a cardiovascular disease selected from one or more of atrial and ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, syslolic heart failure, acute heart failure), Prinzmetal’s (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, récurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, pulmonary hypertension, and intermittent claudication.

[0312[ In another embodiment, the disease state is diabètes or diabetic peripheral neuropathy. In a further embodiment, the disease state results in one or more of neuropathie pain, epilepsy, heachache, seizures, or paralysis.

[0313] In one embodiment, this disclosure provides a method of treating diabètes in a mammal, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I, IA, IB, 11, IIA, IIB, 111, IIIA, IV, V, VI, VIII, VIIIA, IX, X, Xll or XIII or other formulas or compounds disclosed herein. Diabètes mellitus is a disease charactcrized by hyperglyccmia; altered metabolism of lipids, carbohydrates and proteins; and an increased risk of complications from vascular discase. Diabètes is an increasing public heallh problem, as it is associated with both increasing âge and obesity.

|0314| There are two major types of diabètes mellitus: I ) Type 1, also known as insulin

183 dépendent diabètes (IDDM) and 2) Type II, also known as insulin independent or noninsuiin dépendent diabètes (NIDDM). Both types of diabètes mellitus are due to insufficient amounts of circulating insulin and/or a decrease in the response of peripheral tissue to insulin.

10315] Type I diabètes results from the body's failure to produce insulin, the hormone that unlocks the cells of the body, allowing glucose to enter and fuel them. The complications of Type 1 diabètes include heart disease and stroke; retinopathy (eye disease); kidney disease (nephropathy); neuropathy (nerve damage); as well as maintenance of good skin, foot and oral health.

|0316] Type II diabètes results from the body's inability to citlier produce enough insulin or the cells inability to use the insulin that is naturally produced by the body. The condition where the body is not able to optimally use insulin is called insulin résistance. Type 11 diabètes is often accompanied by high blood pressure and this may contribute to heart disease. In patients with type 11 diabètes mellitus, stress, infection, and médications (such as corticosteroids) can also lead to severely elevated blood sugar levels. Accompanied by déhydration, severe blood sugar élévation in patients with type II diabètes can lead to an increase in blood osmolality (hyperosmolar state). This condition can lead to coma.

10317] It has been suggested that ranolazine (RANEXA®, a sélective inhibitor of INaL) may be an antidiabctic agent that causes β-cell préservation and enhances insulin sécrétion in a glucose-dependent manner in diabetic mîce (see, Y. Ning et al. J Pharmacol Exp Ther. 201 1, 337(1), 50-8). Therefore it is contemplated that the compounds of Formula 1, IA, IB, 11, 11A, IIB, III, IIΙΑ, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII or other formulas or compounds discloscd herein can be used as antidîabetic agents for the treatment of diabètes.

5. Pharmaceutical Compositions ami Administration [0318] Compounds provided in accordance with the présent disclosure are usually administered in the form of pharmaceutical compositions. This disclosure therefore provides pharmaceutical compositions that contain, as the active ingrédient, one or more of the compounds described, or a pharmaceutically acceptable sait or ester thereof, and X

184 one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including stérile aqueous solution and various organic solvents, perméation enhancers, soiubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, c.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. ( 1985); and Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.) [0319| The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having simîlar utilities, for example as descrîbed in those patents and patent applications incorporated by référencé, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coatcd device such as a stent, for example, or an artery-inserted cylindrical polymer.

103201 One mode for administration is parentéral, particularly by injection. The fonns in which the novel compositions of the présent disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or émulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as élixirs, mannitol, dextrose, or a stérile aqueous solution, and sîmilar pharmaceutical vehîcles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the présent disclosure. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin dérivatives, and vegetable oîls may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prévention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for exemple, parabens, chlorobutanol, phénol, sorbic acid, thimerosal, and the lîke.

103211 Stérile injectable solutions are prepared by incorporating a compound according to the présent disclosure in the required amount in the appropriate solvent with various other ingrédients as enumerated above, as required, followcd by filtered sterilization. Gcnerally, dispersions are prepared by incorporating the various sterilized active ingrédients into a stérile vehiclc which contains the basic dispersion medium and the X

185 required other ingrédients from those enumerated above. In the case of stérile powders for the préparation of stérile injectable solutions, the preferred methods of préparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingrédient plus any additional desired ingrédient from a previously sterile-filtered solution thereof. Preferably, for parentéral administration, stérile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.1 to 700 mg, of a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and lis relative activity, the âge, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

f0322J Oral administration is another route for administration of compounds in accordance with the disclosure. Administration may be via capsule or enterîc coated tablets, or the like. In making the phannaceutical compositions that înclude at least one compound described herein, the active ingrédient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient seivcs as a diluent, it can be in the form of a solid, semisolid, or lîquid material (as above), which acts as a vehicle, carrier or medium for the active ingrédient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, élixirs, suspensions, émulsions, solutions, syrups, aérosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, stérile injectable solutions, and stérile packaged powders.

103231 Some examples of suitable excipients înclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, stérile water, syrup, and metliyl cellulose. The formulations can additionally înclude: lubricating agents such as talc, magnésium stéarate, and minerai oil; wetting agents; emulsifying and suspending agents; preserving agents such as metliyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

10324| The compositions of the disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingrédient after administration to the patient by

186 employing procedures known in the art. Controlled release drug delîvery Systems for oral administration include osmotic pump Systems and dissoiutional Systems containing polymer-coated réservoirs or drug-polymer matrix formulations. Examples of controlled release Systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the présent disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the présent disclosure in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

(0325] The compositions are preferably formulated in a unit dosage form. The tenu “unit dosage forms” refers to physically discrète units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active malerial calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaccutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g, or alternativeiy, or 100 mg to 500 mg, of a compound described herein, and for parentéral administration, preferably from 0.1 mg to 700 mg, or alternativeiy, 0.1 mg to 100 mg, of a compound a compound described herein. lt will be understood, however, that the amount of the compound aclually administered usually will be determined by a physîcian, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the âge, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[03261 For preparing solid compositions such as tablets, the principal active ingrédient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the présent disclosure. When referring to these preformulation compositions as homogeneous, ît is mcant that the active ingrédient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. 'Λ

187 (0327| The tabiets or pills of the présent disclosure may be coated or otherwise compoundcd to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an înner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two componcnts can be separated by an enteric layer that serves to resist désintégration in the stomach and permit the inner component to pass intact into the duodénum or to be delayed in release. A variety of materials can be used for such cnteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and

I0 cellulose acétate.

|03281 Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administcred 15 by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the ncbulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably 20 orally or nasally, from devices that deliver the formulation in an appropriate manner.

Combination Therapy

10329] Patients being treated by administration of the late sodium channel blockers of the disclosure often exhibit diseases or conditions that benefit from treatment with other therapcutic agents. These diseases or conditions can be of cardiovascular nature or can be 25 related to pulmonary disorders, metabolic disorders, gastrointestinal disorders and the like. Additionally, some coronary patients being treated by administration of the late sodium channel blockers ofthe disclosure exhibit conditions that can benefit from treatment with therapeutic agents that are antibiotics, analgésies, and/or antidepressants and anti-anxicty agents. pi

I88

Cardiovascular Agent Combination Therapy [0330| Cardiovascular related diseases or conditions that can benefit from a combination treatment of the late sodium channel blockers of the disclosure with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythinias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved éjection fraction (diastolic dysfunction), acute heart failure, or récurrent ischemia.

|03311 Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.

[0332J The co-administration of the late sodium channel blockers of the disclosure with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving. ln some embodiments, the late sodium channel blockers of the disclosure are co-administered with ranolazine (RANEXA®).

Anti-anginals [0333] Anti-anginals include beta-blockers, calcium channel blockers, and nitrates. Beta blockers reduce the heart's need for oxygen by rcducing its workload resulting in a decreased heart rate and less vigorous heart contraction. Examples of beta-blockers include acébutolol (Sectral®), atcnolol (Tenormin®), betaxolol (Kerlone®), bisoprolol/hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), carteolol (Cartrol*), esmolol (Brevibloc®), labetalol (Normodyne®, Trandate®), metoproiol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol (Inderal®), sotalol (Betapace®), and timolol (Blocadren®).

[03341 Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycerin, nitrate patelles, isosorbide dinitrate, and isosorbide-5-mononitrate.

189

103351 Calcium channei blockers prevent the normal tlow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart. Examples of calcium channei blockers include amlodipine (Norvasc®, Lotrel®), bepridil (Vascor®), diltiazem (Cardizem®, Tiazac®), felodipine (Plendil®), nifedipine (Adalat®, Procardia®), nimodipine (Nimotop®), nisoldipine (Sular®), verapamil (Calan®, Isoptin®, Verelan®), and nicardipine.

Heart Failure Agents |0336| Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn®), furosemide (Lasix®), bumetanide (Buinex®), spironolactone (Aldactone®), and eplerenone (lnspra®).

103371 Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the blood vessels and decreasing résistance to blood tlow. Examples of ACE inhibitors include benazepril (Lotensin®), captopril (Capoten®), enalapril (Vasotec®), fosinopril (Monopril®), IisinopriI (Prinivil®, Zestril®), moexipril (Univasc®), perindopril (Aceon®), quinapril (Accupril®), ramipril (Altace®), and trandolapril (Mavik®).

10338| Vasodilators reduce pressure on the blood vessels by making thern relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channei activators, and calcium channei blockers also act as vasodilators.

103391 Cardiac glycosides are compounds that increase the force of the heart’s contractions. These compounds strcngthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

A ntithrombotic Agents

10340| Antithrombotîcs înhibit the clotting abîlity of the blood. Therc arc three main types of antithrombotîcs - platelet inhibitors, anticoagulants, and thrombolytic agents. X

190 [0341| Platelet inhibitors înhibit the clotting activity of platelets, thercby reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (Plavix®), prasugrel (Effient®), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein llb/llla inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin®). Beta blockers and calcium channel blockers also hâve a platelet-inhibiting effect.

[0342) Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax®), warfarin (Coumadin®), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

103431 Thrombolytic agents act to break down an existing blood clôt. Examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic agents

10344] Antiarrhythmic agents are used to treat disorders of the heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidinc, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.

|0345] Combinations with amiodarone and dronedarone are of particular interest (see U.S. Patent Application Publication No. 2010/0056536 and U.S. Patent Application Publication No. 2011/0183990, the entirety of which are incorporated hcrcin).

Antihypertensive agents [0346] Antihypertensive agents are used to treat hypertension, a condition in which the blood pressure is consistently higher than normal. Hypertension is assocîated with many aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and clôt formation. Examples of antihypertensive agents include alpha-1 -adrcnergic antagoniste, such as prazosîn (Minipress®), doxazosîn mesylate (Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide (Minizide*), and terazosin hydrochloride (Hytrin®); beta-adrenergic antagonists, such as propranolol (Inderal*), nadolol (Corgard®), timolol (Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); central alpha-adrenoceptor agonists, such as clonidine hydrochloride X

191 (Catapres®), clonidine hydrocltioride and clilortlialidone (Clorpres®, Combipres®), guanabenz Acetate (Wytensin®), guanfacine hydrochlorîde (Tenex®), methyldopa (Aldomet®), methyldopa and chlorothiazide (Aldoclor®), methyldopa and hydrochlorothiazide (Aldorîl®); combined alpha/beta-adrencrgic anlagonists, such as labetalol (Normodyne®, Trandate®), carvedilol (Coreg®); adrenergic neuron blocking agents, such as guanethidine (Ismelin®), reserpine (Serpasil®); central nervous systemacting antihypertensives, such as clonidine (Catapres®), methyldopa (Aldomet®), guanabenz (Wytensin®); anti-angiotensin II agents; ACE înhîbitors, such as perindopril (Aceon®) captopril (Capoten®), enalapril (Vasotec®), lisinopril (Prinivil®, Zestril®); angiotensin-II receptor antagoniste, such as candesartan (Atacand ), eprosartan (Teveten®), irbesartan (Avapro®), losartan (Cozaar®), telmisartan (Micardis®), valsartan (Diovan®); calcium channel blockers, such as verapamil (Calan®, Isoptin®), diltiazem (Cardizem®), nifcdipine (Adalat®, Procardia®); diuretics; direct vasodilators, such as nitroprusside (Nipride®), diazoxide (Hyperstat® IV), hydralazine (Aprcsoline®), minoxidil (Loniten®), verapamil; and potassium channel actîvators, such as aprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

Lipid Lowering Agents [0347] Lipid lowering agents are used to lower the amounts of cholestérol or fatty sugars présent in the blood. Examples of lipid lowering agents inciude bezafibrate (Bezalip®), ciprofibrate (Modalim®), and statins, such as atorvastatin (Lipitor'), fluvastatin (Lescol®), lovastatin (Mévacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®) pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastalin (Zocor*).

10348] In this disclosure, the patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder. Such patients can benefit from treatmcnt of a combination therapy comprising administering to the patient a compound as disclosed herein (e.g., Formula 1, IA, IB, 11, 11A, IIB, III, IIIA, IV, V, VI, VIII, VI1IA, IX, X, XII or XIII) in combination with at least one therapeutic agent. X

192

Pulmonary Disorders Combination Therapy [03491 Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitîs, and emphysema.

(0350) Examples of therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte suppléments. Spécifie examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire®, Bricanyl®), albulerol (Proventil®), salmeterol (Serevent®, Serevent Diskus®), theophylline, ipratropium bromide (Atrovent®), tiotropium (Spiriva®), méthylprednisolone (Solu-Medrol®, Mcdrol®), magnésium, and potassium.

Metabolic Disorders Combination Therapy

103511 Examples of metabolic disorders include. without limitation, diabètes, including type 1 and type H diabètes, metabolic syndrome, dyslipidemia, obesity, glucose intolérance, hypertension, elevated sérum cholestérol, and elevated triglycérides.

(0352] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as describcd in the section “Cardiovascular Agent Combination Therapy” above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanîdes, alpha-glucosidase inhibitors, and incretin mimetics.

Peripheral Vascular Disorders Combination Therapy |0353| Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for exampie peripheral artcrial disease (PAD), a condition that develops when the arteries that supply blood to the internai organs, anns, and legs become completely or partially blocked as a resuit of atherosclcrosis.

Gastrointestinal Disorders Combination Therapy

103541 Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal

193 reflux disease (GERD), inflammatory bowel dîsease (IBD), gastroenterîtis, gastritis and peptic ulcer disease, and pancreatîtis.

[0355] Examples of therapeutic agents used to treat gastrointestinal disorders include proton pump înhibitors, such as pantoprazole (Protonix®), lansoprazole (Prevacid®), esomeprazole (Nexium®), omeprazole (Prilosec®), rabeprazole; FI2 blockers, such as cimetidine (Tagamet®), ranitidine (Zantac®), famotidine (Pepcid®), nizatidine (Axid®); prostaglandine, such as misoprostol (Cytotec®); sucraifate; and antacids.

Antibiotics, analgésies, antidepressants and anti-aiixiely agents Combination Therapy |0356| Patients presenting with an acute coronary disease event may exhibit conditions that benefit from administration of therapeutic agent or agents thaï are antibiotics, analgésies, antidepressant and anti-anxîety agents in combination with a compound as disclosed herein (e.g., Formula I, IA, IB, II, IIA, IIB, III, IHA, IV, V, VI, VIII, VIHA, IX, X, XII or XIII).

Antibiotics |0357] Antibiotics are therapeutic agents that kill, or stop the growth of, microorganisins, including both bactcria and fungi. Example of antibiotic agents include β-Lactam antibiotics, including penicillins (amoxicillin), cephalosporins, such as 'Ιΐ¹ w cefazolin, cefuroxime, cefadroxil (Duricef ), cephalexin (Keflex ), cephradine (Velosef®), cefaclor (Ceclor®), cefuroxime axtel (Ceftin®), cefproztl (Cefzil®), loracarbef (Lorabid ), cefixime (Suprax ), cefpodoxime proxetil (Vantin ), ceftibuten (Ccdax ), cefdinir (Omnicef®), ceftriaxone (Rocephin®), carbapenems, and monobactams; tetracyclines, such as tétracycline; macrolide antibiotics, such as erythroinycin; aminoglycosides, such as gentamicin, tohramycin, amikacin; quinolones such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramins, polymyxins; lincosamides, such as clindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics, such as sulfisoxazolc.

Analgésies

10358] Analgésies are therapeutic agents that are used to relieve pain. Examples of analgésies include opiates and morphinomimetics, such as fenlanyl and morphine; paracétamol; NSAIDs, and COX-2 înhibitors. Given the abilty of the late sodium channel blockers of the disclosurc to treat neuropathie pain via inhibition of the Nav 1.7 and 1.8 </.

194 sodium channels, combination with analgésies are particularly invisioned. See U.S. Patent Application Publication 20090203707.

Antidepressant and Anti-anxiety agents

103591 Antidepressant and anti-anxiety agents include those agents used to treat anxiety disorders, dépréssion, and those used as sédatives and tranquillers. Examples of antidepressant and anti-anxiety agents include benzodiazépines, such as diazepam, lorazépam, and midazolam; enzodiazepines; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft®, Lustral®, Apo-Sertral®, Asentra®, Gladem®, Serlift®, Stimuloton®); escitalopram (Lexapro®, Cipralex®); fluoxetine (Prozac®, Sarafem®, Fluctin®, Fontex®, Prodep®, Fludep®, Lovan®); venlafaxine (Effexor® XR, Efexor®); citalopram (Celexa®, Cipramil®, Talohexane®); paroxetine (Paxil®, Seroxat®, Aropax®); trazodone (Desyrel®); amitriptyline (Elavil®); and bupropion {Wellbutrin®, Zyban®).

[03601 Accordingly, one aspect of the disclosure provides for a composition comprising the late sodium channel blockers of the disclosure and at least one therapeutic agent. In an alternative embodiment, the composition comprises the late sodium channel blockers of the disclosure and at least two therapeutic agents. In further alternative embodiments, the composition comprises the late sodium channel blockers of the disclosure and at least three therapeutic agents, the late sodium channel blockers of the disclosure and at least four therapeutic agents, or the late sodium channel blockers of the disclosure and at least fîve therapeutic agents.

[03611 The methods of combination therapy include co-administration of a single formulation containing the the late sodium channel blockers of the disclosure and therapeutic agent or agents, esscntially contemporaneous administration of more than one formulation comprising the late sodium channel blocker of the disclosure and therapeutic agent or agents, and consecutive administration of a late sodium channel blocker of the disclosure and therapeutic agent or agents, in any order, wherein preferably there is a time period where the late sodium channel blocker of the disclosure and therapeutic agent or agents simultaneously exert their therapeutic affect.

fi. Synthesis of Example Compounds o(

195

10362] The compounds of the dîsclosure may be prepared using methods dîsclosed herein and routine modifications thereof which vvill be apparent gîven the dîsclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein, e.g. compounds having structures described by one or more of Formula l, IA, IB, 11, IIA, ΠΒ, III, IIΙΑ, IV, V, VI, Vlll, VIIIA, IX, X, XII or XIII or other formulas or compounds disclosed herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chcmical suppliers.

General Synthèses |0363] Typical embodiments of compounds in accordance with the présent dîsclosure may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altercd by substitution of the starting materials with other materials having similar structures to resuit in products that are correspond]ngly different. Descriprions of synthèses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials gcnerally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments of the présent dîsclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.

Synthetic Réaction Parameters

10364] The compounds of tliis dîsclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction températures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one ski lied in the art by routine optimization procedures. X

196 [0365] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[03661 Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desircd, such compounds can be prcpared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. Ail such stereoisomers (and cnriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Altcrnatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[03671 The starting materials for the followîng reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Othcrs may be prepared by procedures or obvious modifications thereof, described in standard référencé texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes l-5, and Supplémentais (Elsevier Science Publishers, 1989) organic Reactions, Volumes l-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5^,h Edition, 2001), and Larock's Comprehensive Organic Transformations (VCFI Publishers Inc., I989).

[03681 The ternis “solvent, “inert organic solvent or “inert solvent refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluène, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF), chloroform, methylene chloride (or dîchloromethane), diethyl ether, mcthanol, pyridine and the like). Unless specified to the contrary, the X

197 solvents used in the reactions of the présent disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[03691 The term “q.s.” means adding a quantity sufficient to achieve a stated fonction, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis ofthe Compounds of Formula l |0370| The compounds of Formula I (and Formula IA, IB, II, IIA, IIB, III, ΠΙΑ, IV, V, VI, VIII, VIIIA, IX, X, XII or XIII) are typically prepared by first providing the molecular core 1-1 and then attaching the desired --Q-R¹ substituents using suitable coupling conditions (e.g., Suzuki coupling) and the desired -R² substituents using suitable substitution conditions. These processes arc show beiow in Scheme 1 for the synthesis of a compound of Formula 1, wherein -Q-R¹ is at either Z³ or Z⁴ in each of Formulas 1-1, 12, 1-3 and I shown in Scheme 1, wherein the bromo and/or -Q-R¹ is at either Z³ or Z⁴ in each of the Formulas shown in Scheme 1.

Scheme 1

LG-R²

Pd-cal, base, solvent heat or microwave irradiation

LG-R²

[03711 ln general, a halogenated compound of formula 1-1, in this case a brominated compound, is reacted with an appropriately substituted boronic acid dérivative of formula R‘Q-B(OH)2 or a boronic ester thereof, in an inert solvent, for example aqueous N,Ndimethylformamide, in the presence of a mild base, for example potassium carbonate or sodium bicarbonate. The reaction is typically conducted in the presence of a métal

198 catalyst with an appropriate ligand, for example dichlorobis(triphenylphosphine) palladium(II), at a température of about !20-l70°C, for about 10 minutes to about l hour or at a lower température, i.e., 90-1 l0°C for 2 to 5 days. When the reaction is substantially complété, the product of Formula I is isolated by conventional means. |0372| It will be appreciated that the R² subsitutent can be modified or added either before (as shown in Scheme l) or after the addition of the R^l moiety. The R² moiety may be coupled to the core l-l under substitution reaction conditions with an appropriate reagent of formula LG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy or the like) as shown in Scheme l. Typical substitution reaction conditions include the presence of a base, such as ssium carbonate, sodium bicarbonate, triethylamine, and the like, in a polar aprotic solvent, such as Ν,Ν-dimethylformamide, and optionaliy an elevated température of about 100-150°C or in a microwave. Also, in the case where the R substituent contains a heteroaryl ring, the heteroaryl ring may be synthesized and cyclized before or aller addition of the -Q-R¹ portion.

Opiional Core Syiithesis

103731 In certain embodiments, the core may be synthesized before or after addition of the -Q-R¹ subsitutent (Scheme 2). For example, such alternative routes for the synthesis of 3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one compounds of Formula 2-8 (i.e., Formula ΙΑ, Π, 11A, IIB, IV, V, VI VIII, X, XII and XIII) are shown in Scheme 2, below, wherein the bromo and/or -Q-R¹ is at either Z³ or Z⁴ in each of the Formulas shown in Scheme 2.

199

Schenie 2

B(OH)j

Pd-cat, base, heat or microwave irradiation

NaH

2-5 R⁴

NaN₃

R¹Q_ B(OH)₂

Pd-cat, base, heat or microwave irradiation deprotect

base, heat/microwave

LG-R^Z

|0374| In one embodiment, compounds of Formula 2-3 can be provided from compounds of Formula 2-1 via amide formation with a suitably protected amino alcohol

2-2, where PG is a protecting group, such as benzyl. Compounds of Formula 2-3 are coupled with an appropriately substituted boronic acid dérivative of formula r'Q-B(OH)2 or a boronic ester thereof, under typical coupling reaction conditions. Typical coupling reaction conditions an inert solvent, for example aqueous Ν,Ν-dimethyHbrmamide, in the prcsence of a mild base, for example potassium carbonate or sodium bicarbonate. The reaction is typically conducted in the présence ofa métal catalyst with an appropriate ligand, for example dichlorobis(triphenylphosphine) palladîum(ll), at a température of ί

200 about 12O-17O°C, for about 10 minutes to about l hour orat a lower température, i.e., 9011O°C for 2 to 5 days. When the reaction is substantially complété, the compounds of Formula 2-4 can be isolated by conventional means. Compounds of Formula 2-4 are cyclized to afford compounds of Formula 2-5 using sodium hydride, in a suitable solvent, 5 such as dimethylformamide. Deprotection under suitable conditions provides compounds of Formula 2-6.

|03751 In another embodiment, compounds of Formula 2-8 are prepared from commercially available compounds of Formula 2-7 using sodium azide. Compounds of Formula 2-6 can be obtained from compounds of Formula 2-8 via reaction with an appropriately substituted boronic acid dérivative of formula R'Q-BfOH^ or a boronic ester thereof, under typical coupling reaction conditions as described above.

|0376| The R² moiety may be coupled to compounds of Formula 2-6 under substitution reaction conditions with an appropriate reagent of formula LG-R²(where LG is a leaving group such as a halo, hydroxyl, alkoxy or the like) as shown in Scheme I to afford 3,415 dihydrobenzo[fj[ 1,4]oxazcpin-5(2H)-onc compounds of Formula 2-9. Typical substitution reaction conditions include the presence of a base, such as ssium carbonate, sodium bicarbonate, triethylamine, and the like, in a polar aprotic solvent, such as N,Ndimethylformamide, and optionally an elevated température of about l00-l50°C or in a microwave.

|0377] 2,3,4,5-Tctrahydrobenzo[f][l,4]oxazepine compounds of Formula 3-2 (i.e.,

Formula III and IIIA) are synthesized from compounds of Formula 2-6 as shown in Scheme 3, below, wherein -Q-R¹ is al either C7 or C8 in each of the Formulas shown in Scheme 2.

Scheme 3

|03781 In one embodiment, compounds of Formula 3-1 can be provided from the réduction of compounds of Formula 2-6 via amide formation with a suitably protected amino alcohol 2-2, where PG is a protecting group, such as benzyl. The R² moiety may ΰ

201 be coupled to compounds of Formula 2-6 under substitution reaction conditions with an appropriate reagent of formula LG-R (wherc LG is a leaving group such as a halo, hydroxyl, alkoxy or the like) as shown in Scheme l to afford compounds of Formula 3-2.

|0379| Compounds of Formula 4-3 (i.e., Formula IX) are synthesized as shown in Scheme 4, below, wherein -Q-R¹ is at either C7 or C8 in each of the Formulas shown in Scheme 2.

Scheme 4

4-1

4-3

R¹Q,

B(OH)î

Pd-cal, base, beat or microwave

O OR³ R³

irradiation

LG-R²

103801 In one embodiment, compounds of Formula 4-3 can be provided from compounds of Formula 4-1 via sulfonamide formation with an amino alcohol 4-2. Compounds of Formula 4-3 are coupled with an appropriately substituted boronic acid dérivative of formula R'Q-BiOH)? or a boronic ester thereof, under typical coupling reaction conditions as discussed in Scheme 2. Compounds of Formula 4-4 are cyclized to afford compounds of Formula 5-5 using sodium hydride, in a suitable solvent, such as dimethylformamide.

[0381J The R² moiety may be coupled to compounds of Formula 4-5 under substitution reaction conditions with an appropriate reagent of formula LG-R²(where LG is a leaving group such as a halo, hydroxyl, alkoxy or the like) as shown in Scheme 1 to afford compounds of Formula 4-6. Typical substitution réaction conditions include the presence of a base, such as ssium carbonate, sodium bicarbonate, triethylamine, and the like, in a polar aprotic solvent, such as Ν,Ν-dimethylformamide, and optionally an elevated température of about 100-150 °C or in a microwave.

103821 It will also be appreciated that the addition of any substituent may resuit in the

202 production of a nurnber of isomeric products any or ail of which may be îsolated and purified using conventional techniques.

Examples |03831 The following examples are încluded to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of ski 11 in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventer to fonction well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. Howevcr, those of skill in the art should, in light of the présent disclosure, appreciate that many changes can be made in the spécifie embodiments which are disclosed and still obtain a like or similar resuit without departing from the spirit and scope of the disclosure.

List of abbreviations and acronyms.
Abbrcviation	Meaning
°C	Degree Celcius
anal	Analytical
ATP	Adenosine-5'-triphosphate
ATX 11	Anemonia sulcata toxin
ACN	Acetonitrile
CHO	Chinese hamster ovary
conc.	Concentrated
d	Doublet
DABCO	1,4-Diazabicyclo[2.2.2]octane
dd	Doublet of doublets
DCM	Dichloromethane
DIPEA	N ,N-d iisopropyl ethyl am i ne
DMF	Dimethylformamide
DMSO	Dimethylsulfoxide
dppf	l, l '-Bis(diphcnylphosphino)ferrocene
EA	Ethyl alcohol
ECF	Extracellular fluid
EDTA	Ethylenediaminetetraacetic acid
EGTA	Ethylene glycol tetraacetic acid
equiv/eq	Equivalents
ESI	Electrospray ionization
Ac	Acetate
Et	Ethyl
g	Grams
HEPES	(4-(2-1 Iydroxyethyl)-! -piperazineethanesulfonic acid )
HATU	2-(7-Aza-l H-Benzotriazole -1 -yl)-l, 1,3,3tetramethyluronium hexafluorophosphate
hERG	human Ether-à-go-go Related Gene ^fX

203

HPLC	Higli-performance liquid chromatography
h	H ours
Hz	Hertz
IC50	The half maximal inhibitory concentration
IMR-32	Human neuroblastoma cell line
J	Coupling constant
Kg	Kilogram
kHz	Kilohertz
LCMS/LC-MS	Liquid chromatography-mass spectrometry
M	Molar
m	multiplet
m/z	mass-to-charge ratio
M+	Mass peak
M+H	Mass peak plus hydrogen
Me	Methyl
mg	Milligram
MHz	Mégahertz
min/m	Minute
ml/mL	Milliliter
111M	Millimolar
mmol	Millimole
nmol	Nanomole
mOsmol	Milliosmole
MRM	Magnctic Résonance Microscopy
MS	Mass spectroscopy
ms	Millisecond
mV	Millivolt
mw	Microwave
N	Normal
mol	Mole
NMR	Nuclear magnetic résonance
pA	Picoamps
Ph	Phenyl
prep	Préparative
q.s.	Quantity suffîcient to achieve a stated fonction
Rf	Rétention factor
RT/rt	Room température
s	Second
s	Singlet
SEM	Standard error of the mean
t	Triplet
TB	Tonie Block
TEA	Triethylamine
TFA	Trifluoroacetic acid
THF	Tetrahydrofuran
TLC	Thin layer chromatography
TTX	Tetrodotoxin
UDB	Use Dépendent Block
WT	Wild type
δ	Chemical shift A

204

pg	Microgram
pL/ μΐ	Microliter
μΜ	Micromolar
μιη	Micrometer
μιηοΐ	Micromole

EXAMPLES

Examplc 1

7-(4“(trinuoroniethoxy)phcnyI)-3,4-dihydrobenzo[fJ|l,4]oxazepin-5(2H)-one (Compound II-74)

[03841 Commercially available 6-bromochroman-4-one ( 1.0g, 3 minol) was dissolved in 10 mL methanesulfonic acid. The solution was cooled using an ice bath and sodium azide (0.30 g, 4.5 mmol) was added over a period of 45 min. The mixture was stirred at RT for

h. The mixture was neutralized using conc. HCl. The resulting solid was filtered and washed with water to afford Comound 1-A as analytically pure sample.

[0385| For the Suzuki coupling reaction the following conditions were applied: To a suspension of Compound 1-A ( 1 eq), the substituted boronic acid or boronate ester ( 1.2 eq) and base sodium bicarbonate (3 eq) in solvent (DMF:water in the ratio of 4:1 ) was added palladium catalyst Pd(dppf)Cl₂ (10 mol%) and heated at 80 °C for 2-4h. The reaction progress was followed by LC and after completion, the reaction mixture was filtered through celite, washed with ethyl acetate. The filtrate was concentratcd the llltrate and purified by prep TLC/ prep HPLC or column chromatography to afford Compound

205

Exaniple 2

4-(pyriniidin-2-ylmethyl)-7-((4-(trifluoronicthyl)phenyl)ethynyl)-3,4dihydrobenzo[f|| l,4|oxazepin-5(2H)-onc (Conipound VIII-6)

NaH, DMF.rt

10386| Conipound 2-A was prepared from Compound l-A according to Example l using l -ethynyl-4-(trifluorometliyl)benzene in place of the boronic acid.

[03871 To a solution of 2-A (l eq) in DMF was added the corresponding halidc ( 1.3 eq). To the mixture was added sodium hydride (60% dispersion in oil, 2 mmol) and stirred at room température for 10 min, followed by heating at 80 °C for 24h. The reaction mixture was quenched with water, extracted with ethyl acetate (100 mL). The organic layer was washed with water, brine and dried over sodium sulphate and concentrated And purified using prep TLCZ prep HPLC or column chromatography to afford Conipound VlII-6.

[0388| 'H-NMR (CDClj) δ 8.7I (d, 2H, J = 4.4 Hz), 8.20 (d, IH, J = 2.4 Hz), 7.55-7.59 (m, 5H), 7.20 (t, l H, J = 4.8 Hz), 7.01 (d, IH, ./ = 8.4 Hz), 5.08 (s, 2H), 4.58 (t, 2H, J =

4.6 Hz), 3.76 (t, 2H, J = 5.0 Hz); MS m/z 424.1 (M+H).

206

Example 3

4-(pyridm-2-y!mcthyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobcnzo[f]| l,4|oxazcpin-5(2H)-one (Compound 11-72)

|0389| Compound II -72 was prepared according to Example 1 using the appropriate starting materials. ¹H-NMR (CDCI₃) δ 8.81 (d, 1 H, J = 5.6 Hz), 8.27 (t, 1 H, J = 7.8 Hz), 8.07 (d, 1 H, J =8.4 Hz), 8.02 (d, 1 H, J = 2.4 Hz), 7.75 (t, 1 H, J =6.4 Hz), 7.65 (dd, 1H,J = 8.6, 2.6 Hz), 7.58 (dd, 2H, J = 4.8, 2.8 Hz ), 7.28 (d, 2H, J = 8.4 Hz), 7.12 (d, 1 H, J = 8.4 Hz), 5.24 (s, 2H), 4.39 (t, 2H, J = 5.0 Hz), 3.85 (t, 2H, J= 5.0 Hz); MS m/z 415.1 (M+H).

Example 4

4-(pyridm-3-ylmethyl)-7-(4-(trifluoromcthoxy)phenyl)-3,4dihydrobenzo|f]|l,4]oxazcpin-5(2II)-one (Compound 11-70)

[0390] Compound 11-70 was prepared according to Example 1 using the appropriate starting materials. ‘H-NMR (CDCI3) δ 9.00 (s, 1H), 8.75 (d, !H, J= 5.2 Hz), 8.47 (d, IH, J = 7.6 Hz), 8.05 (d, 1 H, J = 2.4 Hz), 7.83 (dd, 1 H, J = 7.8, 5.4 Hz), 7.66 (dd, 1 H, J = 8.8, 2.4 Hz ), 7.60 (d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 8.4 Hz), 7.13 (d, 1 H, J = 8.0 Hz), 4.99 (s, 2H), 4.37 (t, 2H, J= 5.0 Hz), 3.67 (t, 2H, J= 5.0 Hz); MS m/z 415.1 (M+H).

Example 5

4-(2-(pyi’iniidin-2-yloxy)etbyl)-7-(4-(trifluoromethoxy)pl)cnyl)-3,4dihydrobenzo[f| [ 1,4|oxazcpin-5(2 l-|)-one (Compound 11-69)

207 |0391 ] Conipound 11-69 was prepared accordîng to Example 1 using the appropriate starting materials. ’H-NMR (CDCIj) δ 8.53 (d, 2H, J= 4.8 Hz), 8.03 (d, 1H, J- 2.4 Hz),

7.58-7.61 (m, 3H), 7.27 (d,2H,J= 5.2 Hz), 7.07 (d, 1H,J= 8.0 Hz), 6.97 (t, 1 H, .7 = 4.8

Hz), 4.66 (t, 2H, J= 4.8 Hz), 4.51 (t, 2H, J= 5.2 Hz), 4.07 (t, 2H, J = 5.0 Hz), 3.78 (t, 2H,

J= 5.0 Hz); MS m/z 468.0 (M+Na).

Exaniplc 6

4-(4-fluorobcnzyl)-7-(4-(trifluoroniethoxy)phenyl)-3,4-dihydrobenzo|f]Il,4]oxazepiii5(2II)-one (Conipound 11-62)

|0392| Conipound 11-62 was prepared accordîng to Example 1 using the appropriate starting materials. ’H-NMR (CDCI₃) δ 8.10 (d, IH, J= 2.8 Hz), 7.60-7.63 (m, 3H), 7.35 (dd, 2H, J= 8.4, 1.2 Hz), 7.28 (d, 2H, J= 8.0 Hz), 7.03-7.09 (m, 3H), 4.82 (s, 2H), 4.22 (t, 2H, J= 5.2 Hz), 3.51 (t, 2H, J = 5.2 Hz); MS m/z 432.1 (M+H).

Exaniplc 7

4-(pyriniidin-2-ylniethyI)-7-(4-(tiifiuoroniethyl)phenyl)-3,4dihydrobenzo[f]|l,4]oxazepm-5(2H)-one (Conipound 11-61)

10393] Conipound Π-61 was prepared accordîng to Example 1 using the appropriate starting materials. ^!H-NMR (CDC1₃) δ 8.80 (d, 2H, J = 5.2 Hz), 8.19 (d, 1 H, J = 2.8 Hz), 7.66-7.71 (m, 5H), 7.33 (t, 1 H, J = 5.0 Hz), 7.13 (d, 1 H, J = 8.4 Hz), 5.14 (s, 2H ), 4.59 (t, 2H, J = 4.8 Hz), 3.81 (t, 2H, J= 5.0 Hz); MS wî/z 400.1 (M+H). X

208

Example 8

4-(2-nuorobcnzyi)-7-(4-(trifluoromethoxy)plienyl)-3,4-dihydrobenzo|f||l,4|oxazepin5(2II)-one (Compound 11-57)

[0394| Compound II -57 was prepared according to Example i using the appropriate starting materials. 'H-NMR (CDC1₃) δ 8.07 (d, 1H, J= 2.4 Hz), 7.58-7.61 (m, 3H), 7.497.51 (m, 1 H), 7.26-7.31 (m, 3H), 7.16 (t, 1 H, J = 7.6 Hz), 7.07-7.18 (m, 2H), 4.92 (s, 2H), 4.29 (t, 2H, 4.8 Hz), 3.61 (t, 211, J= 5.0 Hz); MS m/z 432.1 (M+H).

Example 9

4-(2-(pyridin-2-yl)etliyl)-7-(4-(trifluoiOmcthoxy)plicnyl)-3,4dihydrobenzo|f||l,4|oxazepin-5(2H)-onc (Compound 11-54)

[0395| Compound II -54 was prepared according to Example I using the appropriate starting materials. 'H-NMR (CDC1₃) 6 8.57 (d, 1H,J=4.8 Hz), 8.03 (d, 1 H, J = 2.4 Hz),

7.67-7.69 (m, 1 H), 7.57-7.61 (m, 3II), 7.20-7.33 (m, 4H), 7.04 (d, 1 H, J = 8.8 Hz), 4.19 (t,

2I-I, J= 4.8 Hz), 4.06 (t, 2H,J= 7.4 Hz), 3.51 (t, 2H, J= 5.0 Hz), 3.24 (t, 2H, 6.8 Hz); MS m/z 429.1 (M+H).

Example 10

4-(2-( lH-pyrazol-l-yl)ethyl)-7-(4-(trinuoromcthoxy)phcnyl)-3,420 diliydrobenzo|f||l,4)oxazepin-5(2H)-one (Compound 11-50)

209

10396J Compound II -50 was prepared accord:ng to Example I using the appropriate starting materials. 'H-NMR (CDCI₃) δ 8.02 (d, IH, J= 2.4 Hz), 7.58-7.64 (m, 4H), 7.47 (d, IH, J= l .6 Hz), 7.28 (d, 2H, J = 8.8 Hz), 7.04 (d, 1H, J= 8.4 Hz), 6.30 (t, l H, J = 2.2

Hz), 4.55 (t, 2H, J= 5.8 Hz), 4.11 (t, 2H, J= 5.4 Hz), 3.96 (t, 2H, J = 5.0 Hz), 3.28 (t, 2H,

J =5.0 Hz); MSm/z4l8.l (M+H).

Example 11

4-(2,6-dinuorobenzyl)-7-(4-(trifluoronicthoxy)phenyl)-3,4dihydi obcnzo|f|[ l,4|oxazepin-5(2H)-onc (Compound 11-49)

[03971 Compound 11-49 was prepared according to Example 1 using the appropriate starting materials. ‘H-NMR (CDC1₃) δ 8.08 (d, IH, J= 2.4 Hz), 7.57-7.61 (m, 3H), 7.267.33 (m, 3H), 7.05 (d, IH, J= 8.4 Hz), 6.95 (t, 2H, J= 8.0 Hz), 4.98 (s, 2H), 4.23 (t, 2H, J = 4.8 Hz), 3.59 (t, 2H, J = 4.8 Hz); MS m/z 450.1 (M+H).

Example 12

4-(2,6-dichlorobenzyl)-7-(4-(triiluoromcthoxy)plienyl)-3,4dihydrobenzo|fj[l,4|oxazepin-5(2H)-one (Compound 11-48)

[03981 Compound 11-48 was prepared according to Example 1 using the appropriate starting materials. ’H-NMR (CDC1₃) δ 8.06 (d, IH, J= 2.4 Hz), 7.59-7.62 (m, 3H), 7.40 (d, 2H, J = 8.0 Hz), 7.25-7.29 (m, 3H), 7.06 (d, 1 H, J = 8.4 Hz), 5.24 (s, 2H), 4.07 (t, 2H, J= 5.0 Hz), 3.42 (t, 2H, J= 5.2 Hz); MS m/z 483.0 (M+H). q(

210

Examplc 13

4-(2-chlorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo|f||l,4]oxazcpin-5(2H)-one (Compound 11-47)

10399] Compound 11-47 was prepared according to Example 1 using the appropriate starting materials. 'H-NMR (CDC1₃) δ 8.10 (d, 1H, J= 2.4 Hz), 7.60-7.64 (m, 3H), 7.47 (dd, 1H, J = 7.0, 2.2 Hz), 7.41 (dd, 1H, J= 7.4, 1.8 Hz), 7.26-7.30 (m, 4H), 7.09 (d, 1H, J = 8.4 Hz), 5.01 (s, 2H), 4.28 (t, 2H, J= 5.0 Hz), 3.58 (t, 211, J= 5.2 Hz); MS m/z 448.1 (M+H).

Examplc 14

7-(plicnylctliynyl)-4-(pyrimidin-2-ylmethyl)-3,4-diliydrobcnzo|f|| l,4|oxazcpin-5(2H)-

|0400| Compound V1II-5 was prepared according to Example 2 using the appropriate starting materials. ¹ H-NMR (CD₃OD) δ 8.76 (d, 2H, J = 4.8 Hz), 7.92 (d, 1 H, J = 2.4 Hz), 7.60 (dd, 1 H, J =8.6, 1.8 Hz), 7.48-7.51 (m, 2H), 7.35-7.39 (m, 4H), 7.07 (d, I H, J =8.8 Hz), 5.05 (s, 2H), 4.59 (t, 2H, J =4.8 Hz), 3.83 (t, 2H, J= 4.8 Hz); MS m/z 356.1 (M+H).

Examplc 15

4-(pyrimidin-2-ylmcthyl)-7-((4-(trifliioiOmcthoxy)phcnyl)ethynyl)-3,4dihydrobenzo|f||l,4|oxazcpm-5(2II)-onc (Compound VI11-4)

211 |0401] Compound VÎII-4 was prepared according to Example 2 using the appropriate starting materials. 'H-NMR (CD₃OD) δ 8.76 (d, 2H,7 = 7.2 Hz), 7.95 (d, ÎH, J - 2.4 Hz),

7.59-7.63 (m, 3H), 7.38 (t, 1H,7= 5.0 Hz), 7.29 (d, 2H, J= 8.4 Hz), 7.08 (d, 1H, J= 8.8

Hz), 5.05 (s, 2H), 4.60 (t, 2H, J= 5.0 Hz), 3.83 (t, 2H,7 = 4.8 Hz); MS m/z 440.1 (M+H).

Example 16

4-(2-(pynmidin-2-yl)ethyl)-7-(4-(trifluoromcthoxy)phcnyl)-3,4dihydrobenzo|f|[l,4]oxazepin-5(2H)-one (Compound 11-44)

|0402[ Compound 11-44 was prepared according to Example 1 using the appropriate starting materials. ¹ H-NMR (CDC1₃) δ 8.70 (d, 2H, 7 = 5.2 Hz), 8.00 (d, 1 H, J = 2.4 Hz), 7.56-7.59 (m, 3H), 7.26(d, 2H, J = 8.4 Hz), 7.20 (t, 1 H, 7 = 5.2 Hz), 7.04 (d, I H, 7 = 8.8 Hz), 4.36 (t, 2H,7 = 5.0 Hz), 4.16 (t, 2H,7 = 7.0 Hz), 3.59 (t, 2H,7= 5.0 Hz), 3.38 (t, 2H, 7= 6.0 Hz); MS m/z 430.1 (M+H).

Example 17

4-((4,6-dimethoxypyriniidin-2-yl)mcthyl)-7-(4-(trifhioromcthoxy)phcnyl)-3,4dihydi'obenzo[f] | l,4|oxazepin-5(2 H)-one (Compound 11-42)

[0403] Compound H-42 was prepared according to Example I using the appropriate starting materials. ’H-NMR (CD₃OD) δ 8.00 (d, 1 H, 7 = 2.4 Hz), 7.76 (dd, 1 H, 7= 8.2, 2.6 Hz), 7.69 (dd, 2H, 7 = 6.8, 2.0 Hz), 7.34 (d, 2H, 7 = 8.0 Hz), 7.16 (d, 1 H, 7= 8.8 Hz), 6.1 I (s, IH), 4.87 (s, 2H), 4.58 (t, 211,7= 5.0 Hz), 3.93 (s, 6H), 3.84 (t, 211,7= 5.2 Hz); MS m/z 476.1 (M+H).

212

Examplc 18

4-((5-mcthyloxazol-2-yl)nietliyl)-7-(4-(trifluoromcthoxy)plicnyl)-3,4dihydrobenzo[f||l,4[oxazcpin-5(2H)-one (Conipound 11-33)

[0404] Conipound 11-33 was prepared according to Example I using the appropriate starting materials. 'H-NMR (CDjOD) δ 8.00 (d, 1 H, J = 2.4 Hz), 7.77 (dd, I H, J= 8.4, 2.4 Hz), 7.71 (d, 2H, J = 8.8 Hz), 7.34 (d, 2H, J = 8.0 Hz), 7.15 (d, 1 H, J = 8.4 Hz), 6.81 (d, 1H, J= 0.8 Hz), 4.93 (s, 2H), 4.43 (t, 2H, J= 5.2 Hz), 3.76 (t, 2H, J= 5.2 Hz), 2.34 (d, 3H, J = 0.8 Hz); MS m/z 419.1 (M+H).

Examplc 19

4-(pyrazin-2-ylnictliyl)-7-(4-(trilliioronietlioxy)plienyl)-3,4dihydrobcnzo|f|[l,4|oxazcpin-5(2H)-onc (Conipound 11-31)

[0405] Conipound 11-31 was prepared according to Example 1 using the appropriate starting materials. ‘H-NMR (CD₃OD) Ô 8.71 (d, 1 H, J =0.8 Hz), 8.60 (t, !H,J=2.0Hz), 8.53 (d, 1 H, J = 2.4 Hz), 7.99 (d, 1 H, J = 2.4 Hz), 7.77 (dd, 1 H, J = 8.4, 2.4 Hz), 7.72 (dd, 2H, J= 6.6, 2.2 Hz), 7.34 (d, 2H,./= 8.0 Hz), 7.15 (d, 1 H, J = 8.4 Hz), 5.01 (s, 2H), 4.47 (t, 2H, J= 5.2 Hz), 3.82 (t, 2H, J= 5.0 Hz); MS m/z 416.1 (M+H).

Examplc 20

4-((6-nicthylpyridin-2-yl)nictliyl)-7-(4-(trifluoiOnictlioxy)phenyi)-3,4dihydrobcnzo|f'|[l,4|oxazcpin-5(21l)-onc (Conipound 11-17)

[0406| Conipound 11-17 was prepared according to Example 1 using the appropriate starting materials. ¹ H-NMR (CD₃OD) δ 8.28 (t, 1H, J= 7.8 Hz), 8.00 (t, I H, J = 2.4 Hz),

213

7.81 (dd, 1H,J= 8.2, 2.6 Hz), 7.68-7.73 (ni, 4H), 7.35 (dd, 2H,J = 8.6, l.O Hz), 7.20 (d,

ÎH, J= 8.8 Hz), 5.09 (s, 2H), 4.50 (t, 2H, J= 5.0 Hz), 3.86 (t, 2H, J= 5.0 Hz), 2.77 (s,

3H); MS m/z 429.1 (M+H).

Example 21

7-(4-(trifluoromctiioxy)phenyl)-4-((6-(trifluoronietliyl)pyridin-2-yl)incthyl)-3,4diliydrobcnzo|f|[ l,4]oxazepin-5(2H)-one (Conipound 11-15)

[0407| Conipound 11-15 was prepared according to Example 1 using the appropriate starting materials. ’H-NMR (CD₃OD) 6 7.98-8.04 (ni, 2H), 7.68-7.77 (ni, 5H), 733 (d, 2H,J = 8.0 Hz), 7.14 (d, 1 H,./ = 8.4 Hz), 5.01 (s, 2H), 4.48 (t, 211,./ = 5.2 Hz), 3.80 (t, 2H, J = 5.2 Hz); MS m/z 483.1 (M+H).

Example 22

6-((5-oxo-7-(4-(trifluoronietlioxy)plienyl)-2,3-dÎhydrobcnzo|f|| l,4|oxazepm-4(5H)yl)niethyl)picolinonitiile (Conipound 11-14)

|04081 Conipound 11-14 was prepared according to Example 1 using the appropriate starting materials. ’H-NMR (CD₃OD) Ô 7.96-8.00 (m, 2H), 7.69-7.79 (m, 5H), 733 (d, 2H, J =8.0 Hz), 7.15 (d, 1H, J =8.4 Hz), 4.98 (s, 2H), 4.46 (t, 211, J = 5.2 Hz), 3.79 (t, 2H, J= 5.0 Hz); MS m/z 440.1 (M+H).

Example 23

4-(cyclopropylmcthyl)-7-(4-(ti*iniioronicthoxy)phcnyl)-3,4dihydrobcnzo|f]| l,4|oxazepin-5(2H)-onc (Conipound 11-10)

214

10409] Compound 11-10 was prepared according to Example 1 using the appropriate starting materials. ‘H-NMR (CD₃OD) 5 7.92 (d, 1 H, J = 2.8 Hz), 7.69-7.75 (m, 3H), 7.34 (d, 2H, J = 8.0 Hz), 7.13 (d, 1 H, J = 8.4 Hz), 4.48 (t, 2H, J = 5.2 Hz), 3.70 (t, 2H, J = 5.2 Hz), 3.53 (d, 2H,J= 6.8 Hz), 1.13-1.18 (m, 1H), 0.57-0.61 (m, 2H), 0.35-0.40 (m, 2H); MS m/z 378.1 (M+H).

Example 24

4-(quinolin-2-ylnietiiyl)-7-(4-(trif]uoronietlioxy)phenyl)-3,4tliliydrobenzo|f|[l,4]oxazcpin-5(2H)-onc (Compound 11-7)

|0410| Compound 11-7 was prepared according to Example I using the appropriate starting materials. 'H-NMR (CD₃OD) Ô 8.35 (d, I H,./ = 8.8 Hz), 8.02-8.05 (m, 2H), 7.93 (d, III, J = 7.6 Hz), 7.72-7.79 (m, 411), 7.60 (d, 211, J = 8.4 Hz), 7.35 (d, 2H,J= 8.0 Hz), 7.16 (d, III, J = 8.8 Hz), 5.15 (s, 21-1), 4.43 (t, 2H, J= 5.2 Hz), 3.79 (t,2H, J = 5.0 Hz); MS m/z 465.1 (M+H).

Example 25

7-(3-fluoro-4-(ti'ifluoroinetliyl)plicnyl)-4-(pyriniidm-2-ylmcthyl)-3,4tlihydrobcnzol f| [ 1,4]oxazcpin-5(2H)-onc (Compound 11-130)

|04ll| 7 -Bromo-3,4-dihydrobenzo[i][ l,4|oxazcpin-5(2H)-one (1.0g, 4.13mmol) was dissolvcd in DMF (10 mi) cooled down in a ice/water bath and treated with sodium hydride (60% dispersion) (363mg, 9.08mmol) portion wise. Aller 10 min a solution of2(chloromethyl)pyrimidine hydrochloride (813mg, 4.96mmol) in DMF (4ml) was added, the reaction mixture warmed up to room température and qucnched with 12 mL of water aller it was complété. The reaction mixture was extracted with EtOAc and water and the organic phase was dried, evaporated and purified by silica gel chromatography (95% X

215

DCM/MeOH) to afford 7-bromo-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one.

|0412| Similar procedure to Example l forthesynthesisof7-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one was followed to obtain the title compound using instead of 7-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)one.

[0413] A mixture of7-bromo-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][],4]oxazepin-5(2H)-one (50mg, 0.15mmol), 2-(3-fluoro-4(trilluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (52mg, 0.18mmol), césium carbonate (I46mg, 0.45mmol), Ι,Γbis(diphenylphosphino)fenOccne]dichloropalladium (lOmg, 0.015 inmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5 mL). The mixture was heated in microwave at 85 ⁽⁾C for 40 min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dricd over sodium sulfate and loaded onto silica gel. A flash column (5% MeOl l in EtOAc) and reverse phase chromatography gave 7-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one.

[0414] MS found for C_2tH₁₅F₄N₃O2 as (M+ll)’ 418.13. 'h NMR (400 MHz, DMSOd₆): 6: 8.78 (d, J=4.0Hz, 2H), 8.09 (d, J=2.0Hz, IH), 7.91 (dd, J=2.4, 8.0Hz, 111), 7.857.80 (m, 2H), 7.70 (d,J=8.4Hz, II I), 7.41 (t,J=4.8Hz, 1H), 7.17 (d, J=8.4Hz, I H), 4.98 (s, 2H), 4.55 (t, J=4.8Hz, 211), 3.79 (t, J=4.8Hz, 211).

Examplc 26

7-(4-(difliioroinethyl)phenyl)-4-(pyrimidin-2-ylmcthyl)-3,4dihydrobeirzo[f||l,4|oxazcpm-5(2H)-onc (Compound 11-124)

|0415] Compound 11-124 was prcpared according to Example 25 using 4(difluoromethyl)phenylboronic acid. MS found for C21II17F2N3O2 as (M-H1)⁺ 382.15. '11 NMR (400 MHz, DMSO -ίί_Λ): 5: 8.77 (d, J=4.8Hz, 2H), 8.00 (d, J=2.4HzO, 1 H), 7.84-7.77

216 (m, 4H), 7.63 (d, 7=7.6Hz, 2H), 7.40 (t, ./=5.2Hz, IH), 7.I5 (d, ./=8.8Hz, IH), 7.06 (t,

7=56.4Hz, l H), 4.98 (s, 2H), 4.52 (t, 7=4.4Hz, 2H), 3.77 (t, 7=5.2Hz, 2H).

Examplc 27

7-(4-cyclopentyIplienyl)-4-(pyrimidÎn-2-ylmethyl)-3,4-dihydrobenzo[f|| l,4[oxazcpin5(2H)-one (Compound 11-120)

[04I6| Compound 11-120 was prepared according to Example 25 using 4cyclopentylphenylboronic acid. MS found for C25H25N3O2 as (M+H)⁺ 400.2. ^!H NMR (400 MHz, DMSO -dfo δ: 8.77 (d, 7=4.81 Iz, 2H), 7.90 (d, 7=2.4Hz, I H), 7.74 (dd, J=2.4, 8.8 Hz, 1 H), 7.52 (d, 7=8.4Hz, 2H), 7.40 (t, 7=4.8Hz, 1 H), 7.30 (d, 7=8.0Hz, 2H), 7.10 (d, 7=8.8Hz, IH), 4.97 (s, 2H), 4.48 (t,7=4.4Hz, 2H), 3.74 (t,7=5.2Hz, 2H), 3.00-2.96 (m, IH), 2.01-1.97 (m,2H), 1.78-1.51 (m, 611).

Examplc 28

7-(4-chloro-3-fluorophciiyl)-4-(pyriniidin-2-ylmctliyl)-3,4dihydrobcnzo|f] [ 1,4|oxazepin-5(2II)-one (Compound 11-131)

|0417] Compound 11-131 was prepared according to Example 25 using 4-chloro-3fluorophenylboronic acid. MS found for C20H15CIFN3O2 as (M+H)⁺ 384.09. ’H NMR (400 MHz, DMSO^df,)·. δ: 8.78 (d,7=5.2Hz, 2H), 7.99 (d, 7=2.4HzO, IH), 7.83 (dd, J=2.08.0 Hz, IH), 7.72 (d,7=8.8Hz, IH), 7.62 (t,7=8.0Hz, IH), 7.51 (dd, J=i.2-8,4 Hz, IH), 7.42 (t, 7=4.8Hz, I H), 7.13 (d, 7=8.0Hz, I H), 4.98 (s, 2H), 4.52 (t, 7=4.8Hz, 2H), 3.77 (t, 7=4.8Hz, 2H). p<

217

Example 29

7-(2-tert-butoxypyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydi'obeirzo|f|[ l,4|oxazepin-5(2H)-one (Compound VI-2)

[04181 To a mixture of 4-bromo-2-tert-butoxypyridine (1.0 g, 4.34 mmol), bis(pinacolato)diboron (1.32 g, 5.22 mmol), potassium acetate (1.28 g, 13.0 mmol), [1,1'bis(diphenylphosphino)fenOcene]dichloropalladium methylene choloride complex (310 mg, 0.43 mmol) was suspended with degassed dioxane (15 mL) and heated at 85 °C for 60 min. The reaction mixture was diluted with EtOAc, washed with water and brine, dried (MgS(O)q), fillered and concentrated. The concentrate was purified by flash chroinatography on silica gel eluding with 33% percent ethyl acetate/hexanes to afford the compound 2-tert-butoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine.

|0419| Similar procedure as in Example 25 was followed to obtain the title compound using 2-tert-butoxy-4-(4,4,5,5-tetramcthyl-1,3,2-dioxaborolan-2-yl)pyrîdine that was previously prepared.

[04201 MS found for C23H24N4O3 as (M+H)⁺ 405.13. 'H NMR (400MHz, DMSOd₆): δ: 8.77 (d, J=4.8Hz, 211), 8.14 (d, >5.6Hz, 1H), 8.03 (d, J=2.4Hz, 1H), 7.88 (dd, J=2.4-8.4 Hz, 1 H), 7.40 (t, ,/=4.8Hz, 1 H), 7.18 (d, J=5.6Hz, 1 H), 7.12 (d, >8.4Hz, 1 H), 6.89 (s, I H), 4.97 (s, 2H), 4.53 (t, >4.8Hz, 211), 3.77 (t, J=4.4Hz, 2H), 1.54 (s, 9H).

Example 30

7-(5-mctliylthiophcn-2-yl)-4-(pyrimidin-2-ylmcthyl)-3,4diiiydrobenzo|f|[l,4[oxazepin-5(2H)-one (Compound VI-20)

[0421] A mixture of 4-(pyriinidin-2-ylmethyl)-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-3,4-dihydrobenzo[f][I,4]oxazepin-5(2H)-one (50mg, 0.13mmol), 2- ü(

218 bromo-5-methylthiophene (28mg, O.l56mmol), césium carbonate (I28mg, 0.39mmol), l,I’-Bis(diphenylphosphino)ferrocene]dichloropalladium (9mg, 0.013 mmol) was dîssolved in a degassed mixture of DMF and water 3/l .5 (4.5ml). The mixture was heated in microwave at 85°C for 40min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dried over sodium sulfate and loaded onto silica gel. A flash column (5% MeOH in EtOAc) and reverse phase chromatography gave 7-(5-methylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one.

[0422] MS fbund for C19H17N3O2S as (M-i-H)⁺ 352.09. 'H NMR (400 MHz, DMSOI0 d₆)-. ‘H-NMR (DMSO) δ: 8.70 (d, >4.0Hz, 2H), 7.80 (d, J=2.0Hz, ÎH), 7.68 (dd, >2.08.4 Hz, l H), 7.40 (t, J=4.8Hz, l H), 7.23 (d, >3.2Hz, I H), 7.05 (d, J=8.4Hz, l H), 6.77 (d, >2.8Hz, IH), 4.95 (s, 2H), 4.46 (t, J=4.8Hz, 2H), 3.73 (t, J=4.8Hz, 2H), 2.48 (s, 3H).

Example 31 l-(4-(5-oxo-4-(pyrimidin-2-ylnietliyl)-2,3,4,5-tetraliydrobenzo[f)| l,4|oxazepin-7- yl)phcnyl)cyclopcntanccarbonitrilc (Compound H-122)

[0423| To a solution of 2-(4-bromophenyl)acetonitrile (l.O g, 5.10 mmol) and l,4dibromobutane (0.67 ml, 5.6 mmol) in THF (10 ml) was addcd potassium bis (trimcthylsilyl) amide(2.23 g, 11.2 mmol) and tetra-n-butylammonium bromide (I64mg,

0.51 mmol). The mixture was stirred for 2 h and tlien quenched with l N HCl. Ethyl acetate was added, the layers separated and the organic layer was washed with water and brine. Drying, solvent évaporation and flash chromatography (silica gel, 20% EtOAc/hcxancs) gave l -(4-bromophenyl)cyclopentanecarbonitrile.

[04241 Similar procedure as in Example 30 was followcd to obtain the tille compound 25 usîng I -(4-bromophenyl)cyclopentanecarbonitrile.

[0425[ MS fbund for C26H24N4O2 as (M-Hl)⁺ 425.21. 'H NMR (400MHz, DMSOd₆): 'H-NMR (DMSO) Ô: 8.72 (d, >4.01 Iz, 2H), 7.90 (d, >2.4Hz, 1H), 7.74 (dd, >2.48.8 Hz, I H), 7.63 (d, >8.4Hz, 2H), 7.50 (d,>8.41 Iz, 2H), 7.35 (t, >4.8Hz, 1 H), 7.08 (d,

219

J=8.8Hz, IH), 4.92 (s, 2H), 4.45 (t, J=4.4Hz, 2H), 3.71 (t, J=4.8Hz, 2H), 2.37-2.34 (m,

2H), 2.05-2.02 (m, 2H), I.85-1.83 (m, 4H).

Example 32

7-(4-ethoxyphenyl)-4-(pyriniÎdin-2-ylniethyl)-3,4-dihydiObenzo[f||l,4]oxazepin-

[0426| Compound II-123 was prepared according to Example 30 using l-bromo-4ethoxybenzene. MS found for C22H21N3O3 as (M+H)⁺ 376.15. 'H NMR (400MHz, DMSO-dù: δ: 8.77 (d, 7=5.2Ηζ, 2H), 7.86 (d, J=2.4Hz0, IH), 7.71 (dd, J=2.8-8.4 Hz, IH), 7.54 (d, J=8.8Hz, 2H), 7.40 (t, J=4.8llz, IH), 7.08 (d, J=8.0Hz, IH), 6.97 (d, J=8.4Hz, 2H), 4.96 (s, 2H), 4.47 (t, J=4.8Hz, 2H), 4.06-4.01 (m, 2H), 3.74 (t, J=4.4Hz, 2H), l.34-l.30(m, 3H).

Example 33

7-(4-(diniioromethoxy)phciiyl)-4-(pyriniidîn-2-ylmcthyl)-3,4diliydrobenzo|f|| l,4|oxazepin-5(2H)-onc (Compound II-l 19)

|0427| Compound 11-119 was prepared according to Example 30 using l-bromo-4(difluoromethoxy)benzene. MS found for C2IHI7F2N3O3 as (M+H)* 398.13. 'H NMR (400MHz, DMSO-diï 'H-NMR (DMSO) δ: 8.77 (d, J=4.8Hz, 211), 7.92 (d, J=2.0Hz0, IH), 7.77 (dd, J=2.4-8.4 Hz, IH), 7.68 (d, J=8.4Hz, 2H), 7.40 (t, J=4.8Hz, IH), 7.26 (t, ,>74.0Hz, 2H), 7.23 (d, J=8.8Hz, 1 H), 7.12 (d, ,/=8.4Hz, IH), 4.97 (s, 2H), 4.50 (t, J=4.8Hz, 2H), 3.75 (t, J=4.8Hz, 2H).

220

Examplc 34

4-(4-fluorobenzyl)-7-(l-mcthyl-2-oxo-l,2-dihydropyridin-4-yl)-3,4dihydrobenzo[f]| l,4|oxazepin-5(2H)-onc (Compound VI-22)

[0428) Compound Vl-22 was prepared according to Example 30 using l(chloromelhyl)-4-fluorobenzene and 4-bromo-l-methylpyridin-2(lH)-one. MS found for C22H19FN2O3 as (M+H)⁺ 379.27 *H NMR (400MHz, DMSO-d₆): δ: 8.01 (d, J=2.4Hz, ÎH), 7.83 (dd, J=2.0-8.4 Hz, lH), 7.75 (d, J=6.8Hz, IH), 7.42-7.38 (m, 2H), 7.17 (t, J=9.2Hz, 2H), 7.10 (d, J=8.0Hz, IH), 6.63 (s, IH), 6.56 (dd, J=2.0-7.2 Hz, IH), 4.74 (s, 10 2H), 4.27 (t, J=4.8Hz, 2H), 3.56 (t, J=4.8Hz, 2H), 3.42 (s, 3H).

Examplc 35

7-(l-isopropyl-2-metliyl-lH-iinidazol-5-yl)-4-(pyrimidin-2-ylniethyl)-3,4dihydrobcnzo|f|[ l,4]oxazcpin-5(2II)-onc (Compound VI-23)

|0429| Compound VI-23 was prepared according to Example 30 using 5-bromo-lisopropyl-2-methyl-l H-imidazole. MS found for C21H23N5O2 as (M+H)⁺ 378.14 *H NMR (400MHz, DMSO-d^. δ: 8.77 (d, J=4.8FIz, 211), 8.15 (s, IH), 7.63 (d, J=2.0Hz, IH), 7.40 (t, J=4.8Hz, 2H), 7.10 (d, J=8.0Hz, 1 H), 6.68 (s, IH), 4.95 (s, 2H), 4.52 (t, .7=4.8Hz, IH), 4.32-4.29 (s, III), 3.77 (t, J=4.8Hz, 2H), 2.41 (s, 3H), 1.34 (d, J=6.8Hz,

6H). X

221

Examplc 36

7-( I-met hyl-2-oxo-1,2-dihyd ropy ridin-4-yl)-4-(py ri midin-2-ylmethy 1)-3,4dihydi'obcnzo[f]|l,4|oxazepin-5(2H)-one (Compound VI-13)

|04301 A mixture of 7-(4,4,5,5-tetramcthyl-l ,3,2-dioxaborolan-2-yI)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (200 mg, 0.69 mmol), 4-bromo-1 methylpyridin-2(lH)-one (I56mg, 0.83mmol), césium carbonate (674mg, 2.07 mmol), l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium (49 mg, 0.069 mmol) was dissolved in a degassed mixture of DMF and water 3/1.5 (4.5mL). The mixture was heated in microwave at 85°C for 40min. The mixture was poured into EtOAc and washed with water and brine. The organic layer was collected, dried over sodium sulfate and loadcd onto silica gel. A llash column (5% McOFI in EtOAc) and reverse phase chromatography gave 7-( 1 -methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4dihydrobenzo[f][l,4]oxazcpin-5(2H)-one.

|04311 7-( l-methyl-2-oxo-l,2-dihydiOpyridin-4-yl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (50mg, 0.185mmol) was dissolved in DMF (3 mL) and cooled down in a ice/water bath and treated with sodium hydride (60% dispersion) (17mg, 0.41 mmol) portion wise. Arter 10 min a solution of 2-(chloromcthyl)pyrimidine hydrochloride (37mg, 0.22mmol) in DMF (2mL) was added and the reaction mixture was warmed up to room température and cjuenched with 6mL of water after it was complété. The reaction mixture was extracted with EtOAc and water and the organic phase was dried, evaporated and purîfied by silica gel chromatography (95% DCM/MeOH) and then purified by reverse phase chromatography to afford 7-(l-melhyl-2-oxo-l,2-dihydropyridin-4-yl)-4(pyrimidin-2-ylmcthyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one.

10432| MS found for C20H18N4O3 as (M+H)⁺ 363.19. ^lH N MR (400MHz, DMSO-d₆) Ô: 8.77 (d, J=5.2Hz, 2ΙΊ), 7.99 (d, ./=2.81 IzO, 111), 7.83 (dd, J=2.4-8.4 Hz, lH), 7.73 (d, J=7.2Hz, IH), 7.40 (t, J=5.2Hz, IH), 7.12 (d,./=8.8Hz, 1 H), 6.60 (d, >1.6Hz, 1H), 6.53 (dd, J=2.0-7.2 Hz, IH), 4.97 (s, 2H), 4.54 (t,./=4.8Hz, 2II), 3.77 (t, J=4.4Hz, 2H), 3.42 (s, 311). Λ

222

Exaniple 37

7-(l-metliyl-2-oxo-l,2-dÎhydropyridïn-4-yl)-4-(pyridin-2-ylniethyl)-3,4dihydrobenzo[f]|l,4]oxazepin-5(2H)-one (Conipound VI-12)

[0433] Conipound VI-12 was prepared according to Exainple 36 using 2(chloromethyl)pyridine hydrochloride. MS found for C21H19N3O3 as (M+H)⁺ 362.18. 'H NMR (400MHz, DMSO-d_f;y. δ: 8.73 (s, IH), 8.25 (s, IH), 7.99 (s, IH), 7.84-7.75 (m, 4H), 7.12 (d, >8.0Hz, IH), 6.60-6.53 (m, 2H), 5.02 (s, 2H), 4.44 (s, 2H), 3.79 (s, 2H), 3.41 (s, 3H).

Exaniple 38

7-(2-tcrt-butoxypyridin-4-yl)-4-(pyridin-2-ylniethyl)-3,4dihydrobenzo|f]|l,4|oxazepin-5(2H)-onc (Conipound VI-4)

[0434] Conipound VI-4 was prepared according to Example 36 using 7-bromo-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one, 2-tert-butoxy-4-(4,4,5,5-tetramethyI-l,3,2dioxaborolan-2-yl)pyridine and 2-(chloromethyl)pyridine hydrochloride.

10435) MS found for C24H25N3O3 as (M+H)* 404.18. ’H NMR (400MHz, DMSOJ₆): ô: 8.52 (d, J=4.8Hz, 111), 8.15 (d, J=5.2Hz, IH), 8.03 (d, J=2.4Hz, IH), 7.87 (dd, J=2.0-8.0 Hz, IH), 7.79-7.75 (m, IH), 7.35 (d, J=8.0Hz, IH), 7.29 (dd, J=4.8-6.8 Hz, IH), 7.21 (d, 7= 5.6 Hz, 1 H), 7.12 (d,.7=8.4Hz, IH), 6.91 (s, 111),4,85 (s, 2H), 4.39 (t, J=4.4Hz, 2H), 3.69 (t, ./=4.8Hz, 2H), 1.54 (s, 9H). o/

223

Example 39

7-(2-oxo-l,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo{f||l,4|oxazepin-5(2H)“One (Compound VI-3)

10436] Compound VI-3 was generated after the acidic hydrolysis of Compound VI-4 with formic acid. MS found for C20HI7N3O3 as (M+H)⁺ 348.13 ^lH NMR (400MHz, DMSO-d₆): δ: 11.56 (s, IH), 8.52 (d, J=4.8Hz, IH), 7.98 (d, J=2.4Hz, IH), 7.82-7.75 (m, 2H), 7.42 (d, J=6.8Hz, IH), 7.35 (d, J=7.6Hz, IH), 7.28 (dd, J=4.8-6.8 Hz, III), 7.11 (d, J=8.8Hz, lH), 6.53 (s, IH), 6.47 (dd, J=I.6-6.4 Hz, IH), 4.85 (s, 2H), 4.39 (t, J=4.4Hz,

2H), 3.69 (t, J=4.4Hz, 2H).

Example 40

4-(pyrimidin-2-ylmctliyl)-7-(4-(trifiiioromethoxy)plienyl)-3,4 diliydrobenzo|f|[ l,4]oxazcpin-5(211)-onc (Compound 11-73)

rt;4h;95%

224 [0437] To a solution of Compound l-A (20 g, 0.083 mol, l eq.) and Compound 40-A (25 g, 0.15 mol, 1.8 eq.) in DMF (I50 mL), NaOFl solution (20 mL, Ι0Μ, 5 eq.) was slowly added at room température (slightly exothermic) and stirred at r.t. for I0 min, followed by heating at 95 °C for 2h. After cooling the reaction mixture, ethyl acetate (200 mL) was added and the organic layer was separatcd. The organics was washed with water (20 mL), brine, dried over sodium sulphate and concentrated.

|04381 The residuc was dissolved in 1,4-dioxane (50 mL) and to this 4N HCI in dioxane (50 mL) and cône. HCI ( 2mL) was added and stirred at room température for 4h, filtered the precipitate, washed with ethyl acetate and dried. Compound 40-B obtained (30 g) was a light yellow solid.

f0439] To the bromide (15 g, 0.04 mol, l eq), boronic acid (I2.5 g, 0.06 mol, 1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottom flask, solvent ( 150 mL, toluene/isopropano/water : 2/1/1 ) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst (I g, 0.012 mol, 0.02 eq) was added and heated al 85 ^(,C for 2h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound H-73 (13 g).

|0440| To a solution of Compound 11-73 (26 g) in 1,4-dioxane (25 mL), 4N HCl/dioxane (25 mL) was added followed by conc. HCl (2 mL) and stirred at room température for 4h. Solvent was distilled off, dichloromethane was added and distilled off and to the residue, ethyl acetate ( 150 mL) was added and stirred at room température overnight and filtered the precipitate, washed with ethyl acetate, hexane and dried under vacuum. Compound H-73-IICI obtained (24.8 g) was a white solid.

104411 'H-NMR (CDCI₃) δ 8.72 (d, 2H,7 = 5.2 Hz), 8.17 (d, 1H, J= 2.4 Hz), 7.59-7.63 (m, 3II), 7.26 (d, 211,7 = 3.2 Hz), 7.22 (t, 1 H, J = 4.8 Hz), 7.10 (d, 1 H, 7= 8.4 Hz), 5.10 (s, 2H), 4.56 (t, 211,7= 5.0 Hz), 3.77 (t, 2H,7= 5.0 Hz); MS zw/zr 416.1 (M+H).

225

Exaniplc 41

7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f||l,4]oxazcpin-5(2H)-one (Conipound 11-128)

10442] 7-Bromo-3,4-dihydrobenzo[l][l ,4]oxazepin-5(2H)-one (2.0 g), 4trifluoromcthoxyphenylboronic acid (2.2 g) and potassium carbonate (2.0 g) were combined in a mixture of toluene (20 mL), isopropanol ( 10 mL) and water ( 10 mL) and the resulting suspension was degassed with nilrogen. Palladium chloride dppf complex was added (0.42 g) and the reaction was heated overnight at 85 °C. After cooling aqueous layer was discarded and the organic laycr was diluted 2-fold with cthyl acetate, dried over MgS(O)₄ and concentrated. Recrystailization was conductcd by dissolving in a minimum necessary amount of dichloromethane and crushing with excess hexane, resulting in 7-(4(trifluoiOmethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one as a grey solid (1.43 g).

|0443] ‘H NMR: 8.42 (t, 1H); 8.12 (d, II I); 7.86-7.76 (m, 5H); 7.13 (d, 1 H); 4.38 (t, 2H); 3.37 (quartet, 2H).

Example 42

4-(iniidiizo|l,2-a|pyridin-2-ylniethyl)-7“(4“(trifluorometliyl)phcnyl)-3,4dihydrobenzo|f|11,4|oxazcpin-5(21l)-one (Conipound 11-129)

226

NaH,THF

[0444] 7-(4-(trifiuoromethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (50 mg) was dissolved in dry THF and the NaH suspension (6 mg, 60% in oil) was added, followed shortly by 2-(chloroniethyl)imidazo[l,2-a]pyridine (29 mg) and stirred overnight at room température. Worked up with ethyl acetate and pH 7 buffer organic layer dried over MgS(O)₄ and concentrated. Purification was conducted on normal phase (CH₂CI₂ / 10% EtOH in ethyl acetate gradient) followed by reverse-phase (ACN ! H₂O, 0.1 % TFA). Resulting glassy solid was dissolved in dioxane, diluted l O-fold with 0.1N

HCl and lyophilized resulting in 4-(imidazo[l,2-a]pyridin-2-ylmethyl)-7-(4(trilluoromethyl)phenyi)-3,4-dihydrobcnzotf][ l ,4]oxazepin-5(2H)-one hydrochloride sait as a white solid (42.2 mg).

[0445[ 'i l NMR: 7.95 (s, l H); 7,53 (d, 2H); 7.36 (m, 2H); 7.31 (d, 2H); 7.20 (d, l H); 5.30 (s, 2H); 2.16 (s, 3H); ^l<JF NMR: -58.36 (s); MS (ESI+): 391.0 (base peak, M+H’);

803.2 (2M+Na⁺).

Example 43

8-(4-(tnfluoromethyl)phcnyl)-3,4-dihydro-2H-benzo[bI|l,4,5[oxathiazepin-sulfone (Compound IX-1)

227 [0446| To a cooled (0°C) solution of Compound 43-A (l .368 g, 5.0 mmol) in anhydrous THF (10 mL) was added dropwise 2-aminoethanol (1.833 g, 30.0 mmol) in THF (I0 mL) with stir. After completion of addition, the reaction mixture was allowcd to warm to room température overnight. The mixture was concentrated in vaccuo, taken up in EA-H₂O ( 100-50 mL), transferred to séparation funnel, the aqueous layer was extracted with EA (50 mL x 3), combined organic phase was washed with 0.1 N HCl ( 100 mL x 2), dried, concentrated to give Compound 43-B (1.355 g). LCMS m/z 226.0 (M+H), 228.0 (M+H+2), anal HPLC > 98%. It was used directly in the next step without further purification.

|<)447| To a solution of Compound 43-B (920 mg, 3.11 mmol) and 4trifluoromethylphenylboronic acid Compound 43-C (886 mg, 4.66 mmol) in DMF (6 mL) was added K.2CO3 (I.932 g, 13.98 mmol), triethylamîne (I mL) and H₂O (l mL). The reaction mixture was stirred for 5 min under an atmosphère of dry N₂. PdCl₂(dppf) (68 mg, 0.09 mmol) was added and the resulting mixture was heated at 130°C for 30 min in a Biotage microwave. The reaction mixture was cooled, diluted with EtOAc (30 mL), filtered through a layer of celite, washed with 20% DMF in EtOAc (60 mL), combined filtrate concentrated in vaccuo. To the resulting slurry was added I % MOI ! in CH₂Cl₂ ( 10 mL), filtered and the filtrate was subjected to Yamazen chromatography, eluting with a gradient of EtOAc in CH₂Cl₂ to afford the desired product Compound 43-D (823 mg, 2.26 mmol, 73%). LCMS m/z 364.1 (M+H), anal HPLC > 92% in purity.

[04481 To a cooled (0°C) solution of Compound 43-D (73 mg, 0.20 mmol) in anhydrous DMF (3 mL) was added 95% NaH (10 mg, 0.40 mmol) in 3 portions and the resulting mixture was allowed to warm to room température under an atmosphère of N₂for 3 h. The reaction was quenched with solid NH4CI (159 mg, 3.0 mmol), then EtOAcI l₂O (30 mL and 10 mL) was added, transferred to a séparation funnel. The aqueous layer was extracted with EtOAc (3 x 10 mL), combined organic phase dried (MgS(O)4), concentrated. The crude mixture was subjected to Yamazen chromatography, eluting with a gradient of EtOAc in CH₂Cl₂(0% to 25%) to afford Compound IX-1 (34 mg, 0.10 mmol, 50%).

104491 LCMS m/z 344.0 (M+H), anal HPLC > 96% in purity. 'H NMR (400 MHz; DMSO-d6) δ 7.97 (d, J = 2.3 Hz, l H); 7.93 (dd, J = 8.3, 2.4 Hz, ÎH ); 7.90 (s, l H ); 7.85 (m, 4H ); 7.35 (d, J = 8.2 Hz, l H ); 4.14 (m, 2H ); 3.47 (m, 2H ). ^t9F NMR (400 MHz; DMSO-d6) δ-61.50 (s, 3F).

228

Example 44

2-((5-chloropyrimidin-2-yl)methyl)-8-(4-(trif]uoromcthyl)phenyl)-3,4-dihydro-2Hbenzo|b|| 1,4,5]oxathiazepin-sulfonc (Compound IX-3)

IX-1

IX-3

10450] A mixture of chloromethyl-5-chloropyrimidine (82 mg, 0.50 mmol), Compound IX-1 (17 mg, 0.05 mmol), K.2CO3 (169 mg, 1.22 mmol), triethylamine (0.5 mL) anhydrous DMF (3 mL) in a Biotage microwave vial was capped and irradiated al 130 C for 30 min in a Biotage microwave. The reaction was cooled, taken up in EtOAc (30 mL), filtered through a silica gel plug and concentratcd. The crude mixture was subjected to Gilson préparative HPLC, eluting with a gradient of ACN in I bO (5% to 95%) to afford Compound IX-3 (19 mg, 0.04 mmol, 80%).

[04511 LCMS m/z 470.0 (M+H), 472.0 (M+H+2), anal HPLC > 98% in purity,¹H NMR (400 MHz; acetone-d6) 8.77 (s, 2H); 8.04 (d, J= 2.3 Hz, 1H ); 7.95 (m, 3H ); 7.84 (d, J = 8.4 Hz, 2H ); 7.37 (d, J = 8.4 Hz, 1H ); 4.57 (s, 2H ); 4.41 (m, 2H ); 4.00 (m, 2H ). ¹⁹F NMR (400 MHz; acetone -d6) -63.62 (s, 3F).

Example 45

8-(4-(trinuoromethoxy)pheiiyl)-3,4-diliydro-2II-benzo[b]|l,4,5]oxatliiazcpin-sulfonc (Compound IX-5)

229 [0452] Compound IX-5 was prepared according to Example 44 using the appropriate starting materials [m/z 360.1, M+H].

Example 46

2-(2,2,2-trifluoroeth-l-yl)-8-(4-(trifluorometliyl)phenyl)-3,4-dihydro-2Hbcnzo|b]11,4,5]oxathiazcpin-sulfonc (Compound IX-4)

[0453] Compound 1X-4 was prepared according to Example 44 using the appropriate starting materials [m/z 426.1, M+H].

Example 47

2-(2,2,2-trifluoroeth-l-yl)-8-(4-(tiïfluoiOmethoxy)phenyl)-3,4-diliydro-2Hbenzo|b]| l,4,5]oxatliïazepin-sulfone (Compound IX-7)

|0454| Compound IX-7 was prepared according to Examplc 44 using the appropriate starting materials.

Examplc 48

2-((pyrimidin-2-yl)nietliyl)-8-(4-(trilluoiOmethyl)phenyl)-3,4-diliydiO-2Hbenzo|b]11,4,5]oxathïazepin-sulfone (Compound IX-2)

10455| Compound 1X-2 was prepared according to Example 44 using the appropriate starting materials [m/z 436.1, M+H],

230

Example 49

2-((pyrimidin-2-yl)nicthyl)-8-(4-(trifluoiOmcthoxy)phenyl)-3,4-dihydro-2Hbcnzofb|[ 1,4,5|oxathiazcpin-sulfonc (Compound IX-6)

[0456] Compound IX-6 was prepared according to Example 44 using the appropriate starting materials.

Example 50

2-((5-cyclobutyl-l,3,4-oxadiazol-2-yl)mcthyl)-8-(4-(tnlluoromcthoxy)phcnyl)-3,4dihydro-2H-bcnzo[b]|l,4,5]oxathiazepin-sulfonc (Compound IX-8)

[0457| Compound 1X-8 was prepared according to Example 44 using the appropriate starting materials.

Examplc 51

2-(cyclopropylmethyl)-8-(4-(trinuoromethyl)phcnyl)-3,4-dihydro-2H15 benzo]b] |1,4,SJoxathiazepin-sulfoiie (Compound IX-9)

[0458] Compound IX-9 was prepared according to Example 44 using the appropriate starting materials. rJ

231

Examplc 52

2-(2-methoxycth-l-yl)-8-(4-(trifluoromcthyl)plienyl)-3,4-dihydro-2Hbcnzo|b]|l,4,5|oxathiazcpîn-sulfonc (Conipound IX-10)

|0459] Conipound IX-10 was prepared according to Example 44 using the appropriate starting materials [m/z 402.1, M+H],

Examplc 53

4-((5-cyclobutyl-l,3,4-oxadiazol-2-yl)nicihyl)-7-(4-(trinuoromctlioxy)plicnyl)-3,4dihydrobcnzo|f|| l,4]oxazcpin-5(21I)-one (Conipound 11-4)

[0460] Conipound II-4 was prepared according to the Examples disclosed herein using the appropriate starting materials. ’H-NMR. (CDjOD) δ 8.01 (d, 1H, J = 2.0 Hz), 7.78 (dd, 1 H, J= 8.8, 2.4 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.16 (d, 1 H, J = 8.8 Hz), 5.07 (s, 2H), 4.49 (t, 2H,J = 5.0 Hz), 3.75-3.83 (m, 3H), 2.41-2.47 (m, 4H), 2.00-2.21 (m,2H); MS m/z 460.1 (M+H).

Examplc 54

4-((3-mcthylpyridin-2-yl)nietliyi)-7-(4-(triniioiOmcthoxy)phcnyl)-3,4dihydrobenzo[f]|l,4|oxazcpin-5(2H)-onc (Conipound 11-75)

|0461] Conipound II -75 was prepared according to the Examples disclosed herein using the appropriate starting materials. ’lI-NMR (CD₃OD) δ 8.35 (d, 1 H, J= 4.8 Hz),

8.00 (d, 111,./ = 2.4 Hz), 7.70-7.77 (m, 311),7.66 (d, I H, J =7.6 Hz), 7.35 (d, 1 H, 7=8.0 ¢/

232

Hz), 7.26-7.29 (in, 2H), 7.13 (d, IH, J = 8.0 Hz), 5.01 (s, 2H), 4.25 (t, 2H, J= 5.2 Hz),

3.68 (t, 2H, J= 5.2 Hz), 2.43 (s, 3H); MS m/z 429.1 (M+H).

Examplc 55

7-(2-fluoro-4-(trifluorometliyl)phcnyl)-4-(pyrïmidin-2-ylmethyl)-3,4dihydt'obcnzo[f|| l,4|oxazcpin-5(2II)-one (Compound II-105)

|0462] Compound II-105 was prepared according to the Examples disclosed herein using the appropriate starting materials. ’H-NMR (CD₃OD) δ 8.76 (d, 2H, J= 4.8 Hz), 8.02 (s, IH), 7.71-7.75 (m, 2H), 7.54-7.59 (m, 2H), 7.38 (t, l H,./ = 4.8 Hz), 7.18 (d, 1H,J = 8.4 Hz), 5.07 (s, 2H), 4.62 (t, 2H, J= 4.8 Hz), 3.86 (t, 2H,J= 4.8 Hz); MS »?/z4l 8.1 (M+H).

Examplc 56

7-(2-chloro-4-(ti'inuoromcthyl)plienyl)-4-(pyriniidin-2-ylmethyl)-3,4dihydrobcnzo| f| 11,4|oxazcpin-5(21 l)-onc (Compound 11-110)

|0463| Compound II-l 10 was prepared according to the Examples disclosed herein using the appropriate starting materials. ’l l-NMR (CD₃OD) δ 8.76 (d, 2H, J = 4.8 Hz), 7.88 (d, IH, J = 2.4 Hz), 7.82 (s, 1 H), 7.69 (d, 1 H, J = 7.6 Hz), 7.60-7.63 (m, 2I-I), 7.38 (t, 1 H, J = 5.0 Hz), 7.17 (d, I H, J = 8.0 Hz), 5.07 (s, 211), 4.62 (t, 2H, J = 4.8 Hz), 3.86 (t, 2H, J = 4.8 Hz); MS m/z 434.0 (M+H).

233

Example 57

7-(4-(trifluoromethoxy)phenyl)-4-((4-(trilluoiOniethyl)pyrimidin-2-yl)nicthyl)-3,4dihydrobenzo[f|[l,4)oxazepin-5(2II)-one (Conipound 11-113)

|0464| Conipound 11-113 was prepared according to the Examples disclosed lierein using the appropriate starting materials. 'H-NMR (CD₃OD) δ 9.08 (d, 1 H, J= 5.2 Hz), 8.01 (d, IH,J=2.0Hz), 7.76-7.79 (m, 211), 7.71 (d,2H,J=9.2 Hz), 7.34 (d, 2H, 8.0

Hz), 7.17 (d, I H, J = 8.4 Hz), 5.16 (s, 2H), 4.63 (t, 2H, J = 5.0 Hz), 3.88 (t, 2H, J = 4.8 Hz); MS m/z 484.1 (M+H).

Example 58

7-(4-(trifluoromethoxy)plieiiyl)-4-((3-(trifliioroiiictliyl)pyridin-2-yl)mcthyl)-3,4dihydrobenzo[l'H l,4]oxazepin-5(2II)-one (Conipound 11-126)

|0465| Conipound 11-126 was prepared according to the Examples disclosed herein 15 using the appropriate starting materials. 'H-NMR (CD₃OD) Ô 8.74 (d, 1 H, J = 5.2 Hz),

8.13 (d, 1H, J= 7.6 Hz), 8.01 (d, 1H,J = 6.4 Hz), 7.77 (dd, IH, J= 8.2, 2.2Hz), 7.71 (d, 2H, J= 8.4 Hz), 7.48 (dd, 1H, J= 7.4, 5.0 Hz), 7.34 (d, 2H, J= 8.4 Hz), 7.16 (d, IH, J = 8.8 Hz), 5.18 (s, 2H), 4.57 (t, 2H, J= 4.8 Hz), 3.81 (t, 211, J = 5.2 Hz); MS m/z 483.1 (M+H). X

234

Examplc 59

4-(οχιιζο1-2-γ1ηΐΰΗιγΙ)-7-(4-(ίΐΊίΊιιθΓοηΐΰί1ιοχγ)ρΙιαιγ1)-3,4diliydiObcnzo[f||l,4]oxazepin-5(2H)-one (Compound I1-127)

[04661 Compound II-127 was prepared according to the Examples disclosed herein using theappropriatestartingmaterials. ’H-NMR (CDjOD) δ 8.00 (d, IH, J= 2.4 Hz), 7.92 (s, IH), 7.77 (dd, 1H,7 = 8.6, 2.2 Hz), 7.72 (d, 2H,7= 8.4 Hz), 7.35 (d, 2H,7= 8.0 Hz), 7.14-7.17 (m, 2H), 4.99 (s, 2H), 4.44 (t, 2H,7= 5.0 Hz), 3.78 (t, 2H,7= 5.0 Hz); MS m/z 405.0 (M+H).

Example 60

4-(2-(bcnzyloxy)ethyl)-l-mcthyl-7-(4-(trilluoiOniethoxy)plicnyl)-3,4-diliydiO-IHbenzo|e|[l,4|dÎazepinc-2,5-dioiie (Compound X-7)

O II	Mel
ïŸ'9	DMF
	Na₂COa
H

B(OH)j

KgCOj e//-PrOH |0467] 6-Bromo-lH-bcnzo[d][l,3]oxazine-2,4-dione (5.0 g, 20.66 mmol), iodomethane (1.94 mL, d = 2.28, 4.4 g, 31.0 mmol, 1.5 equiv.) and Na₂COj (4.38 g, 41.3 mmol, 2 equiv.) were placed in a round bottomcd llask. To the ilask were added DM F (40 mL) at

235 ambîent température, The mixture was stirred overnight at room température and then filtered through a glass filter. Obtained filtrate was diluted with water to form précipitâtes, The précipitâtes were dissolved in EtOAc and the solution was dried over MgS(O)4. The solvent was removed under reduced pressure. At this point, since the conversion was -50%, K2CO3 (14.3 g, 103.3 mmol, 5 equiv.) and iodomethane (2.58 mL, d = 2.28, 41.3 mmol, 2.0 equiv.) were added to the solution of the crude material in DMF. The mixture was heated at 30°C so that the reaction can go to completion and then filtered through a glass filter, Obtained filtrate was diluted with water to form précipitâtes. Formed précipitâtes were filtered through a glass filter to give the desîred product (6-bromo-lmethy!-IH-benzo[d][l,3|oxazine-2,4-dione). This was used for the subséquent step without further purification.

|0468| 6-Bromo-I-methyl-lH-benzo[d][l,3]oxazine-2,4-dione (5.29 g, 20.66 mmol) and glycine ( l .7 g, 22.73 mmol, l. I equiv.) were dissolved in AcOH ( 100 mL) in a round bottomed flask. The mixture was heated under reflux conditions for 2 hours. The mixture was purified by automated silica-gel column chromatography using EtOAc/hexane gradient as the eluent. The purification give the desired product (7-bromo-l-methyl-3,4dihydro-l H-benzo[e][ 1,4]diazepine-2,5-dione, colorless powder, 446.7 mg).

|0469] 7-Bromo-l-methyl-3,4-dihydro-llI-benzo[e][ l,4]diazepine-2,5-dione (446.7 mg, I.66I mmol), 4-trifiuoromethoxyboronic acid (445.0 mg, 2.I59 mmol, 1.3 equiv.) Pd(dppf)Cl2-CH₂Cl2 ( 120.0 mg, 0.166 mmol, 10 mol%) and K₂CO₃ (482.0 mg, 3.49 mmol, 2.1 equiv.) were dissolved in a mixed solvents, I LO/toluene/i-PrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL round bottomed flask under a nitrogen atmosphère. The mixture was heated at 60°C l'or 64 h. The mixture was purified by automated silica-gel column chromatography using EtOAc/hexane gradient as the eluent. The purification give the desired product (l-methyl-7-(4-(trifluoiOmethoxy)phenyl)-3,4-dihydro-lHbenzo[e][ l ,4]diazepine-2,5-dione, 415.0 mg).

|0470| l-Methyl-7-(4-(trifluoromethoxy)phcnyl)-3,4-dihydro-l IIbenzo[e|[ l ,4]diazepine-2,5-dione (50.0 111g, 0.143 mmol) and NaH ( 17 mg, 0.428 mmol, 3.0 equiv.) were placed in a 2-5 mL Smith process vial under a nitrogen atmosphère. To the vial was added DMF (5 mL) to observe hydrogen extlusion. And then ((2bromoethoxy)methyl)benzene (45 pL, 0.285 mmol, d = 0.135, 2 equiv.) was added at room température. After stirring for 50 min, the reaction was qucnched with AcOH. Resulting mixture was dircctly injectcd to a préparative HPLC to give the desired product el

236 (4-(2-(benzyloxy)ethyl)-l-methyl-7-(4-(trifluoromcthoxy)-phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione, 42.7 mg) as a light yellow film.

[04711 LCMS (El: 70 eV) 503 (M⁺+Na), 486 (M⁺H).

Example 61

4-(pyi'iniidin-2-ylmctliy])-7-(4-(trÎfluoromctliyl)phenyl)-3,4-dÎliydro-lHbenzo|e|| l,4|diazepine-2,5-dione (Compound X-9)

10472J Procedure to 61-B To a mixture ol'compound 61-A (4.380 g, 20.0 mmol), NBoc dîamine (5.000 g, 31.2 mmol) and EDC (5.600 g, 38.74 mmol) in anhydrous CH2CI2 (80 mL) was added dropwise Hunig’s base (10 mL, 56.16 mmol) with stir. After compietion of addition, the reaction mixture was concentrated in vaccuo, taken up in EAH₂O (200-100 mL), transferred to séparation funnel, the aqueous layer was extracted with EA (100 mL x 3), combined organic phase was washed with 0.1 N HCl ( 100 mL x 2), dried, concentrated, column chromatographed using Yamazen, eluting with EaOAc/nhexane to give compound 61-11 (6.386 g, 17.67 mmol, 88%). LCMS m/z 362.0 (M+H), anal HPLC > 90%. It was used directly in the next step without further purification.

[0473] Procedure to Compound 61-C Standard Suzuki coupling as described above, starting from compound 61-B (658 mg, 1.8 mmol), a pale yellow solid 61-D (610 mg, 1.4 mmol, 79%) was obtained using Yamazen chromatography eluting with EaOAc/n

237 hexane, LCMS m/z 327.1 (M-t-Butyl), 876.3 (2M+Na), it was used directly in the next step without further purification.

[0474| Procedure to Compound 61-D and 61-E To a anhydrous DMF (30 mL) solution of compound C (213 mg, 0.500 mmol) and chloromethyl pyrimidine HCl sait (248 mg, 1.50 mmol) was added slowly 95% NaH (65 mg, 2.7 mmol) and stirred 5 min. Another portion of 95% NaH (55 mg, 2.3 mmol) was added, stirred for 5 min. The crude mixture was quenched by 30% aqueous NH^Cl (40 mL), extracted with EtOAc (3 x 100 mL), combined organic phase was washed with saturated NaHCO₃ ( 100 mL), brine (100 mL), dried, concentrated in vaccuo, Reverse-phase HPLC was used to obtain a yellow solid 61-1) (75 mg, 0.14 mmol, 29%). LCMS m/z 519.2 (M+H). It was used directly in the next step without further purification.

[0475| To a solution of compound 61-D (70 mg, 0.13 mmol) in DCM (5.0 mL) was added TFA (2.0 mL) and stirred overnight. Then it was concentrated in vaccuo, only one single peak in LCMS as compound 61-E, m/z 419.1 (M+H), anal HPLC > 95 in purity.

[0476] Procedure to compound X-9 To a anhydrous DMF solution ( 15 111L) of the abovc compound 61-E (54 mg, 0.13 mmol) was added Hunig's base (2 mL), capped in a Biotage microwave vial and subjected to microwave heating at 150°C for 40 min. The reaction mixture was fillered, concentrated in vaccuo and subjected to Gilson préparative HPLC, eluting with a gradient of ACN in H₂O (5% to 95%) to afford X-9 (16 mg, 0.04 mmol, 31%). LCMS m/z 399.1 (M+H), anal HPLC > 98% in purity.

Examplc 62 l-metliyl-4-(pyrimidin-2-yImcthyl)-7-(4-(trifluoromcthyl)phenyl)-3,4-dihydro-l Hbenzo[c]|l,4]diazcpin-5(2H)-one (Compound X-10)

238

NaBH(OAc)₃, DCM H_ZO, rt

HO

H '

O-H

H n

X-10

Paraformaldéhyde (04771 Procedure to compound X-l 0 To a anhydrous DCM solution (3 mL) of the compound X-9 (14 mg, 0.035 mmol) was added paraformaldéhyde (0.5 mL) and H₂O (l mL), stirred for 5 min, THF ( l mL) was added to help solubîlity. After 5 min, borohydride (63 mg, 0.31 mmol) was added, stirred for 30 min until the starting material disappeared in LCMS. The crude mixture was quenched by 30% aqueous NH₄Cl (l 0 mL), extracted with EtOAc (3 x 30 mL), combined organic phase was washed with saturated NaHCOj (30 mL), brine (30 mL), dried, concentrated in vaccuo. Reverse-phase HPLC was used to obtain a yellow solid X-10 (6 mg, 0.015 mmol, 42%). LCMS m/z 412.1 (M+l-l), anal HPLC > 98%.

Example 63

4-((l-methyl-lII-iniidazol-2-yl)mcthyl)-7-(4“(trinuoroniethoxy)plienyl)-3,4diliydrobcnzolf|11,4|oxazcpin-5(2H)-one (Compound II-186)

|0478| Compound 11-186 was prepared according to the Examples disclosed herein using the appropriate starting materials. The Suzuki coupling was performed under standard conditioned explained in the other procedures using Pd(dppf)CI₂.

104791 Alkylation of the amide was performed using sodium hydride following the standard procedure to provide the final products. X

239 {()480) Mass (M+H)⁺4l8.l. 'H NMR (400 MHz; dmso-d₆) δ 7.93 (s, l H ); 7.75 (m, 3H ); 7.58 (m, 2H ); 7.42 (ni, 2H ); 4.86 (ni, 2H); 4.18 (m, 2H); 3.75 (s, 3H); 3.65 (m, 2H). ^l9F NMR (400 MHz; DMSO-d6) Ô -57.26 (s, 3F).

Example 64

4-(2-niorpholinoethyl)-7-(4-(tnfluoromethoxy)phenyl)-3,4dihydrobenzo|f|[l,4|oxazepin-5(2II)-onc (Compound H-188)

[04811 Compound II-188 was prepared according to the Examples disclosed herein using the appropriate starting matcrials. Mass (M+I-I)⁺ 437.1.

Example 65

4-((5-mcthylpyrazin-2-yl)methyl)-7-(4-(trinuoiOmcthoxy)phenyl)-3,4diliydrobenzo|f|| l,4|oxazcpin-5(2II)-one (Compound 11-172)

[0482J Compound 11-172 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 430.1. ¹H NMR (400 MHz; DMSO-d6) Ô 8.50 (m, 2H ); 7.94 (s, 1H ); 7.78 (m, 3 H ); 7.41 (d, J = 8.5 Hz, 2H ); 7.13 (d, .1 = 8.1 Hz, 1 H); 4.86 (s, 2H); 4.38 (m, 2H); 3.71 (m, 211); 2.48 (s, 3H). ^iyF NMR (400 MHz; DMSO-d6) δ -57.26 (s, 3F).

Example 66

4-((6-incthylpyrazin-2-yl)metliyl)-7-(4“(trifluorometlioxy)phenyl)-3,4diliydrobcnzo|f|11,4|oxazepin-5(2II)-one (Compound 11-175)

240 |0483| Conipound 11-175 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 430.1 'H NMR (400 MHz; CD₃OD) δ 8.48 (s, IH ); 8.41 (s, IH ); 7.97 (s, IH ); 7.73 (m, 3H ); 7.32 (d, J = 8.6 Hz, 2H ); 7.13 (d, J = 8.6 Hz, 1 H); 4.95 (s, 2H); 4.46 (m, 2H); 3.80 (m, 2H); 3.30 (s, 3H). ^I9F NMR (400 MHz; CD3OD) δ -56.96 (s, 3F).

Example 67

4-((l-bcnzyl-llI-iniidazol-2-yl)niethyl)-7-(4-(trilluoiOnicthoxy)plienyl)-3,4dihydrobenzo|f|[l,4|oxazcpin-5(2H)-one (Conipound 11-187)

|0484] Conipound II -187 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 494.1. *H NMR (400 MHz; dmsod_f.) δ 7.00 - 8.00 (m, 12H ); 5.32 (s, 211 ); 4.82 (s, 2H); 4.26 (m, 2H); 3.49 (m, 2H). ^I9F NMR (400 MHz; DMSO-d6) δ -57.25 (s, 3F).

Exaniple 68

4-(imidazo| l,2-a|pyridin-2-ylniethyl)-7-(4-(trifluoi-oniethoxy)plienyl)-3,4dihydrobcnzo|f|| l,4|oxazepin-5(2H)-onc (Conipound 11-189)

|0485| Conipound 11-189 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 454.1. ‘i l NMR (400 MHz; dmsod₆) Ô 6.80 - 8.50 (m, 12H ); 5.36 (s, 2H ); 4.82 (m, 2H); 4.24 (m, 2H). ^I9F NMR (400 MHz; DMSO-d6) δ-57.38 (s, 3F).

241

Example 69 tert-butyl 2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo|f||l,4]oxazepiiie4-carbonyl)-5,6-dihydroimidazo|l,2-a|pyrazine-7(8H)-carboxylate (Compound III40)

[0486] Décarboxylation of the amide was perlormed using lM BH₃ in THF for l-5 days following the standard procedure to provide amine 69-A. This was followed by a standard HATU catalyzed condensation reaction to afford Compound III-40. Mass (M+H)⁺543.2.

Examplc 70 (5,6,7,8-tetraliydroimidazo|l,2-a|pyrazin-2-yl)(7-(4-(trifluoroniethyl)plienyl)-2,3diliydrobenzo[fJ|l,4|oxazcpin-4(5H)-yl)methanonc (Compound 111-42)

ill-40

111-42 [0487] Compound 111-40 was dcprotected using TFA in dichioromethane in a standard procedure to give Compound II1-42. Mass (M-i-H)⁺443.1.

242

Example 71 l-(2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobcnzo{f|| l,4]oxazepine-4carbonyl)-5,6-dihydroimidazo| l,2-a|pyrazin-7(8H)-yl)ethanone (Compound III-48)

111-42

111-48

104881 Standard acylation using acetic anhydride at room température of Compound

111-42 afforded Compound II1-48. Mass (M+H)* 485.1.

Example 72 (l-metliyl-lH-imidazol-5-yl)(7-(4-(trifluoromcthyl)phcnyl)-2,310 dihydrobenzo|f]|l,4|oxazcpin-4(5H)-yl)methanonc (Compound III-32)

[Ü489| Compound II1-32 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)* 402.1.

Example 73 (lH-imidazol“2-yl)(7-(4-(trifliio!Onielhyl)phenyI)-2,3-dihydrobcnzo|f|| l,4|oxazepin4(5H)-yl)metbanonc (Compound II1-33)

243 |0490] Conipound 111-33 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)¹ 388.1.

Exaniplc 74 (1-((1 H-iniidazol-l-yl)methyl)cyclopropyl)(7-(4-(trifiuoromethyl)phcnyl)-2,35 diliydrobenzo[f|[l,4|oxazepin-4(5H)-yl)nictlianone (Conipound 111-34)

|04911 Conipound 111-34 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 442.1.

Exaniplc 75 (1-mcthyl-l H-iniidazol-2-yl)(7-(4-(trifluoronicthyl)phcnyl)-2,3diliydrobenzo[l'|| l,4]oxazcpin-4(5il)-yl)nicthanonc (Conipound 111-37)

[0492] Conipound II1-37 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 402.1.

Exaniplc 76 (R)-tcrt-butyl 2-(7-(4-(trifluoromcthyl)phcnyl)-2,3,4,5tctraliydrobcnzo[ f| 11,41 oxazcpinc-4-carbony l)pyrrolidinc-1 -carboxylatc (Conipound Il 1-52)

244 |0493| Compound III -52 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. Mass (M+H)⁺49l.2.

Example 77 (lII-l,2,3-triazol-5-yl)(7-(4-(triiluoromcthyl)phcnyl)-2,3dîhydrobenzo[f)|l,4]oxazepin-4(5H)-yl)methanone (Compound lil-49)

|0494| Compound II 1-49 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. Mass (M+H)⁺ 389.1.

Example 78 ( 1 H-1,2,4-ti-iazol-3-yl)(7-(4-(trifiuoromethyl)phenyl)-2,3dihydiObenzo|f||l,4|oxazcpin-4(5H)-yl)mcthanone (Compound 111-50)

|0495| Compound III -50 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. Mass (M+H)⁺389.1.

Example 79 (3-ainino-lH-l,2,4-triazol-5-yl)(7-(4-(trifiuoromcthyl)pheiiyl)-2,3dihydrobenzo[f)|l,4]oxazepin-4(5H)-yl)niethanone (Compound I! 1-51)

|0496| Compound III -51 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. Mass (M+ H)⁺ 404.1. A

245

Examplc 80 (R)-pyrrolidin-2-yl(7-(4-(trifluoromethyl)phcnyl)-2,3-dihydrobenzolf||l,4]oxazepm4(5H)-yI)methanone (Compound 111-53)

[0497] Compound II1-53 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)¹ 391.1.

Examplc 81 (l-phenyl-lH-l,2,3-triazoI-5-yl)(7-(4-(trifiuoromethyl)phcnyl)-2,3diliydrobenzo|i']|l,4|oxazcpin-4(5H)-yl)methanone (Compound 111-54)

|0498| Compound 111-54 was prepared according to the Examples disclosed herein using the appropriate starting materials.

Examplc 82 (R)-l-(2-(7-(4-(trifluotOmcthyl)phenyl)-2,3,4,5-tctrahydrobcnzo(f]|l,4|oxazcpinc-415 carbonyl)pyrrolidin-l-yl)cthanonc (Compound 111-55)

|0499] Compound II 1-55 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 433.1. c/

246

Examplc 83 (lH-imidazol-2-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobcnzo[f]|l,4)oxazcpin-4(5H)-yl)mcthanone (Compound III-56)

|0500| Compound III-56 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 404. i.

Examplc 84 (S)-4-bcnzyl-3-mcthyl-7-(4-(trifluoromcthyl)phcnyl)-3,4dihydrobcnzo[f]| l,4|oxazepin-5(2II)-onc (Compound II-132)

F

3) NaH, DMF

|050l | A solution of 5-bromo-2-fluorobenzoic acid ( l mmol), benzyl (S)-valinol ( l mmol), HATU (l mmol) and diisopropyiethylamine (3 mmol) in DMF (3 mL) was stirred at room température for 30 minutes. The reaction mixture was poured into a l : l solution of IM HCl and brine and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried and concentrated. The residcd was taken up in a mixture of toluene, isopropanol and water ( I mL each) and added to a flask containing4-trifluoromethylphenyl boronic acid (3 mmol), K2CO.1 (3 X

247 mmol) and dppfPdClj (40 mg) under nitrogen. The reaction mixture was stirred at 90^l’C for l h. The organic layer was separated and concentrated before being purified by flash chromatography (rf= 0.28 in 2:l hexanes/ethyi acetate) to give a viscous oil. The product was dissolved in DMF (5 niL) and sodium hydride was added (5 mmol). The reaction mixture was stirred at room température for 40 minutes and was poured into a l : l solution of IM HCl and brine and extracted with ethyl acetate. Theorganic layer was washed with saturated sodium bicarbonate solution and brine, dried and concentrated before being purified by flash chromatography (rf = 0.59 in 2:l hexanes/ethyi acetate) to give (S)-4-benzyl-3-methyl-7-(4-(trifluoromethyl)phenyl)-3,4dihydiObenzo[f][l,4]oxazepin-5(2H)-one as an oil.

10502J To a solution of the above product in chloroform was added NBS (2.5 equiv) and N-methylacetamide ( 10 mol%). The reaction was stirred for 18 hours at room température before being concentrated under vacuum. The resîdue was dissolved in ethyl acetate (10 mL) and IM NaOH solution was added (10 mL). The mixture was stirred vîgorously for 5 minutes and the organic layer was separated, washed with brine and concentrated. Flash chromatography (rf = 0.10 in 2: l hexanes/ethyi acetate) gave the debenzylatcd product.

(05031 To a solution of the above product (20 mg) and 2-chloromethylpyrimidine HCl sait (30 mg) in DMF was added sodium hydride (40 mg) and the reaction was stirred for l h at room température. The reaction mixture was quenched with l M HCl and purified by préparative HPLC to give (S)-3-methyl-4-(pyrimidin-2-yhnethyl)-7-(4(trifluoiOmethyl)phenyl)-3,4-dihydrobenzo[ij[l,4]oxazepin-5(2H)-onc TFA sait as a white powder.

Example 85 (2S,1 laS)-2-aniino-7-(4-(trifluoromethyl)phenyl)-2,3,l l,l latctrahydrobcnzo|f|pyrrolo(2,l-cj| l,4]oxazcpin-5(lII)-one (Compound II-5I)

(0504] Compound II-51 was prepared according to the Examples disclosed herein using the appropriate starting materials. C19H17F3N2O2 x TFA. 363.1 (M+1). ‘H NMR

248 (DMSO) δ 8.34 (d, J = 2.8 Hz, ÎH), 8.20 (br, 3H), 7.85 (ni, 5H), 7.16 (d, J = 8.4 Hz, ÎH), 4.61 (d, J = 12.0 Hz, 1H), 4.16 (m, 2H), 3.96 (m, IH), 3.83 (br, 1 H), 3.58 (m, 1 H), 2.54 (m, IH), 1.80 (ni, 1H). ^|yF NMR (DMSO) δ -61.4 (s, 3F).

Examplc 86 (R)-2-(pyriniidin-2-yJmetliyl)-8-(4-(trifluoiOmctliyl)plicnyl)-3,4,12,l2a-tctraliydrolH-bcnzo|f[pyrazino|2,l-c|[l,4|oxazcpin-6(21I)-onc (Conipound 11-8)

[0505| Conipound 11-8 was prepared according to the Exaniples disclosed herein using the appropriate starting materials. C24H21F3N4O2X 2-TFA. 455.1 (MH).

Examplc 87 (S)-2-(pyrimidin-2-ylnictliyl)-8-(4-(triiluoronictliyl)plieiiyl)-3,4,12,12a-tctrahydrolH-bcnzo|f]pyrazino|2,l-c||l,4|oxazepin-6(2II)-one (Conipound 11-9)

[0506] Conipound 11-9 was prepared according to the Examples disclosed herein using the appropriate starting materials. C24H21F3N4O2 x 2-TFA. 455.1 (M+1 ).

Examplc 88 (S)-3-methyl-4-(pyrimidin-2-ylmcthyl)-7-(4-(trifluoromethy))plicnyl)-3,4dihydrobenzo[f||l,4]oxazcpin-5(2H)-onc (Conipound 11-12)

|0507| Conipound II- 12 was prepared according to the Exaniples disclosed herein using the appropriatestartingmaterials. C22H18F3N3O2x TFA. 414.1 (M+l). '11 NMR ¢/

249 (DMSO) δ 8.77 (d, J = 5.2 Hz, 2H), 8.38 (d, J = 2.4 Hz, I H), 7.85 (m, 5H), 7.40 (t, J = 5.0 Hz, lH), 7.20 (d, J = 8.4 Hz, IH), 5.10 (J = 17.0 Hz, lH), 4.79 (d, J = 17.0 Hz, lH), 4.60 (m, 2H), 4.05 (m, IH). 1.22 (d, J = 6.8 Hz, 3H). ^lyF NMR (DMSO) δ -61.37 (s, 3F).

Examplc 89 (R)-3-inethyl-4-(pyriniidiii-2-ylnietliYl)-7-(4-(tiifliioroniethvl)plienyl)-3,4dihydrobenzo[f]|l,4|oxazcpin-5(2II)-onc (Compound II-13)

10508] Compound 11-13 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22H18FJN3O2 x TFA. 414.1 (M+1 ). '11 NMR (DMSO) δ 8.77 (d, J = 5.2 Hz, 2H), 8.38 (d, J = 2.4 Hz, 111), 7.85 (m, 5H), 7.40 (t, J = 5.0 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 5.10 (J = I7.0 Hz, I H), 4.79 (d, .1 = 17.0 Hz, I H), 4.60 (m, 2H), 4.05 (m, IH). 1.22 (d, J = 6.8 Hz, 3H). ^|1>F NMR (DMSO) δ -61.37 (s, 3F).

Examplc 90 (S)-3-mcthyl-7-(4-(trifluoromcthyl)plienyl)-3,4-dihydrobenzo[f|| l,4]oxazcpin-5(2H)one (Compound 11-18)

[0509] Compound 11-18 was prepared according to the Examples disclosed herein using the appropriate starting materials. C’nHt.iFjNO;. 322.1 (M+1). '11 NMR (DMSO) δ

8.41 (d, J =4.4 Hz, IH), 8.20 (d, J = 1.6 Hz, 111),7.85 (m, 5H), 7.16 (d, J = 8.4 Hz, 1 H), 4.22 (m, 2 H), 3.68 (br, 1 H), 1.15 (d, J = 6.4 Hz, 3H). X

250

Examplc 91 (R)-3-methyl-7-(4-(trifluoromethyl)phcnyl)-3,4-dihyd!'obcnzo|f|[ l,4]oxazepin5(2H)-one (Compound 11-19)

[0510| Compound 11 -19 was prepared according to the Examples disclosed herein using the appropriate starting materials. C17I114F3NO2. 322.1 (M+l ). *H NMR (DMSO) δ 8.41 (d, J = 4.4 Hz, 1 H), 8.20 (d, J = 1.6 Hz, 1 H), 7.85 (m, 511), 7.16 (d, J = 8.4 Hz, IH), 4.22 (m, 2 H), 3.68 (br, 1 H), 1.15 (d, J = 6.4 Hz, 3H).

Examplc 92 (2R,1 laS)-2-aniino-7-(4-(trifluoromctliyl)pl)cnyl)-2,3,l 1,11atetrahydrobenzojf|pyrrolo{2,l-c|[ l,4|oxazcpin-5(l H)-onc (Compound 11-21)

|0511| Compound Π-21 was prepared according to the Examples disclosed herein using the appropriate starting materials. C19II17F3N2O2x TFA. 363.1 (M+l).

Examplc 93 (R)-2-(2,2-difluoroethyl)-8-(4-(triHuoroinethyl)plienyl)-3,4,12,12a-tetrahydro-lIIbcnzo[f]pyrazino|2,l-c||l,4|oxazcpin-6(2H)-onc (Compound 11-22)

|0512| Compound II -22 was prepared according to the Examples disclosed herein using the appropriate starting materials. C21H [9F5N2O? x TFA. 427.1 (M+1 ). ¹H NMR (DMSO) δ 8.22 (d, J = 2.4 Hz, 1 H), 7.84 (m, 5H), 7.18 (d, J = 8.4 Hz, 1 H), 6.22 (tm, J = X

251

55.6 Hz, lH), 4.53 (m, IH), 4.27 (m, IH), 3.97 (br, 2H), 3.62 (m, III), 2.90-2.60 (m, 6H). ^iyF NMR (DMSO) δ -61.4 (s, 3F), -119.4 (dt, 55.6, 16.2 Hz, 2F).

Example 94 (R)-2-ethyl-8-(4-(trifluoronietliyl)plicnyl)-3,4,l2,l2a-tetraliydro-lHbenzo|f|pyrazino|2,I-c]| l,4|oxazepin-6(2II)-onc (Conipound 11-23)

[05131 Conipound 11-23 was prepared according to the Examples disclosed herein using the appropriate starting materials. C₂tH₂|FjN2O₂x TFA. 391.1 (M+l).

Example 95 (S)-2-(2,2-difluorocthyl)-8-(4-(trinuoronictliyl)plienyl)-3,4,12,12a-tetrahydro-1IIbenzo[f|pyrazino|2,l-c||l,4|oxazepin-6(2H)-onc (Conipound 11-24)

[0514| Conipound 11-24 was prepared according to the Examples disclosed herein using the appropriate starting materials. C21I I19F5N2O2X TFA. 427.1 (M+l). 'H NMR (DMSO) δ 8.22 (d, J = 2.4 Hz, IH), 7.84 (in, 5H), 7.18 (d, J = 8.4 Hz, IH), 6.22 (tm, J =

55.6 Hz, IH), 4.53 (m, IH), 4.27 (m, IH), 3.97 (br, 2H), 3.62 (m, IH), 2.90-2.60 (m, 6H).

^I<JF NMR (DMSO) δ -61.4 (s, 3F), -119.4 (dt, 55.6, 16.2 Hz, 2F).

Example 96 (S)-2-etliyl-8-(4-(trilluoiOmethyl)plienyl)-3,4,12,12a-tctialiydro-lIl· benzo|f|pyrazino[2,l-c||l,4|oxazepin-6(2II)-one (Conipound 11-25)

252 [0515| Compound 11-25 was prepared according to the Examples disclosed herein using the appropriate starting materials. C21H21F3N2O2x TFA. 391.1 (M+l).

Example 97 (S)-3-isopropyI-7-(4-(tniluoromcthyl)phenyl)-3,4-dihydrobcnzo[f||l,4|oxazepin5(2H)-onc (Compound 11-77)

[05161 Compound 11-77 was prepared according to the Examples disclosed herein using the appropriate starting materials. C19H1KF3NO2. 350.1 (M+l).

Example 98 (R)-3-methyl-4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phcnyl)-3,4diliydrobenzo[l|| l,4|oxazepin-5(2H)-onc (Compound 11-80)

[0517| Compound II -80 was prepared according to the Examples disclosed herein using the appropriate starting materials. C23H19F3N2O2 x TFA. 413.1 (M+l).

Example 99 (S)-3-nicthyl-4-(pyi'Îdin-2-ylmcthyl)-7-(4-(trifluorometliyl)plicnyl)-3,4dihydrobenzo| f| [ 1,4|oxazepîn-5(2II)-oiie (Compound 11-81)

|0518| Compound 11 -81 was prepared according to the Examples disclosed herein using the appropriate starting materials. C23Ht9F3N₂O₂ x TFA. 413.1 (M+1 ).

253

Example KM)

4-(l-(pyrïdin-2-yl)ethyl)-7-(4-(trifluoromethyl)plicnyl)-3,4dihydrobenzo[f|| l,4]oxazepiii-5(2H)-one (Compound II-82)

[0519] Compound II -82 was preparcd according to the Examples disclosed herein using the appropriate starting materials. CitHisFîNjC^x TFA. 414.1 (M-i-l)

Example I01 (R)-2-(2,2,2-ti-ifliioroetliyl)-8-(4-(ti inuoi'omethyl)phenyl)-3,4,I2,l2a-teti ahydro-l Hbcnzo|l'|pyrazino|2,i-c|[ l,4|oxazepin-6(2H)-onc (Compound II-83)

[05201 Compound II-83 was preparcd according to the Examples disclosed herein using the appropriate starting materials. CiiHisFftNiCbx TFA. 445.1 (M+l)

Example 102 (R)-4-benzyl-2-inctliyl-7-(4-(trifluoiOinethyl)phenyl)-3,415 dihydrobcnzo|f|| l,4[oxazcpin-5(2II)-one (Compound 11-85)

|05211 Compound 11-85 was preparcd according to the Examples disclosed herein using the appropriate starting materials. C24I I20F3NO2 412.1 (M+1 ). oc

254

Example 103 (S)-4-benzyl-2-methyl-7-(4-(trifluoromethyl)phcnyl)-3,4dihydrobcnzo|f]| 1,4|oxazepin-5(2H)“Onc (Compound 11-86)

10522| Compound II -86 was prepared according to the Examples disclosed herein using the appropriate starting materials. C24I I20F3NO2.412.1 (M+l ).

Example 104 (S)-2-niethyl-4-(pyrimidiii-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobcnzo|f|| l,4|oxazepin-5(2II)-onc (Compound 11-101)

[0523] Compound 11-101 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22H18F3NJO2. 414.1 (M+l)

Example 105

2-(pyridin-2-yl)-l“(7-(4-(trifluoromcthyl)phcnyl)-2,3-dihydrobcnzo[fJ|l,4]oxazepin15 4(5H)-yl)cthanonc (Compound III-29)

|0524] Compound 111-29 was prepared according to the Examples disclosed herein using the appropriate starting materials. C23M19F3N2O2· 413.1 (M+1 ). X

255

Examplc 106

2-(pyrimidin-2-yl)-l-(7-(4-(trifluoromethyl)phcnyl)-2,3dihydrobenzo[f|| l,4|oxazepin-4(5H)-yl)cthanone (Compound ΠΙ-30)

J0525] Compound III -30 was prepared according to the Examples disclosed herein using the appropriate starting materials. CiiHisFj^O?. 414.1 (M+l).

Examplc 107

4-(5-oxo-4-(pyriniidin-2-ylmcthy 1)-2,3,4,5-tctra liydro bcnzo| f][ l,4|oxazepin-7yl)phcnyl trifluoromcthancsulfonate (Compound 11-171)

|0526| Compound 11-171 was prepared according to the Examples disclosed herein using the appropriate starting materials. C21II16F3N3O5S. 480.1 (M+l).

Examplc 108 (R)-(2-niethyl-7-(4-(trifluoiomethoxy)phcnyl)-2,3-dihydiObcnzo|f|| I,4|oxazcpin15 4(5H)-yI)(pyrimidin-2-yl)methanone (Compound II 1-38)

[0527| Compound III -38 was prepared according to the Examples disclosed herein using the appropriatestarting materials. C22H1BF3N3O3. 430.1 (M+l). À

256

Example 109 (S)-(2-methyl-7-(4-(trifluoromethoxy)phenyi)-2,3-dihydrobenzo|fni,4|oxazepin4(5H)-yl)(pyrimidin-2-yl)methanone (Compound 111-39)

|0528| Compound III -39 was prepared according to the Examples disclosed herein using the appropriate starting materials. C22H18F3N3O3.430.1 (M+1 ).

Example 110

I’hcnyl(7-(4-(trifluoromcthoxy)phciiyl)-2,3-diliydrobenzo[f]| l,4|oxazepin-4(5II)yl)mcthanone (Compound II 1-4)

|0529] Compound II1-4 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23I I18F3NO3 as (M+H)⁺ 414.1.

Example 111

4-(pjTÎmidin-2-ylmetliyl)-7-(4-(2,2,2-trifluoroethyl)plicnyl)-3,415 diliydrobenzo[f|| l,4|oxazcpin-5(2H)-onc (Compound 11-150)

10530] Compound 11-150 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23H18F3NO3 as (M+H)⁺ 414.2. ¢/

257

Exaniplc 112

4-(pyridin-2-ylnictliyl)-7-(4-(2,2,2-trifluoroethyl)phcnyl)-3,4diliydrobcnzo[f]| l,4]oxazepin-5(2II)-one (Conipound 11-151)

|05311 Conipound 11-151 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. MS found for C23II19F3N2O2 as (M+H)⁺ 413.2 *H NMR (400MHz, dmso-d₆): 6: 8.54 (d, 7=5.6 Hz, 1H), 7,96 (d, 7=2.4 Hz, 1H), 7.80-7.76 (m, 2H); 7.67 (d,7 = 8.0 Hz, 1 H), 7.42-7.28 (m, 4H); 7.14 (d,7= 8.4 Hz, I H); 4.86 (s, 2H), 4.38-4.36 (m, 2H), 3.72-3.64 (m, 411).

Exaniplc 113 (l-incthylcyclopi-opyl)(7-(4-(trifluoionicthoxy)plicnyl)-2,3-dihydiObcnzo[f|[l,4| oxazcpin-4(5II)-yl)mctlianonc (Conipound ΙΠ-10)

[0532] Conipound 111-10 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. MS found for C21I I20F3NO3 as (M+H)⁺ 392.0.

Exaniplc 114 (3,3-difhiorocyclohutyl)(7-(4-(ti'ifluoroniethoxy)plienyl)-2,3-diliydrobenzo|f]|l,4] oxazcpin-4(5ll)-yl)inctlianone (Conipound III-l 1)

|0533| Conipound III-l 1 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. MS found for C21I I18F5NO3 as (M+H)¹ 428.1.

258

Example 115 ( 1 -mcthyl-1 II-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobcnzo [ η [ 1,4| oxazepin-4(5H)-yl)methanonc (Compound 111-12)

[0534| Compound III -12 was prepared according to the Examples disciosed herein using the appropriate starting materials. MS found for C21H18F3N3O3 as (M+H)⁺ 418.1.

'H NMR (400MHz, dmso-d₆): 8: 8.03 (s, I H), 7.73-7.41 (m, 7H); 7.03 (d, J= 8.0 Hz, 1H), 4.82 (s, 2H), 4.26 (m, 2H); 4.00 (m, 2H); 383 (s, 3H).

Example 116 ( 11 l-pyrazol-3-yl)(7-(4-(trifluoromethoxy)pIienyl)-2,3-dihydrobcnzo|f| [ 1,4| oxazepin-4(5H)-yl)mcthanone (Compound 111-15)

105351 Compound 111-15 was prepared according to the Examples disciosed herein using the appropriate starting materials. MS found for C20H16F3N3O3 as (M+H)⁺ 404.1.

Example 117 ( 1,5-dimethyl-1 ll-pyrazol-3-yl)(7-(4-(trifluoiOmctlioxy)phenyl)-2,3dihydiOhenzo|f||l,4|oxazepin-4(5II)-yl)methanone (Compound ΙΠ-58)

J0536| Compound 111-58 was prepared according to the Examples disciosed herein using the appropriate starting materials. MS found for C22H20F3N3O3 as (M+H)⁺ 432.1

259

Examplc 118

Pyrazin-2-yl(7-(4-(trifluoiOmcthoxy)plicnyl)-2,3-dihydrobenzo|f[[l,4|oxazcpin4(5H)-yl)methanonc (Compound 111-23)

[05371 Compound III-23 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS tound for C21H16F3N3O3 as (M+H)⁺ 416.1.

Examplc 119

Pyridazin-3-yl(7-(4-(trifluoi'ometlioxy)plienyl)-2,3-dihydrobenzo|f||l,4]oxazepin4(5H)-yl)mcthanonc (Compound 111-24)

|0538| Compound 111-24 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS tound for C16H14F3NO2 as (M+H)⁺ 310.1 .MS found for C21II16F3N3O3 as (M+H)⁺ 416.1.

Examplc 120

4-(pyrimidin-2-ylmcthyl)-7-p-tolyI-3,4-dihydiObcnzo[f)[l,4|oxazepin-5(2H)-one (Compound 11-87)

|0539| Compound 11-87 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H19N3O7 as (M+H)⁺ 346.1 'fl NMR (400MHz, dmso-df,): δ: 8.77 (d, J=5.2Hz, 2H), 7.90 (d,./=2.4Hz, 1 H), 7.75 (dd, .1=2.4, 8.8 Hz, I H), 7.52 (d, J=8.8Hz, 2H), 7.40 (t, J=5.2Hz, 1 H), 7.25 (d, J=8.0Hz, 2H), 7.42 (d, J=8.4Hz, 1I I), 4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.31 (s, 3H).

260

Exaniple 121

7-(4-chlorophenyl)-4-(pyriniidin-2-ylnietliyl)-3,4-dihydrobcnzo[f||l,4)oxazepin5(2H)-onc (Conipound 11-88)

|0540] Conipound 11-88 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C20H16N3O2CI as (M+H)⁺ 366.1 '1-1 NMR (400MHz, dmso-d₆)'. Ô: 8.77 (d, J=5.2Hz, 2H), 7.94 (d, J=2.4Hz, 111), 7.79 (dd, J=2.4, 8.8 Hz, 1 H), 7.67 (d, J=8.8Hz, 2H), 7.49 (d, J=8.0Hz, 2H), 7.40 (t, J=5.2Hz, 1 H), 7.13 (d, J=8.4Hz, IH), 4.97 (s, 2H), 4.51-4.49 (m, 2H), 3.77-3.74 (m, 2H).

Exaniple 122

7-(4-isopropylphcnyl)-4-(pyrimidin-2-ylnietliyl)-3,4-dihydrobenzo|Î|[l,4|oxazepin5(2II)-one (Conipound 11-89)

|0541 ] Conipound 11-89 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23II23N3O2 as (M+H)⁺ 374.1 'H NMR (400MHz, dmso-d_fi): Ô: 8.77 (d, J=5.2Hz, 2H), 7.90 (d, J=2.4Hz, IH), 7.75 (dd, .1=2.4, 8.8 Hz, IH), 7.55 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, 1 H), 7.29 (d, J=8.0Hz, 2H),

7.11 (d, J=8.4Hz, IH), 4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.91 (m, îH);

1.22 (d, J = 7.2 Hz, 6H).

Exaniple 123

7-(4-ethylphenyl)-4-(pynniidin-2-ylnietliyl)-3,4-dihydrobcnzo|f|[ l,4]oxazepin-5(2 II)onc (Conipound 11-91)

261 |0542] Compound II -9l was prepared according to the Examples disclosed herein using the appropriate starting materials, MS found for C22H21N3O2 as (M+H)⁺ 360.1 'H NMR (400MHz, dmso-d₆)·. δ: 8.77 (d, J=5.2Hz, 2H), 7.91 (d, J=2.4Hz, I H), 7.75 (dd, J=2.4, 8.8 Hz, ÎH), 7.54 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, ÎH), 7.28 (d, J=8.0Hz, 2H), 7.12 (d, J=8.4Hz, IH), 4.97 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H); 1.20 (d, J = 7.6 Hz, 3H).

Examplc 124

7-(4-cyclopropylphcnyl)-4-(pyrimidin-2-ylmcthyl)-3,4-dihydrobenzo[f]|l,4|oxazepin5(2H)-one (Compound 11-92)

[05431 Compound 11-92 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C22H21N3O2 as (M+H)⁺ 372.1 ’H NMR (400MHz, dmso-d₆): Ô: 8.77 (d, J=5.2Hz, 2H), 7.88 (d, J=2.4Hz, 1H), 7.74 (dd, J=2.4, 8.8 Hz, IH), 7.50 (d, J=8.8Hz, 2H), 7.41 (t,J=5.2Hz, 1H), 7.14 (d, J=8.0Hz, 2H),

7.10 (d, J=8.4Hz, 1 H), 4.96 (s, 2H), 4.49-4.47 (m, 2H), 3.75-3.73 (m, 2H), 1.94-1.89 (m, 1 H); 0.97-0.93 (m, 2H); 0.70-0.66 (m, 2H).

Example 125

7-(4-methoxyphenyl)-4-(pynmidin-2-ylmethyl)-3,4-dihydrobcnzo[f||l,4]oxazcpin5(2H)-onc (Compound 11-94)

10544] Compound 11-94 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C₂iH19N3O3 as (M+H)⁺ 362.1 '11 NMR (400MHz, dmso~d^’. δ: 8.78 (d, J=5.2Hz, 2H), 7.86 (d, J=2.4Hz, IH), 7.72 (dd, J=2.4, 8.8 Hz, 111), 7.56 (d, J=8.8Hz, 2H), 7.41 (t,./=5.2Hz, IH), 7.10 (d, J=8.0Hz, 2H), 7.00 (d, J=8,4Hz, I H), 4.97 (s, 2H), 4.48-4.45 (m, 2H), 3.76 (s, 3H); 3.74-3.72 (m, 2H). o(

262

Examplc 126

7-(4-isobutoxyphcnyl)-4-(pynmidin-2-ylmethyl)-3,4-dihydrobenzo[f||l,4|oxazepin5(2H)-one (Compound 11-97)

[0545] Compound 11-97 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C24H25N3O3 as (M+H)⁺ 404.1. ¹H NMR. (400MHz, dmso-d₆)'. δ: 8.78 (d, J=5.2Hz, 2H), 7.85 (d, J=2.4Hz, IH), 7.72 (dd, J=2.4, 8.8 Hz, 1 H), 7.54 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, 1 H), 7.10 (d, J=8.0Hz, 2H), 6.99 (d, J=8.4Hz, IH), 4.97 (s, 2H), 4.48-4.46 (m, 2H), 3.76-3.72 (m, 4H); 2.03-1.97 (m,

1 H); 0.97 (d, .1 = 6.4 Hz, 6H).

Examplc 127

7-(4-tcrt-butylphciiyl)-4-(pyi'imidin-2-ylnicthyl)-3,4-dihydrobcnzo|f|[l,4|oxazcpin5(2H)-one (Compound 11-98)

10546| Compound 11-98 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C24H25N3O3 as (M+H)⁺ 404.1 ’l-I NMR (400MHz, dmso-d₆)'. δ: 8.78 (d, J=5.2Hz, 2H), 7.91 (d, J=2.4Hz, IH), 7.75 (dd, J=2.4, 8.8 Hz, IH), 7.55 (d, J=8.8Hz, 2H), 7.46 (d, J=8.0Hz, 2H); 7.41 (t, J=5.2Hz, IH);

7.11 (d, J=8.4Hz, 1 H), 4.97 (s, 2H), 4.50-4.47 (m, 2H), 3.76-3.73 (m, 4H); 1.29 (s, 911).

263

Examplc I28

7-(4-cyclopropoxyphcnyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobcnzo[f|[ l,4|oxazcpin-5(2II)-one (Compound 11-102)

10547| Compound 11-102 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C23H21N3O3 as (M+H)⁺ 388.1 ¹ I I NMR (400MHz, dmso-d₆): δ: 8.78 (d, J=5.2I4z, 2H), 7.86 (d, J=2.4Hz, 1 H), 7.72 (dd, J=2.4, 8.8 Hz, III), 7.57 (d, J=8.8Hz, 2H), 7.41 (t, J=5.2Hz, IH); 7.46 (d, J=8.0Hz, 211),

7.11 (m, 3H), 4.97 (s, 2H), 4.48-4.46 (m, 2H), 3.87-3.86 (m, 1 H); 3.84-3.74 (m, 2H); 0.80-0.75 (m, 2H); 0.67-0.65 (m, 2H).

Examplc 129

7-(4-chloro-2-lluorophcnyl)-4-(pyrimidin-2-ylmcthyl)-3,4dihydrobcnzo[f|[l,4|oxazepin-5(211)-onc (Compound 11-117)

|0548| Compound Π-117 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C20H15N3O2FCI as (M+H)⁺ 384.1 'H NMR (400MHz, dmso-d^. δ: 8.77 (d, J=5.2Hz, 2H), 7.87 (d, J=2.4Hz, 1 H), 7.66 (dd, J=2.4, 8.8 Hz, I H), 7.57-7.51 (m, 2H); 7.41-7.35 (m, 2H); 7.16 (d, J=8.0Hz, 1 H), 4.97 (s, 2H), 4.54-4.52 (m, 2H), 3.79-3.76 (m, 2H).

Examplc 130 pyrimidin-2-yl(7-(4-(trinuoromethoxy)phenyl)-2,3-dihydrobcnzo|f||l,4|oxazepin4(51l)-yl)mcthanonc (Compound III-1)

264 |0549| To a solution of 7-(4-(trifluoromethoxy)phcnyl)-3,4dihydrobenzo[f][l,4]oxazepîn-5(2H)-one (660 mgs, 2.0 mmol) in THF (6 mL), I.OM Borane in THF (6.0 mL, 6.0 mmol) was added and the mixture was heated at 70 °C. After I6h, the mixture was coolcd to rt and Methanoi (22 mL) and 6.0M HCl (22 mL) was added and stirred at rt for 2h. The reaction mixture was then concentrated and the solids formed were filtcred and washed with ether and dried to give 7-(4(triiluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepinc as HCl sait. The above compound (I00 mgs, 0.29 mmol), pyrimidine-2-carboxylic acid (47 mgs, 0.38 mmol), HATU (143 mgs, 0.38 mmol), in DMF (l mL) was added NMM (0.1 mL, 0.86 mmol) and stirred at 60 °C for 30inin.The reaction mixture was then diluted with EtOAc and washed with NaIICO₃, brine and dried (MgS(O).|). The mixture was the filtcred, concentrated and chromatographed (SiOi, 50% EtOAc/DCM) to provide the tille compound.

|(1550] MS found for C₂|H_J6F₃N₃O₃ as (M+Ilf 415.9. 'il NMR (400MHz, dmso-d,,): mixture of rotomers (-2:1): 'H-NMR (DMSO) of the major rotomer: δ 8.86 (d, >5.2Hz, 2H), 7.77 (d, >8.8 Hz, 2H), 7.75 (m, 1H); 7.69-7.54 (m, 2H); 7.47-7.40 (m, 2H); 7.11 (d, J = 8.0 Hz, 1H); 4.85 (s, 2H); 4.25-4.03 (m, 4H); 3.58-3.56 (m, 2H).

Example 131

7-cyclohexenyl-4-(pyrimidin-2-ylmctliyl)-3,4-dihydrobenzo|f][l,4|oxazcpin-5(2H)onc (Compound V-3)

[0551] Compound V-3 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. MS found for C2oH2iN₃0₃ as (M+H)⁺ 336.1.

Example 132

7-(4-methylcycloliex-1 -enyl)-4-(pyriniidin-2-ylmethyl)-3,4diliydrobenzo|f]|l,4]oxazcpin-5(2H)-one (Compound V-5)

265 (05521 Compound V-5 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C21H23N3O2 as (M+H)⁺ 350.1 *H NMR (400MHz, dmso-d₆)·. δ: 8.76 (d, J=5.2Hz, 2H), 7.65 (d, J=2.4Hz, l H), 7.53 (dd, J=2.4, 8.4 Hz, l H), 7.42-7.39 (m, l H); 6.98 (d, J= 84Hz, l H); 6,08 (m, l H); 4.94 (s, 2H), 4.44-4.42 (m, 2H), 3.69-3.67 (m, 2H); 2.36-2.23 (m, 4H); 1.81-1.66 (m, 5H); 1.3I-1.26 (m, IH).

Example 133

7-(4-cthylcyclohex-l-enyl)-4-(pyrimidin-2-ylmctliyl)-3,4dihydrobcnzo|f|[l,4|oxazcpin-5(2H)-one (Compound V-6)

[0553] Compound V-6 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS found for C22H25N3O2 as (M+H)⁺ 364.1 'H NMR (400MHz, dmso-d₆Y δ: 8.77 (d, J=5.2flz, 2H), 7.65 (d, J=2.4Hz, IH), 7.52 (dd, J=2.4, 8.4 Hz, IH), 7.42-7.38 (m, IH); 6.98 (d, J= 8.4Hz, 1 H); 6.09 (m, 1 H); 4.94 (s, 2H), 4.444.42 (m, 2H), 3.70-3.67 (m, 2H); 2.36-2.25 (m, 3H); 1.84-1.77 (m, 2H); 1.32-1.26 (m, 4H); 0.91-0.88 (m, 311).

Examplc 134 (R)-7-(4-mctliylcyclohcx-l-cnyl)-4-(pyrimîdin-2-ylmctliyl)-3,4dihydrobcnzo[f|| l,4]oxazepin-5(2II)-onc (Compound V-8)

|0554| The raccmic 7-(4-mcthylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-onc was separted using chiral préparative HPLC to give pure enantioiners of Compound V-8 and Compound V-9.

|0555| R-enantiomer: MS found for C21I I23N3O2 as (M+H)⁺ 350.1 À

266

Examplc 135 (S)-7-(4-mcthylcyclohex-l-enyl)-4-(pyrimidin-2-ylmcthyl)-3,4diliydrobenzo[f|[l,4[oxazepin-5(2H)-onc (Compound V-9)

|0556| Compound V-9 was prepared according to the Exemple above. S-enantiomer:

MS found for C21H23N3O2 as (M+H)⁺ 350.1

Examplc 136

3-(pyridin-2-ylmctliyl)-7-(4-(trifluoromctlioxy)plienyl)-3,4- dihydrobenzo[f|| l,4]oxazcpin-5(2H)-one (Compound II-I42)

[05571 Synthesis of 6-(4-(trifluoromethoxy)phenyl)chroman-4-one. See previous

Suzuki reaction conditions, m/z = 309.0

10558| Synthesis of 3-(pyridin-2-ylmethylene)-6-(4-(trilluoiOmethoxy)phcnyl)chroman4-one. A solution of 400mg 6-(4-(trifluoromethoxy)phenyl)chroman-4-one ( 1.3 mmol,

1.0 eq), 150 pL 2-pyridine carboxaklehyde ( 1.6 mmol, 1.2 eq) and 130 μL pyrrolîdinc (

1.6 mmol, 1.2 eq) in 10 mL éthanol was refluxed 3h. The reaction was concentrated and

267 purified on silica gel column eluting with EA:Hex. 160 mg of a yellow solid was collected. m/z = 398.0

[0559] Synthesis of3-(pyridin-2-ylmethyl)-6-(4-(trifluoromethoxy)phenyl)chroman-4one. A solution of 150 mg 3-(pyridin-2-ylmcthylene)-6-(4(trifluoromethoxy)phenyl)chroman-4-one (0.38 mmol) in 20 mL EtOH with calalytic Pd/C was stirred under 1 atm of hydrogen gas for 16 h. The reaction was filtered through celite and the filtrate concentrated. The filtrate was purified on silica gel column eluting with EA:Hex. 85 mg of an off-white solid was collected. m/z= 400.

[0560] Synthesis of3-(pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one. To a solution of 72 mg 3-(pyridin-2-ylmethyl)6-(4-(trifluoromethoxy)phenyl)chroman-4-one (0.18 mmol) in lmL methylsulfonic acid mg sodium azide (0.54 mmol) was added. After I h, reaction was diluted with 5 mL water and neutralized with addition of IN NaOH solution. The precipitate was filter off to afford 65 mg off-white powder of product. m/z= 415.0

Example 137

7-(4-(cyclobutylmethoxy)phenyl)-4-(pyriniidin-2-ylniethyl)-3,4diliydrobenzo|f][l,4|oxazepin-5(2H)-onc (Compound H-144)

[0561 ] Compound 11-144 was prepared according to example 25 using 2-(4(cyclobutylmethoxy)phenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane. MS found for

C25H25N3O3 as (M+H)' 416.22 *11 NMR (400MHz, dmso-d_fl): ¹ H-NMR (DMSO) δ: X

268

8.78 (d, J= 5.2Hz, 2H), 7.86 (d, J=2.0Hz, IH), 7.72 (dd, J=2.4-8.4Hz, IH), 7.54 (d, J=8.4Hz, 2H), 7.41 (t, J= 5.2Hz, l H), 7.09 (d, J=8.4Hz, IH), 6.99 (d, J=8.8Hz, 2H), 4.97 (s, 2H), 4.48 (t, 7=4.4Hz, 2H), 3.97 (d, 7=6.8Hz, 2H), 3.74 (t, 7=4.8IIz, 2H), 2.75-2.67 (m, IH), 2.09-2.03 (m, 2H), l.94-1.79 (m, 4H).

Example I38

4-(pyrimidin-2-ylmetliyl)-7-(6-(2,2,2-trifluoroethyl)pyridin-3-yl)-3,4dihydrobenzo|f|| l,4]oxazepin-5(2II)-one (Compound VI-24)

F

[0562] Compound VI-24 was prepared according to example 25 using 5-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)pyridine.

Example 139

7-(2-methyl-4-(trifluoromcthyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobcnzo|f||l,4|oxazepin-5(2H)-onc (Compound II-145)

10563] Compound 11-145 was prepared according to example 25 using 2-methyl-4(trifluoromethyl)phenylboronic acid. MS fourni for C22H18F3N3O2 as (M+H)* 414.32

Example 140

7-(2-mcthyl-4-(trifluoi'omethoxy)phcnyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobcnzo[f|| l,4|oxazcpin-5(2II)-one (Compound 11-146)

|0564] Compound II -146 was prepared according to example 25 using 2-methyl-4(trifluoromethoxy)phenylboronic acid. MS found for C22H18F3N3O3 as (M+H)* 430.19

269 ‘H NMR (400MHz, dmso-d₆): 'H-NMR (DMSO) 5: 8.77 (d, J= 5.2Hz, 2H), 7.64 (d,

J=2.4Hz, IH), 7.48 (dd, J=2.4-8.4Hz, lH), 7.40 (t, J=4.8Hz, lH), 7.31 (d, J= 8.4Hz, 2H), 7.23 (d, J=8.8Hz, IH), 7.11 (d, J=8.4Hz, IH), 4.96 (s, 2H), 4.52 (t, J=4.4Hz, 2H), 3.78 (t, J=4.4Hz, 2H), 2.25 (s, 3H).

Examplc 141

7-(4-(dilluorometliyl)phenyl)-4-(pyridin-2-yImetliyl)-3,4diliydrobenzo[f||l,4]oxazepin-5(21I)-onc (Compound Π-157)

|0565] Compound II -157 was prepared according to examplc 25 using 410 (difluoromethyl)phenylboronic acid. MS found for C22H18F2N2O2 as (M+H)⁺ 381.20 ‘H NMR (400MHz, dmso-da)’. 'H-NMR (DMSO) Ô: 8.54 (s, 111), 8.02 (s, 1 H), 7.85-7.80 (m, 4H), 7.65 (d, J=7.6Hz, 2H), 7.38-7.31 (m, 2H), 7.16 (d,J= 8.0Hz, 1 H), 7.08 (t, J=55.6Hz, 1 H), 4.87 (s, 2H), 4.40 (s, 2H), 3.71 (s, 2H).

Examplc 142

4-(pyridin-2-ylmethyl)-7-(2-(trifluoronicthyl)pyridin-4-yl)-3,4dihydrobcnzo[f||l,4|oxazcpin-5(2H)-onc (Compound VI-25)

[0566] Compound VI-25 was prepared according to examplc 25 using 4-(4,4,5,5tetramethyl-l,3,2-dîoxaborolan-2-yi)-2-(trifluoromethyl)pyridiiie. X

270

Examplc 143

7-(4-chloro-3“fluorophcnyI)-4-(pyridin-2-ylmethyl)-3,4dihydrobcnzo[f]| l,4|oxazepin-5(2H)-onc (Compound 11-158)

[0567| Compound 11-158 was prepared according to example 25 using 4-chloro-3fluorophenylboronic acid. MS found for C21H16CIFN2O2 as (M+H)⁺ 383.17 ^lH NMR (400MHz, dmso-dfi): 'H-NMR (DMSO) δ: 8.60 (d, J= 4.8Hz, IH), 8.01 (d, J=7.2Hz, IH), 7.94 (d, J=2.4Hz, IH), 7.79 (dd, J=2.4-8.4Hz, IH), 7.69 (dd, J= 2.0-Ι0.8Ηζ, IH), 7.617.47 (m, 4H), 7.09 (d, J=8.4Hz, 1 H), 4.90 (s, 2H), 4.36 (t, J=4.8Hz, 2H), 3.69 (t, >4.8Hz, 2H).

Examplc 144

7-(4-(difluoromethoxy)plienyl)-4-(pyridin-2-ylmctliyl)-3,4dihydi‘obcnzo[f||l,4]oxazcpin-5(211)-oiie (Compound 11-159)

[0568| Compound 11-159 was prepared according to example 25 using 2-(4(difluoromethoxy)plienyl)-4,4,5,5-tetramctliyl-l ,3,2-dioxaborolane. MS found for C₂₂H|_SF₂N₂O₃ as (M+H)⁺ 397.22.

Example 145

4-(pyiïdin-2-ylmetliyl)-7-(5-(trifluorometliyl)pyridin-2-yl)-3,4diliydrobcnzo|f|| l,4|oxazcpin-5(2II)-onc (Compound VI-26)

271 [0569] Compound VI-26 was prepared according to example 25 using 2-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine. MS found for C21HI6F3N3O2 as (M+H)⁺ 400.21.

Example 146

7-( 1-methy I-11I-pyrazol-4-yl)-4-(pyrimidin-2-y lmethyl)-3,4dihydrobcnzo[f||l,4|oxazepin-5(2II)-onc (Compound VI-27)

[0570] Compound VI-27 was prepared according to example 25 using l-methyl-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1 H-pyrazole.

Example 147

7-(l-isopropyl-lH-pyrazol-4-yl)-4-(pyrimidin-2-ylmetliyl)-3,4diliydrobenzo[f|| l,4|oxazepin-5(2II)-one (Compound VI-28)

|05711 Compound VI-28 was prepared according to example 25 using 1 -isopropyl-415 (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l H-pyrazole.

Example 148

7-( 1 -methyl-11I-pyrazol-3-yl)-4-(pyridin-2-ylmctliyl)-3,4diiiydrobenzo|i|| l,4|oxazepin-5(2H)-onc (Compound VI-29)

[05721 Compound VI-29 was prepared according to example 25 using 1 -methyl-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-IH-pyrazole.

272

Example 149

7-(2-Îsopropylthiazol-4~yl)-4-(pyridiri-2-ylnietliyl)-3.4-dihydrobenzo|f|| l,4|oxazcpin5(2II)-one (Compound VI-30)

(0573J Compound VI-30 was prepared according to example 25 using 2-isopropyI-4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)lhiazole. MS found for C21H21N3O2S as (M+H)⁺ 380.20 'H NMR (400MHz, dmso-dt): ‘H-NMR (DMSO) δ: 8.53 (d,7=4.8Hz,

H), 8.26 (d,7=2.0Hz, 1H), 8.01 (dd, 7=2.0-8.8 Hz, 1H), 7.94 (s, 1H), 7.78 (t, 7= 7.2Hz,

1H), 7.36-7.28 (m, 2H), 7.09 (d,7=8.0Hz, I H), 4.85 (s, 2H), 4.36 (t,7=4.4Hz, 2H), 3.66 (t, 7=4.8Hz, 2H), 1.36 (d, 7=6.8Hz, 6H).

Example 150

4-(pyrimidin-2-ylmctliyl)-7-(2,3,4-triiluoroplicnyl)-3,4dihydrobenzo|f||l,4|oxazcpin-5(2II)-one (Compound Π-162)

|0574| Compound II -162 was prepared according to example 25 using 2,3,4trifluorophcnylboronic acid. MS found for C20H14F3N3O2 as (M+H)⁺ 386.14.

Example 151

7-(3,4-difluorophenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f|| l,4]oxazepin5(2H)-one (Compound 11-163)

|0575| Compound II -163 was preparcd according to example 25 using 3,4diiluorophenylboronic acid. MS found for C20H15F2N3O2 as (M+I-I)' 368.15.

273

Example 152

4-(pyridin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4dihydrobenz.o[f||l,4]oxazcpin-5(2H)-one (Compound VI-31)

10576] Compound VI-31 was préparée! according to example 29 using 2-bromo-5(trifluoromethyl)thiophene. MS found for C20HI5F3N2O2S as (M+H)⁺ 405.16 '11 NMR (400MHz, dniso-d^: 'H-NMR (DMSO) δ: 8.53 (d, J= 4.8Hz, IH), 8.02 (d, J=2.0Hz, 1 H), 7.87-7.71 (m, 3H), 7.59 (d, J= 3.2Hz, I H), 7.37-7.28 (m, 2H), 7.13 (d, 8.4Hz, 1 H), 4.85 (s, 2H), 4.40 (t, J=4.8Hz, 2H), 3.70 (t, J-4.8Hz, 2H).

Example 153

7-(5-cyclopropylthiophcn-2-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f||l,4]oxazepin-5(2H)-one (Compound VI-32)

105771 Compound VI-32 was prepared according to example 29 using 2-bromo-515 cyclopropylthiopliene. MS found for C22H20N2O2S as (M+H)⁺ 377,18 'H NMR (400MHz, dmso-diï ¹ H-NMR (DMSO) δ: 8.53 (d, J= 4.8Hz, IH), 7.81-7.76 (m, 2H), 7.68 (dd, J=2.4-8.0Hz, 1 H), 7.36-7.24 (m, 3H), 7.04 (d, J= 8.4Hz, I H), 6.80 (d, J= 3.6Hz, 1 H), 4.84 (s, 2H), 4.34 (t, J=5.2Hz, 2H), 3.66 (t, J=5.2Hz, 2H), 2.14-2.10 (m, 1 H), 1.020,97 (m, 2H), 0.71 -0.67 (m, 2H). X

274

Example I54

7-(2-mcthylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4-dihydrobcnzo]f|| l,4]oxazepin5(2H)-one (Compound VI-33)

DMSO. Λ

O A_NBn

10578] Compound VI-33 was prepared according to example 29 using 4-bromo-2methylthiazole.

Examplc 155

4-bcnzyi-7-(4-(trilluoromctliyl)plicnyl)-3,4-dihydro-l il-benzo(c|[ l,4|diazepinc-2,5dîonc (Compound X-8)

F

[0579] A mixture of 5-bromoisatoic anhydride ( 1 g, 4J3mmol), N-benzylglycine (0.628g, 4.13mmol) and DMSO (3mL) was heated in the microwave at 200^l1C for one hour. Aller cooling, the mixture was diluted with water and the precipitate was filtered off, washcd with water and dried, giving 4-benzyl-7-bromo-3,4-dihydro-l Hbenzo[e][ 1,4]diazepine-2,5-dione ( 1.4g, 98%) as an off-while powder.

10580] 4-Benzyl-7-bromo-3,4-dihydro-1 H-benzo[e][ 1,4 |diazepine-2,5-dione ( 1.4g, 4.05mmol) was combincd with 4-(trif1uoromethyl)phenylboronic acid (0.77g, 4.05mmol), potassium carbonate ( I g) and [1,1'Bis(diphenylphosphino)fcrrocene]dichloropalladium(ll) (148 mg, 0.202 mmol) in 5mL DMF. Water (3mL) was added and the mixture was heated under nitrogen atmosphère at 80ⁿC for three hours. Aller cooling the mixture was diluted with etliyl acetate, washed witli water and brine, dried with magnésium sulfate and evaporated. Purification by silica

275 gel chromatography (20-100% ethyl acetate in hexane) followed by recrystallization gave

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-1 H-benzo[e][ 1,4]diazepine-2,5-dione (1.25g, 75%) as a white powder.

10581| ¹ H-NMR (DMSO) δ: 10.61 (s, 1H), 8.13 (d, J=1.6Hz, 111), 7.92 (d, J=8.4Hz,

311), 7.11 (d, J=8.4Hz, 2H), 7.36-7.25 (m, 5H), 7.22 (d, >8.4Hz, 1H), 4.79 (s, 2H), 3.92 (s, 2H). MS: 411 (MH*).

Examplc 156

4-bcnzyl-l-mctliyl-7-(4-(triiluoi-omethyl)plicnyl)-3,4-dihydro-lIIbenzo|c|| l,4]diazcpinc-2,5-dione (Compound X-l 1)

|0582] 4-Benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lH-benzo[e][l,4]diazepine2,5-dione (9.80 mg, 0.024 mmol) and K.₂CO₃ (10 mg, 0.072 mmol, 3.0 equiv.) were placed in a 0.5-2 mL Smith process vial under a nitrogen atmosphère. To the vial were added DMF (0.5 mL) and iodomethane (2.25 pL, 0.036 mmol, d = 2.28 g/cm³, 1.5 equiv) at room température. After heating, stirred, at 60”C for 2 hours, the reaction mixture was concentrated en vacuo. The resulting crude mixture was dilutcd with acetonitrile (1 mL), filtered through a syringe filter and injected into a préparative HPLC to give desired product (4-benzyl-l-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione, 1.8 mg) as a ycllow film.

[0583J ^fH-NMR (400 MHz; CD3CN) δ 8.16 (d, IH, J= 2 Hz), 7.93 (dd, 1H, J= 8.4 Hz, 2 Hz), 7.92 (d, 2H, J = 7.8 Hz), 7.82 (d, 211, J = 7.8 Hz), 7.47 (d, 1 H, ./ = 8.4 Hz), 4.98 (d, 111,./ = 15 Hz), 4.73 (d, IH,J = 15 Hz), 4.10 (d, 1H,J= 15 Hz), 3.70 (d, 1H, J= 15 Hz), c/

276

3.37 (s, 3H). ^I9F-NMR (400 MHz; CD₃CN) δ -63.96 (s, 3F). LCMS (El: 70 eV) 447.1 (M++Na), 425.1 (M++I).

Example 157 (S)-3-(2-hydroxyethyl)-l-mcthyl-7-(4-(trifliioromethoxy)phenyl)-3,4-dihydro-lll benzo[e]|l,4|diazepme-2,5-dione (Compound X-l)

[05841 2-Amino-5-iodobenzoic acid ( 1.327 g, 5.05 mmol), 4-trifluoromethoxyboronic acid (1.455 g, 7.07 mmol, 1.4 equiv.), Pd(dppf)CI₂-CH₂Cl₂ (183.0 mg, 0.252 mmol, 5 mol%) and K₂CO₃ ( 1.604 g, 11.61 mmol, 2.3 equiv.) were dissolved in a mixture of H20/toluene/i-PrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL Smith process vial equipped with a stir bar under a nitrogen atmosphère. The mixture was heated at 90°C for 1 hour. After aqueous workup and reinoval of volatile solvents en vacuo, the mixture was purified by automated silica-gel column chromatography using an EtOAc/hexane gradient as the eluent. The purification gave the desired product (4-amino-4'-(trilluoromethoxy)biphenyl3-carboxylic acid, 462.0 mg) as a colorless powder.

|05851 To a suspension of 4-ainino-4'-(trilluoromethoxy)biphenyl-3-carboxylic acid (462.0 mg, 1.554 mmol) in CH₂C1₂ (10 mL) in a round bottomed flask was added triethylamine (210pL, 1.492 mmol, d = 0.726 g/cm , 0.96 equiv.). Flask was charged with nitrogen, cooled to 0*’C and a solution of triphosgene (148.0 mg, 0.497 mmol, 0.32 equiv.) in 2 mL DCM was added, followed by a solution of N,N-dimethyl-4-aminopyridine (30 mg, 0.246 mmol, 25 mol%) in CI I₂C1₂ (2 mL). Reaction mixture was allowed to stir 2 hours, then quenched with a small portion of IN HCl. Reaction mixture with resulting precipitate was filtered through a disposai! le fl lier funnel and air-dried to give desired

277 product (6-(4-(trifluoromethoxy)phenyl)-lH-benzo[d][l,3]oxazine-2,4-dione, 348.6 mg) as a colorless solid.

105861 6-(4-(Trifluoromethoxy)phenyl)-1 H-benzo[d][ l ,3]oxazine-2,4-dione (348.6 mg,

1.077 mmol) and K.₂CO₃ (228 mg, 2.153 mmol, 2 equiv.) were placed in a 0.5-2 mL Smith process vial. To the vial was added DMF (3 mL) and iodomethane (101 pL, d = 2.28, 1.615 mmol, 1.5 equiv.) at ambient température. The mixture was stirred ovemight at room température and then iiltered through a disposable fiiter funnel. Obtained filtrate was diluted with water to form précipitâtes, which were collected on a disposable fiiter tunnel and allowed to air-dry to give desired product (l-methyl-6-(4(trifluoromethoxy)phenyl)-lH-benzo[d][l,3]oxazine-2,4-dione, 357.2 mg) as a colorless solid.

105871 1 -Methyl-6-(4-(trifluoromethoxy)phenyl)-l H-benzo[d][ l,3]oxazîne-2,4-dione (60 mg, 0.178 mmol) and L-homoserine (23.3 mg, 0.196 mmol, 1.1 equiv.) were added to a magnetically stirred 0.5-2 mL Smith process vial containing 0.75 mL glacial acetîc acid. Reaction mixture was then heated for 2 hours at 130“C. Excess acetîc acid was then removed en vacuo, residue was dissolved into a minimal amount of acetonitrile and purificd by reverse-phase préparative HPLC to give the tille compound (7.6 mg) following removal of solvent as a clear yellow film.

|0588| LCMS (El: 70 eV) 459.1 (M++Na), 437.1 (M++1)

Example 158 l-methyl-7-(4-(trifliioromethoxy)phenyl)-3,4-dihydro-lH-benzo|e]|l,4|diazcpine-2,5dione (Compound X-2) ‘0

Br.

|0589| 6-Bromo-lIl-benzo[d]| l,3]oxazine-2,4-dione (5.0 g, 20.66 mmol), iodomethane:

(1.94 mL, d = 2.28, 4.4 g, 31.0 mmol, 1.5 equiv.) and Na₂CO₃ (4.38 g, 41.3 mmol, 2

278 equiv.) were placed in a round bottomed flask. To the flask were added DMF (40 mL) at ambient température. The mixture was stirred ovemight at room température and then filtered through a glass filter. Obtained filtrate was diluted with water to form précipitâtes. The précipitâtes were dissolved in EtOAc and the solution was dried over MgS(O)4. The solvent was removed under reduced pressure. At this point, since the conversion was ~50%, K.2CO3 (14.3 g, 103.3 mmol, 5 equiv.) and iodomethane (2.58 mL, d = 2.28, 4I.3 mmol, 2.0 equiv.) were added to the solution of the crude material in DMF. The mixture was heatcd at 30°C so that the reaction can go to complction and then filtered through a glass filter. Obtained filtrate was diluted with water to form précipitâtes. Formed précipitâtes were filtered through a glass filter to give the desired product (6-bromo-lmethyl-IH-benzo[d][l,3]oxazine-2,4-dione). This was used for the subséquent step without further purification.

|0590| 6-BromO“l-methyl-lH-benzo[d][],3]oxazine-2,4-dione(5.29 g, 20.66 mmol) and glycine ( 1.7 g, 22.73 mmol, l. I equiv.) were dissolved in AcOH (100 mL) in a round bottomed flask. The mixture was heated under reflux conditions for 2 hours. The mixture was purified by automated silica-gel column chromatography using EtOAc/hexane gradient as the eluent. The purification give the desired product (7-bromo-l-methyl-3,4 dihydro-l H-benzo[e][l,4]diazepine-2,5-dione, colorless powder, 446.7 mg).

105911 7-Bromo-1-methyl-3,4-dihydro-l H-benzo[e][l,4]diazepine-2,5-dione (446.7 mg, I.66I mmol), 4-trifluoromethoxyboronicacid (445.0 mg, 2.159 mmol, 1.3 equiv.) Pd(dppf)Cl₂-CH₂Cl2 (l 20.0 mg, 0.166 mmol, 10 mol%) and K₂CO₃ (482.0 mg, 3.49 mmol, 2.1 equiv.) were dissolved in a mixture of H2O/toiuene/LPrOH (2.5 mL: 5 mL: 2.5 mL) in a 10 mL round bottomed flask under a nitrogen atmosphère. The mixture was heated at 60°C for 64 hours. The mixture was purified by automated silica-gel column chromatography using EtOAc/hexane gradient as the eluent. Evaporation of solvent en vacuo gave the title compound (415.0 mg) as a white powder.

[0592] LCMS (El: 70 eV) 373.I (M++Na), 35l.l (M++l)

279

Exaniple 159 l-nicthyl-4-(pyrimidin-2-ylniethyl)-7-(4-(tnfluoromethoxy)phenyl)-3,4-dïhydro-lHhcnzo|e]| l,4]diazepine-2,5-dîone (Conipound X-3)

10593] l-Methyl-7-(4-(tritluoiOmethoxy)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (22.9 mg, 0.065 inmol) and NaH (15.6 mg, 0.650 mmol, 10.0 equiv.) were placed in a 0.5-2 niL Smith process vial. To the vial was added DMF (0.5 mL) followed by 2-(chloromethyl)pyrimidine hydrochloride (53.9 mg, 0.327 mmol, 5 equiv.) was added at room température. After stirring for 50 min, reaction was quenched with AcOH. Resulting mixture was filtered and purified via préparative reverse phase HPLC to give the title compound (2.2 mg) as a clear yellow film.

|0594| LCMS (El: 70 eV) 443,1 (M++1)

Exaniple 160 l-nicthyl-4-(pyridin-2-ylnietliyl)-7-(4-(trifluoroniethoxy)phenyl)-3,4-diliydro-1Hbenzo|e|[l,4|diazepine-2,5-dione (Conipound X-4) ]05951 Conipound X-4 was prepared according to the above cxample using the appropriate starting materials. J

280

Example I6l

4-(4-( lH-pyrazol-l-yl)benzyl)-l-mcthyl-7-(4-(trittuoromethoxy)phenyl)-3,4-dihydrol H-benzo|cJ[l,4|diazepiiie-2,5-dione (Conipound X-6)

[0596] Conipound X-6 was prepared accordîng to the above example using the appropriate starting materials.

Example 162

l-(4-nietlioxybenzyl)-7-(4-(trifluorometlioxy)plicnyl)-3,4-dihydro-l Hbenzo|e|| l,4]diazepine-2,5-dione (Conipound X-5)

[0597] 7-Bromo-3,4-dihydro-1 H-benzo[e][ 1,4]diazepine-2,5-dione (510.0 mg, 2 mmol) and Cs₂CO₃ (1.955 mg, 6 mmol, 3 equîv.) were placed in a round bottomed flask. To the réaction vessel was added DMF (10 mL) and 4-methoxybenzyl chloride (273 pL, 1.615 mmol, d = 1.15 g/mL, I equiv.) at ambient température. The mixture was stirred overnight at room température and then filtered through a disposable filter funnel. Resulting filtrate was concentrated en vacuo and purified by automated silica-gel column chromatography using an EtOAc/hexane gradient as the eluent to give the desired product (7-bromo-l-(4-methoxybenzyl)-3,4-dihydro-IH-benzofe][ l,4]diazepine-2,5-dione, 378.3 mg) as a colorless solid. q/

281 |0598| 7-Bromo-l-methyl-3,4-dihydro-IH-benzo[e][ 1,4]diazepine-2,5-dione (375.0 mg, l.007 mmol), 4-trifluoromethoxyboronic acid (270.0 mg, l.3l mmol, 1.3 equiv.) Pd(dppf)Cl₂-CH₂Cl₂ (72.9.0 mg, O.lOl mmol, 10 mol%) and K₂CO₃ (292.0 mg, 2.116 mmol, 2.1 equiv.) were dissolved in a mixture of H₂O/tolucne/i-PrOH ( l .25 mL: 2.5 mL:

1.25 mL) in a 2-5 mL Smith process vial equipped with a stir bar under a nitrogen atmosphère. The mixture was heated at 50°C for 17 hours. After aqueous workup and removal of volatile solvents en vacuo, the mixture was purified by automated silica-gel column chromatography using an EtOAc/hexane gradient as the eluent. The purification gave the title compound (419 mg) as a colorless powder.

|0599] LCMS (El: 70 eV) 479.1 (M++Na), 457.1 (M++l)

Examplc 163

4-bcnzy)-7-(4-(trifluoromethoxy)plicnyl)-3,4-dihydropyrido[4,3-f]|l,4|oxazepin5(21I)-onc (Compound XII-1)

Pd(dppf)CI2 Tol/isopropanol/H20 85 C. 2h

(0600] To 2-bromo-5-fluoroisonicotinic acid (5 g, 22.72 mmol) benzyl amino éthanol (4.20 g, 27.27 mmol, 1.2 eq) was added in the presence of EDCI (5.2 g, 27.27 mmol, 1.2 eq) in dichloromethane ( 100 mL) and stirred at room température for 4h. The reaction mixture was diluted with dichloromethane, washed with water, brine, dried over sodium sulfate and concentrated (5.0 g). The residue (5.0g, 14.16 mmol) was cyclized by X

282 dissolving ΐη DMF (20 mL), sodium hydride (1.2 g, 28 mmol) was added and stirred at room température for 2h. The réaction mixture was neutralized with dil. HCl and extracted with ethyl acetate, washed with watcr, brine, dried over sodium sulfate and concentrated. Purified by flash chromatography furnished 4.4 g of the cyclized product.

10601 ) The Suzuki coupling was performed under standard conditioncd explained in the other procedures using Pd(dppf)CI₂. Mass (M+H)⁺ 415.1. CDC1₃: 8.46 (S, 1 H), 8.28 (S, 1 H), 8.05 (d, J = 8.8 Hz, 2H), 7.42-7.32 (m, 5H), 7.30 (d, J = 8.0 Hz, 2H), 4.86 (s, 2H), 4.31 (t, J = 4 Hz, 2H), 3.57 (t, J = 4 Hz, 2H)

Examplc 164

4-(cyclopropyImcthyl)-7-(4-(trifluoi'omcthoxy)plicnyl)-3,4-dihydropyrido|4,3f][l,4|oxazcpin-5(2H)-one (Compound XI1-9)

XII-4 XI1-9 (06021 Alkylation of the amide was performed using sodium hydride following the standard procedure to provide Conipound XlI-9. Mass (M+H)⁺ 379.0.

Examplc 165

4-(pyiimÎdin-2-ylmcthyl)-7-(4-(trifluoiOmethoxy)phcnyl)-3,4-dÎhydropyrido|4,3f|(l,4|oxazcpin-5(2II)-onc (Compound XII-5)

|0603] Compound XI1-5 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)' 417.0.

283

Examplc 166

4-((3-mcthoxypyndin-2-yl)mcthyl)-7-(4-(tnfluoromethoxy)phenyl)-3,4dihydropyrido(4,3-f|[l,4|oxazepin-5(2H)-onc (Compound XII-10)

[06041 Compound XII-10 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 446.1. CDCl₃: 8.55 (s, 1 H), 8.41 (s, 1 H), 8.22 (s, I H), 7.97 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 2.8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.12 (s, 2H), 4.55 (t, J = 4 Hz, 2H), 4.03 (s, 3H), 3.89 (t, J = 4 Hz, 2h).

Examplc 167

4-((4-mcthylpyrimidin“2-yl)methyl)-7-(4-(trifluoromcthoxy)phenyl)-3,4dihydropyrido|4,3-f]|l,4|oxazcpin-5(2H)-one (Compound XII-8)

|06051 Compound X11-8 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 431.1. CDCI₃: 8.54 (d, J = 4.8 Hz, 1 H), 8.50 (s, I H), 8.32 (s, 1 H), 80.2 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 83.4 Hz, 2H), 7.08 (d, J = 5.2 Hz, 1 H), 5.05 (s, 2H), 4.72 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 4.4 Hz, 2H), 2.52 (s, 3H).

Examplc 168

4-((3-iluoropyridin-2-yl)mcthyl)-7-(4-(trifiuoromcthoxy)plicnyl)-3,4dihydropyrido|4,3-f][l,4]oxazepin-5(211)-onc (Compound XII-11)

284 [0606] Conipound XIΙ-l I was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 434.0. CDCl₃: 8.42 (s, IH), 8.30 (d, J = 4.4 Hz, IH), 8.23 (s, IH), 7.96 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 8.4 Hz, JH), 7.22 (d, J = 8 Hz, 2H), 7.21 (d, J = 8.4 Hz, l H), 4.99 (s, 2H), 4.53 (t, J = 4.4 Hz, 2H), 3.78 (t, J =

4Hz, 2H).

Example 169

4-((4-inethoxypyriiiiîdin-2-yl)inethyl)-7-(4-(trinuoromcthoxy)plienyl)-3,4dihydropyrido|4,3-f| [ 1,4]oxazcpin-5(2I I)-onc (Conipound XII-14)

[06(>7| Conipound XI1-14 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)¹ 447.1.

Example 170

4-benzyl-9-fIuoro-7-(4-(trifluoromcthoxy)phenyl)-3,4-diliydrobenzo[fH l,4]oxazepin5(21l)-one (Conipound 11-165)

11-165

285 |0608| Compound II -165 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. Mass (M+H)⁺ 432.1. CDCI₃:7.80 (s, l H), 7.53 (d, J = 8.8 Hz, 2H), 7.37 (dd, J l = 2.4 Hz, J2 = 11.2 Hz, II I), 7.31 (d, J = 4 Hz, 2H), 7.29-7.20 (m, 5H), 4.79 (s, 2H), 4.21 (t, J = 5.2 Hz, 2H), 3.47 (t, J = 5.2 Hz, 2H).

Example 171

4-beiizyl-9-fluoro-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobcnzo|f|| l,4|oxazepin5(2H)-one (Compound 11-166)

F

|0609| Compound 11-166 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. Mass (M+H)⁺ 416.1. CDCI₃:7.87 (s, 1 H), 7.63 (s, 4H), 7.42 (dd, J1 = 1.6 Hz, J2 = 10.8 Hz, 1 H), 7.32 - 7.24 (m, 5H), 4.79 (s, 2H), 4.22 (t, J = 5.2 Hz, 2H), 3.48 (t, J = 5.2 Hz, 2H).

Example 172

4-benzyl-8-nuoro-7-(4-(tnfluoiOmethoxy)pheiiyl)-3,4-diliydrobenzo|i|| l,4|oxazepin5(2II)-one (Compound 11-167)

286

[0610] Compound 11-167 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)* 432.1. CDCh:8.07 (d, J = 9.2 Hz,

IH), 7.58 (d, J = 7.6 Hz, 2h), 7.40 - 7.32 (m, 5H), 7.28 (d, J = 8.4 Hz, 2H), 6.81 (d, J =

11.2 Hz, IH), 4.84 (s, 2H), 4.24 (t, J = 4.8 Hz, 2II), 3.54 (t, J = 4.8 Hz, 2H).

Example 173

4-benzyI-8-fluoiO-7-(4-(trifluoi'omethyl)phenyl)-3,4-diliydrobenzo[f|| 1,4]oxazcpin5(21I)-one (Compound 11-168)

11-168 |0611| Compound II -168 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 416.1. CDCIî:8. 11 (d, J = 9.2 Hz,

H), 7.74 - 7.64 (m, 4H), 7.40 - 7.30 (m, 5H), 6.83 (d, J = 11.6 Hz, I H), 4.85 (s, 2H),

4.26 (t, J = 4.8 Hz, 2H), 3.56 (t, J = 4.8 Hz, 211). ¢/

287

Example 174

4-benzyl-7-(4-(trifluoronicthoxy)phcnyl)-3,4-diliydropyndo|2,3-f||l,4|oxazcpin5(2H)-one (Compound XI1-2)

OH

XII-2 [0612] Compound XII-2 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 415.1. CDCI₃: 8.09 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1 H), 7.46 (d, J = 8.8 Hz, 1 H), 7.44-7.32 (m, 5H), 7.30 (d, J = 8 Hz, 2H), 4.91 (s, 2H), 4.18 (t, J = 5.2 Hz, 211), (t, J = 5.2 Hz, 2H).

Example 175

4-benzyI-7-(4-(trifluorometliyl)phcnyl)-3,4-diliydropyrido|2,3-f||l,4]oxazepin-5(2II)one (Compound XI1-3)

288

|0613| Compound XII-3 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)* 399.1. CDClj: 8.18 (d, J = 8.4 Hz,

2H), 7.84 (d, J = 8.4 Hz, I H), 7.71 (d, J = 8Hz, 2H), 7.48 (d, J = 8 Hz, l H), 7.46-7.30 (m, 5H), 4.91 (s, 2H), 4.20(t, J = 5.2 Hz, 2H), 3.54 (t, J = 5.2 Hz, 2H).

Examplc 176

4-(pyrimÎdin-2-ylmcthyl)-7“(4-(triiluoromcthoxy)phcnyl)-3,4-dihydropyrido[2,3f||l,4]oxazepin-5(2H)-onc (Compound XI1-6)

Xll-6 [06141 Compound XII-6 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁴ 417.0. ¢/

289

Example 177

4-(pynmidin-2-yImcthyI)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydropyrido[2,3fl| l,4|oxazcpin-5(2H)-onc (Compound XII-7)

XII-3

XII-7 |06l5] Compound XII-7 was prepared according to the Examples disclosed herein using the appropriate starting materials. Mass (M+H)⁺ 401.0.

Example 178

2,2,3,3-tetradeutero-4-(pyrimidin-2-ylmediyl)-7-(4-(trilluoromcthoxy)pIienyl)-3,410 dîhydrobenzo[f||l,4]oxazcpin-5(2Il)-onc (Compound 11-174)

290

Step 1

DD [ Ο Ο I ηΛ^{0Η +}

DD _n I O DD ^s,ep2 AAnV^h ^H &

Step 3

Step 5

Toluene/Et3N

MeOH

O

|0616] Step l : To a solution of 2-aminoethanol (2.0 g, 30 mmol) in methanol (50 mL) at 0 °C, Boc?0 (6.0 g, 27 mmol) was aildcd slowly and the reaction mixture was stirred at

r.t. for 2h. Concentrate the reaction mixture to remove methanol, the residue was dissolved in ethyi acetate, the organic layer was washed with brine, dried over sodium sulfate and concentrated to get the Boc protected amino éthanol (5.0 g) and used directly for the next reaction.

[0617] Step 2: To a solution of DABCO (5 g, 45 mmol) in toluene (50 mL), N-Boc-210 aminoethanol (5 g, 30 mmol) in toluene was added at room température. The reaction mixture was cooled to 0 ⁽⁾C and benzenesulfonyl chloridc (5.8 g, 33 mmol) was added slowly and stirred at room température for 2h. Water was added to the reaction mixture, adjust the pH of the mixture to 2~3 by adding 6N HCl. The organic layer was separatcd, washed with water, sodium bicarbonate, water and brine. Dried over sodium sulfate and concentrated to get an oily product (6.0 g, 70% yield from two steps) which was used directly for the next step.

[0618| Step 3: To a solution of protected aminoethanol (6 g, 19.5 mmol) in DMF (20 mL) methyl 5-bromo-2-hydroxybenzoate (3 g, 13 mmol) was added followed by c/

291 potassium carbonate (3.58 g, 26 mmol) and heated the mixture at 70 °C for 4 h. Solvent was distilled off, the residue was treated with ethyl acetate. The organic layer was washed with water, brine and concentrated to give an oily product (4 g, 81%) and is used for the next step.

|0619J Step 4: To the above oily product in methanol (10 mL) at room température HCl in methanol (2 ml in 10 mL) was added and heated at 70 °C for 2h. Solvent was distilled off, the residue was treated with ether, filtered the precipitate. The product obtained (2.5 g, 85%) is used for the cyclization step.

[0620] Step 5: To the above product (2.5 g, 9 mmol) in toluene ( 10 mL), triethylamine (4 ml, 36 mmol) was added and heated at 105 C for 48 h, until the LC-MS no starting material. The reaction mixture was cooled, diluted with methylene chloride, separated the organic layer. Add water to the organic layer and treated with 6N HCl, to adjust the pl i 2. The organics were washed with water, brine and dried and concentrated. The residue was treated with dichloromethane and hexane and lîltered the product 178-A (2.0 g, 90% yield).

178-B

N-—'

178-D

B(OH)₂

[06211 Suzuki: To thebromide 178-A (2 g, 8.16 mmol, l eq), boronic acid 178-IÏ (2.5 g, 12.2 mmol, 1.5 eq) and potassium carbonate (3.4 g, 24.48 mol, 3 cq) in a round bottom llask, solvent (60 mL. toluene/isopropano/water : 2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst Pd(dppf)CL (142 mg, 0.16 mmol, 0.02 eq) was added and heated at 85 C for 2h. The réaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hcxane as eluent provided 178-C (2 g, 75% yield). J

292

106221 Alkylation: To a solution of 178-C (2 g, 6.12 mmol, 1 eq.) chloromethyl pyrimidine 178-D (1.5 g, 9.17 mmol, 1.5 eq.) in DMF (10 mL), NaH (60% dispersion in oil) (600 ing, 25 mmol, 4 eq.) was slowly added at room température (slightly exothermic) and stirred at r.t. for 30 min. The reaction mixture was treated with few drops of HCl, diluted the réaction mixture with ethyl acetate and treated with water. The organic layer was separated, washed with brine, dried and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound 11-174 (1.8 g, 70% yield). Mass (Μ i H)⁺ 420.1. CDC1₃:8.65 (d, J = 5.2 Hz, 2H), 8.10 (s, 1 H), 7.58-7.50 (m, 3H), 7.18 (d, J = 8 Hz, 2H), 7.14 (t, J = 5.2 Hz, 1 H), 7.02 (d, J = 8.4 Hz, IH), 5.02 (s, 2H).

Examplc 179

4-((3-methyloxctan-3-yl)nietliyl)-7-(4-(trifluoromctlioxy)phcnyl)-3,4dihydrobenzo] l | 11,4]oxazcptn-5(211 )-onc (Compound 11-1 )

|(>623] 4-((3-Methyloxetan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one was prepared according to Example 25 using 3(bromomethyl)-3methyioxetane.

[0624] 'H-NMR. (400 MHz, DMSO) 1.305 (s, 3H), 3.618-3.643 (m, 2H), 3.750 (s, 2H), 4.183-4.198 (d, 211,7 = 6 Hz), 4.346-4.322 (t, 2H, 7, = 4.8 Hz), 4.563-4.577 (d, 2H, 7, = 5.6 Hz), 7.109-7.131 (d, 111,7= 8.8 Hz), 7.413-7.433 (s, 211,7=8 Hz), 7.752-7.786 (m, 3I-I), 7.878-7.883 (d, 1 H, 7 = 2 Hz), MS m/z 407.1 (M⁺).

293

Example 180

4-((3-((2-oxopyrrolidin-l-yl)mcthyl)oxetan-3-yl)methyl)-7-(4(trilluoromctlioxy)phenyI)-3,4-dihydrobenzo|f][l,4]oxazepm-5(2H)-one (Compound 11-108)

O

11’74

]0625| Compound 180-A and Compound 11-108 was prepared according to Example using (3-(bromomethyl)oxctan-3-yl)metliyl methanesulfonate.

Example 181

4-(2“(2-oxopyn'olidin-l-yl)cthyl)-7-(4-(trifluoroniethoxy)phcnyl)-3,4dihydrobenzo|f|[l,4|oxazepin-5(2H)-oiic (Compound 11-116)

[0626| Compound 11-116 was prepared according to Example 25 using l-(2bromoethyl )pyrrol i d i n-2-o ne.

294

Examplc I82

7-(2-methoxypyrimidm-5-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo|f|[l,4Joxazepin-5(2H)-one (Compound VI-7)

40-B

VI-7 [0627| 40-B (0.405 mmol), potassium carbonate (l 11 mmol) and Palladium chloride dppf catalyst (0.05 mmol) were combined in a mixture of toluène (3 mL), isopropanol ( l mL) and water ( l mL). The resultïng suspension was heated at 85 degrees for 2 hours.

The reaction mixture was concentrated down and diluted with ethyl acetate and filtered through celite. The filtrate was washed with water. The organic layer was purifîed by prep HPLC and prcp TLC to afford Compound VI-7.

Examplc 183 l-(4-(5-oxo-4-(pyrimidin-2-ylmctliyl)-2,3,4,5-tctrahydrobcnzo| f| [ 1,4] oxazepin-7I5 yl)piicnyl)cyclopropanccarbonitrile (Compound 11-109)

[0628| Compound 11 -109 was prepared according to the Examples disclosed herein using the appropriate starting materials.

295

Examplc I84

N-(2-(5-oxo-4-(pyrimidin-2-ylmcthyl)-2,3,4,5-tetrahydrobenzo|f|[l,4]oxazcpin-7-yl)5-(ti'ifluoromcthoxy)phcnyl)acctamidc (Compound 11-111)

[06291 Compound 11-111 was picparcd according to the Examples disclosed herein using the appropriate starting materials.

Examplc 185

7-(2”(4-methylpipcrazin-l-yl)pyrimidiii-5-yl)-4-(pyrimidin-2-ylmctbyl)-3,4diliydrobcnzo|f|[l,4|oxazcpin-5(2H)-onc (Compound VI-14)

|0630| Compound VI-14 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 432.2 (M⁺).

Examplc 186

4-(pyrimidin-2-ylmethyl)-7-(2-(2,2,2-trifluoroethylamino)pyrimidin-5-yl)-3,415 dihydi’obcnzo[f|| l,4|oxazcpin-5(2II)-onc (Compound VI-15)

|0631 J Compound VI-15 was prepared according to the Examples disclosed herein using the appropriate starting materials. J

296

Exaniple 187

7-(6-morpholinopyridin-3-yl)-4-(pyrimidin-2-ylniethyl)-3,4dihydrobenzo|f|[l,4]oxazepîn-5(2H)-one (Conipound VI-16)

[0632] Conipound VI-16 was prepared according to the Examples disclosed herein using the appropriate starting materials.

Exaniple 188

N“(2-(5“OXO-7-(4-(trifluoiOnietlioxy)plienyl)-2,3-dihydrobenzo[f]|l,4|oxazepin-4(5H)-

yl)ethyl)etliancsulfonaniide (Conipound 11-178)

THFMeOH 1B8-B

|0633| 11-74 (1.04 mmol) and NaH (3.13 mmol) was stirred in THF (6mL) at 0 degrees under nitrogen. Bromoacetonitrile was added dropwise. The resulting reaction mixture was allowed to slowly warm up to room température over the period of’2 hours after which time the reaction mixture was quenched witli water and then extracted with dichloromethane. The organic layer was purified by prep HPLC to afford 188-A.

|0634| 188-A (0.635 mmol) was dissolved in a mixture of THF:McOH (4:6 mL). To this was added cobalt chloride (2.49 mmol) and di-tert-butyldicarbonate (1.26 mmol)

297 under nitrogen follow by addition ofsodium borohydride (0,762 mmol). The resulting mixture was stirred at ambient température overnight. The mixture was filtered through celite and washed with 9:l mixture of Me0H/FI₂O. The filtrate was washed with saturated NaIICO₃ and then extracted with ethyl acetate. The organic layer was dried over Na₂S(O)4 and concentrated down to afford 188-B as an oil which was used without further purifications to make 188-C.

[0635] 188-B (200 mg) was combined with TFA (9 mL) and 1I₂O (1 mL) and stirred under nitrogen for 2 hours. The reaction mixture was concentrated and used without further purifications to make Conipound 11-178,

10636| A solution of 188-C (25mg) in dicholoromethane (3 mL) was chilled in an ice balh. To tins was added triethylamine (0.1 mL) followed by ethanesul fonyl chloride (0.05 mL). The reaction mixture was stirred under cold conditions for 2 hours after which it was quenchcd with water. The mixture was extracted with dichloromethane and purified by prep HPLC to afford Conipound 11-178. MS m/z 459.1 (M⁺).

Example 189

N-(2-(5-oxo-7-(4-(tntluoromcthoxy)phcnyl)-2,3“dihydrobenzo|f]|l,4|oxazcpin-4(5H)yl)ctliyl)cyclopi’opancsulfonaniide (Conipound 11-179)

O _ Il '0 |0637] Conipound 11-179 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 471.1 (M * ). çJ

298

Example 190

4-fiuoro-N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3dihydrobenzo|f|[l,4]oxazepin-4(5H)-yl)cthyl)benzcncsulfonaniide (Compound II-

[06381 Compound II-181 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 525.1 (M⁺).

Example 191

N-(2-(5-oxo-7-(4-(trifluoroniethoxy)phcnyl)-2,3-dihydrobenzo[f|[l,4|oxazepin-4(5H)yl)cthyl)cyclopentanesulfonamidc (Compound 11-183)

[0639] Compound 11-183 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 499.1 (M⁺).

Examplc 192 l-nicthyl-N-(2-(5-oxo-7-(4-(trifluoromcthoxy)plicnyl)-2,35 dihydrobenzo[f] 11,4|oxazepin-4(5H)-yl)ethyl)-1 H-imidazole-2-sulfonamide (Compound 11-184)

|0640| Compound Π-184 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 511.1 (M⁴). cX

299

Example 193

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo|f||l,4|oxazepin-4(5H)yl)cthyl)benzencsulfonamidc (Compound 11-177)

[06411 Compound 11-177 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. MS m/z 507.1 (M⁺).

Example 194

N-methyl-N-(2-(5-oxo-7-(4-(trinuoromctboxy)plicnyl)-2,3“ dihydrobcnzo|f|| l,4|oxazcpin-4(5II)-yl)cthyl)bcnzcnesulfonamide (Compound 11-

[0642] Compound 11-182 was prepared according to Example 25 using iodomethane and Compound 11-177.

Examplc 195

N-(2-(5-oxo-7-(4-(trifluo!'omcthoxy)phcnyl)-2,3-diliydrobenzo|f||l,4|oxazcpin-4(5H)yl)etliyl)-2-(pyrimidin-2-yl)acetamide (Compound 11-185)

300

DMF

[0643] 188-C (0.054 mmol) was dissolvcd in DMF (3mL) follow by addition of HATU and DIPEA. The resulting mixture was stirred at room température for 3 hours after which water was added and extracted with dichloromethane. The organic was purified by prep HPLC to afford Compound II-185.

Examplc 196

4-((5-cyclopropyl-l,3,4-oxadiazol-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobcnzo[f|| l,4)oxazepin-5(2II)-one (Compound 11-68)

|0644| Compound 11-68 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 446.1 (M+H).

Example 197

4-(pyridin-4-ylmcthyl)-7-(4-(trilluoromcthoxy)phcnyl)-3,415 dihydrobcnzo|f|[l,4|oxazcpin-5(2H)-onc (Compound 11-67)

[0645J Compound 11-67 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 415.1 (M+H). J

301

Example 198

4-((5-chIoropynmidin-2-yl)methyl)-7-(4-(trïfluoromethoxy)phenyl)-3,4dihydrobenzo|f|| 1,4|oxazepin-5(2ll)-onc (Compound 11-65)

10646] Compound 11-65 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 450.0 (M+H).

Example 199

4-((l-methyl-llΊ-pyrazol-3-yl)metllyl)-7-(4-(trifluoromet^loxy)pllenyl)-3,4dihydrobcnzo|f||l,4|oxazcpin-5(2H)-one (Compound 11-64)

10647| Compound 11-64 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 418.1 (M+H).

Example 200

4-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydiObenzo|f][ l,4|oxazcpin-5(2II)15 one (Compound 11-46)

|0648| Compound 11-46 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 338.1 (M+11).

302

Example 201

4-(3,4-difluorobcnzyl)-7-(4-(trifluoromcthoxy)phenyl)-3,4dihydi*obenzo[f]| 1,4]oxazcpin-5(2H)-one (Compound 11-45)

[0649] Compound 11-45 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 450.1 (M+H).

Example 202

4-((5-(pyridin-2-yl)isoxazol-3-yl)methyI)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo|f|[ l,4|oxazepin-5(2H)-one (Compound 11-41)

|0650] Compound II-41 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 482.1 (M+H).

Example 203

7-(4-(trifluoroniethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,415 dihydrobenzo|f| [l,4]oxazcpin-5(2H)-one (Compound 11-16)

|0651 j Compound 11-16 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 483.1 (M+H).

303

Example 204

4-(2-mcthoxyethyl)-7-(4-(trifluorometlioxy)phenyl)-3,4diliydrobenzo[f|| l,4|oxazepin-5(2H)-one (Compound II-l 1)

10652] Compound 11-11 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 382.1 (M+H).

Example 205

4-(2,2“dinuoroethyl)-7-(4-(trifluoromethoxy)plicnyl)-3,4dihydrobenzo|f][ l,4|oxazepin-5(2H)-one (Compound 11-6)

[0653] Compound 11-6 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 388.1 (M+H).

Example 206

4-((2,3-dihydrobenzo|b|[l,4|dioxin-6-yl)metliyl)-7-(4-(trifluoiOmethoxy)phcnyl)-3,415 dihydrobcnzo|f]|l,4]oxazepin-5(2H)-onc (Compound 11-5)

[0654] Compound 11-5 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 472.1 (M+H).

304

Exaniplc 207

7-(4-nuorophenyl)-4-(pyrimidin-2-ylmetliyl)-3,4-diliydrobenzo|f]|l,4|oxazepin5(2H)-onc (Conipound 11-104)

[0655] Conipound li-104 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. MS m/z 350.1 (M+H).

Example 208

7-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-4-(pyriniidin-2-ylniethyl)-3,4dihydrobcnzo[f][l,4|oxazcpin-5(2II)-one (Conipound 11-106)

[0656] Conipound 11-106 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. MS m/z 448.1 (M+H).

Example 209

4-(pyriniidin-2-ylmethyl)-7-(4-(2,2,2-trifluoroctlioxy)phenyl)-3,415 dihydrobenzo[f][l,4]oxazcpin-5(2II)-onc (Conipound 11-107)

|0657] Conipound 11-107 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. MS m/z 430.1 (M+H).

305

Example 2ΙΟ

7-(4-(trifIuoromethoxy)phenyl)-4-((5-(6-(tiïfluorometliyl)pyridin-3-yl)pyrimidin-2yl)methyl)-3,4-dïhydrobenzo[f||l,4|oxazepin-5(2H)-onc (Compound II-l 15)

[0658] Compound II-1 15 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 561.1 (M-ι H).

Example 211

4'(0^_(py^,'^,‘^olidin-l-yl)pyriniidin-2-yl)mctliyl)-7-(4-(ti'ifluoromctlioxy)plienyl)-3,4dîliydrobenzo|f| 11,4|oxazcpin-5(21 l)-one (Compound 11-125)

|0659| Compound 11-125 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 485.1 (M+H).

Example 212

4-((4-niorpliolinopyrimidin-2-yl)methyl)-7-(4-(trifluorometlioxy)phcnyI)-3,415 dihydrobenzo]f]|l,4|oxazepin-5(2II)-one (Compound H-133)

[0660] Compound 11-133 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 501.1 (M+H).

306

Example 213

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f|[l ,4|oxazepin-5(2H)one (Compound II-134)

[06611 Compound 11-134 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD₃OD)6 8.01 (d, IH,/=2.4 Hz), 7.72-7.78 (m, 3 H), 7.31-7.42 (m, 7H), 7.14 (d, 1 H, J = 8.0 Hz), 4.85 (s, 2H), 4.25 (t, 2H, J = 5.0 Hz), 3.60 (t, 2H, J= 5.4 Hz); MS m/z 414.1 (M+H).

Example 214

4-((4-methoxypyrimidin-2-yl)metliyl)-7-(4-(trifluoromethoxy)pheiiyl)-3,4dihydrobenzo|f|[l,4|oxazepin-5(2!I)-one (Compound 11-137)

[0662J Compound 11-137 was prepared according to the Examples disclosed herein using the appropriatestartingmaterials. 'll-NMR (CD₃OD) δ 8.41 (d, IH, J= 6.0 Hz), 8.01 (d, IH, J= 2.4 Hz), 7.77 (dd, IH, J= 8.8, 2.4 Hz), 7.71 (d, 2H, J= 8.4 Hz), 7.35 (d, 2H, J = 8.0 Hz), 7.17 (d, 1 H, J = 8.0 Hz), 6.75 (d, I H, J = 6.0 Hz), 4.97 (s, 2H), 4.58 (t, 2H, J = 4.8 Hz), 3.95 (s, 3H), 3.84 (t, 2H, J= 5.2 Hz); MS m/z 446.1 (M+H).

Example 215

4-((4-methylpyrimidïn-2-yl)methyl)-7-(4-(trifluorometlioxy)phcnyl)-3,4dihydrobenzo|fJ|l,4|oxazepin-5(2H)-onc (Compound 11-138)

[0663[ Compound 11-138 was prepared according to the Examples disclosed herein using the appropriate starting materials. ¹ H-NMR (CD₃OD) δ 8.59 (d, 111,./= 5.2 Hz),

307

8.02 (d, l H, J =2.4 Hz), 7.76 (dd, I H, J= 8.4, 2.4 Hz), 7.71 (d, 2H, J= 8.4 Hz), 7.34 (d, 2H, J = 8.0 Hz), 7.28 (d, l H, J = 5.2 Hz), 7.16 (d, I H, J = 8.4 Hz), 5.03 (s, 2H), 4.59 (t, 2H, J= 5.0 Hz), 3.83 (t, 2H, J= 5.0 Hz) ), 2.53 (s, 3H); MS m/z 430.1 (M+H).

Example 216

4-((4-(piperidin-l-yl)pyrimidin-2-yl)mcthyI)-7-(4-(tiifluoromethoxy)phenyl)-3,4dihydrobenzo(f||l,4joxazcpin-5(2H)-onc (Compound 11-139)

|Ü664| Compound II -139 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CDjOD) δ 8.10 (d, 1 H, J = 7.2 Hz), 7.98 (d, IH, J= 2.4 Hz), 7.81 (dd, IH,.J = 8.4. 2.4 Hz), 7.71 (d,2H,J = 9.2 Hz), 7.35 (d, 2H, J =8.0 Hz), 7.20 (d, I H, J =8.8 Hz), 7.01 (d, 1 H, J = 7.6 Hz), 4.91 (s, 2H), 4.56 (t, 2H, J= 5.0 Hz), 4.01 (br, 2H), 3.88 (t, 2H,J = 4.8 Hz) ), 3.73 (br, 2H), 1.59-1.73 (m, 6H); MS m/z 499.2 (M+H).

Example 217

4-((4-(diniethylamino)pyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobcnzo|f|| l,4|oxazepin-5(2II)-one (Compound 11-140)

|0665| Compound 11-140 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CDjOD) δ 8.14 (d, 1 H, J = 7.2 Hz), 7.99 (d, 1 H, J = 2.4 Hz), 7.81 (dd, I H, J = 8.0, 2.4 Hz), 7.70 (d, 2H, J = 9.2 Hz), 7.35 (d, 2H,J = 8.4 Hz), 7.19 (d, 1H,J= 8.4 Hz), 6.93 (d, IH, J = 7.2 Hz), 4.93 (s, 2H), 4.59 (t, 211, J = 5.0 Hz), 3.90 (t, 2H,J= 5.0 Hz) ), 3.30 (s, 6H); MS m/z 459.1 (M+H). q(

308

Example 218

4-bcnzyl-7-(4-(trifluoi'omcthyl)phenyl)-3,4-diliydrobenzo|f|[l,4|oxazepin-5(2H)-one (Compound 11-141)

[0666| Compound 11-141 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CDjOD) Ô 8.08 (d, 1 H, J = 2.4 Hz), 7.79-7.84 (m, 3H), 7.74 (d, 2H, J= 8.4 Hz), 7.29-7.41 (m, 511), 7.15 (d, II I, J = 8.4 Hz), 4.86 (s, 2H), 4.26 (t, 2H, J= 5.2 Hz), 3.60 (t, 2H, J = 5.2 Hz); MS m/z 398.1 (M+H).

Example 219

4-((3-methoxypyndin-2-yl)methyl)-7-(4-(trifluoromcthoxy)phcnyl)-3,4diliydi’obenzo|f|| l,4|oxazcpin-5(2H)-one (Compound 11-143)

|0667) Compound 11-143 was prepared according to the Examples disclosed herein using the appropriatestarting materials. ‘Η-NMR (CD₃OD) δ 8.23 (d, IH, J= 5.6 Hz), 8.00 (d, 1 H, J = 2.8 Hz), 7.92 (d, 1 H, J = 8.4 Hz), 7.77 (dd, 1 H, J = 8.4, 2.4 Hz), 7.687.71 (m, 3H), 7.34 (d, 2H, J= 8.0 Hz), 7.15 (d, 111,./= 8.8 Hz), 5.03 (s, 2H), 4.45 (t, 2H, 7=4.8 Hz), 4.05 (s, 3H), 3.82 (t, 211, J= 5.0 Hz); MS m/z 445.1 (M+H).

Example 220

4-(( I -(difluoronicthyl)-1 H-pyrazol-3-yl)nicthyl)-7-(4-(trifliioronicthoxy)phcnyl)-3,4dihydrobcnzo|f|| l,4|oxazcpin-5(2H)-one (Compound 11-147)

309 [0668] Compound 11-147 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.01 (dd, 2H, J = 9.4, 2.6

Hz), 7.76 (dd, IH, J= 8.2, 2.6 Hz), 7.72 (d, 2H, J= 8.8 Hz), 7.73-7.76 (m, 2H), 7.13 (d,

H, J = 8.4 Hz), 6.54 (d, 1 H, J = 2.4 Hz), 4.88 (s, 2H), 4.35 (t, 2H, J = 5.0 Hz), 3.69 (t,

2H, J = 5.0 Hz); MS m/z 454.0 (M+H).

Examplc 221

7-(4-(trifiuoromcthoxy)phcnyl)-4-((3-(trifluoiOmctliyl)-lIl-pyrazol-l-yl)mcthyl)-3,4dihydrobcnzo[f|| l,4]oxazcpin-5(2H)-one (Compound 11-148)

|0669| Compound 11-148 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 494.0 (M+Na).

Examplc 222

4-((l-cyclopcntyl-lH-pyrazoi-3-yl)mcthyl)-7-(4-(trifluorometlioxy)plicnyl)-3,4dîhydrobcnzo|l|| l,4]oxazcpin-5(2II)-onc (Compound 11-152)

[0670| Compound 11-152 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 472.1 (M+H).

Examplc 223

4-((l-cthyl-lH-pyrazol-3-yl)methyl)-7-(4-(trinuoiOnicthoxy)phcnyl)-3,4dihydrobcnzo|f|[l,4]oxazcpin-5(2II)-onc (Compound 11-153)

310 [06711 Conipound 11-153 was préparée! according to the Exaniples disclosed herein using the appropriate starting materials. ¹ H-NMR (CD3OD) Ô 7.99 (d, 1 H, J = 2.4 Hz),

7.71-7.76 (m, 3H), 7.61 (d, 1 H, 7 = 2.4 Hz), 7.35 (d, 2H,7= 8.0 Hz), 7.12 (d, 1 H, 7= 8.4

Hz), 6.31 (d, 1 H, 7= 2.4 Hz), 4.82 (s, 2H), 4.29 (t, 2H,7= 5.0 Hz), 4.17 (q, 2H,7= 7.2

Hz), 3.64 (t, 2H, 7 = 7.4 Hz), 1.45 (t, 3H, 7= 7.4 Hz); MS m/z 432.1 (M+H).

Examplc 224

4-(( 1-mcthyl-11I-imidazol-4-yl)niethyl)-7-(4-(trifluoromcthoxy)phenyl)-3,4dihydrobcnzo[f||l,4]oxazcpin-5(2H)-one (Compound 11-154)

[0672] Compound 11-154 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 418.1 (M+H).

Examplc 225

4-((4-niethyl-lH-pyrazol-l-yl)mctliyl)-7-(4-(trinuoiOnicthoxy)phenyl)-3,4dihydrobcnzo|f|| l,4]oxazcpin-5(2II)-onc (Conipound 11-155)

[0673J Compound 11-155 was prepared according to the Examples disclosed herein using the appropriate starting materials. '1I-NMR (CD3OD) δ 7.98 (d, 1 H,7= 2.4 Hz), 7.76 (dd, 1 H, 7= 8.2, 2.6 Hz), 7.71 (d,2H,7=8.4 Hz), 7.61 (s, I H), 7.34-7.37 (m, 3H), 7.11 (d, 1 H, 7 =8.8 Hz), 5.83 (s,2H),4.21 (t, 211,7= 5.0 Hz), 3.76 (t, 2H, 7= 5.0 Hz), 2.09 (s, 3H); MS m/z 418.1 (M+H).

311

Examplc 226

4-((4-chloro-llI-pyrazol-l-yl)mcthyl)-7-(4-(trifliioromethoxy)phenyl)-3,4dihydrobcnzo|f|| l,4]oxazepin-5(2II)-one (Compound Π-156)

[0674] Compound 11 -156 was prepared according to the Examples disclosed herein using the appropriate starting materials. ¹ H-NMR (CD₃OD) Ô 7.99 (d, I H, J = 2.4 Hz), 7.91 (s, 1 H), 7.77 (dd, 1H,J=8.4,2.4 Hz ),7.71 (d, 2H, J= 8.8 Hz), 7.52 (s, IH), 7.35 (d, 2H, J = 8.0 Hz), 7.13 (d, I H, J = 8.8 Hz), 5.85 (s, 2H), 4.29 (t, 2H, J = 5.0 Hz), 3.81 (t, 2H, J= 5.2 Hz); MS m/z 438.0 (M+H).

Example 227

4-((l-mcthyl-lll-pyrazol-4-yl)methyl)-7-(4-(trilluorometlioxy)phcnyl)-3,4dihydrobcnzo|f||l,4|oxazcpin-5(2H)-onc (Compound 11-160)

|0675] Compound 11-160 was prepared according to the Examples disclosed herein using the appropriate starting materials. ¹ H-NMR (CD3OD) ô 7.98 (d, I H, J = 2.8 Hz),

7.67-7.76 (m, 4H), 7.53 (s, I H), 7.35 (d, 2H, J = 8.0 Hz), 7.12 (d, 1 H, J = 8.0 Hz), 4.69 (s,

2H), 4.31 (t, 211,./ = 5.2 Hz), 3.87 (s, 3H), 3.62 (t, 211,./ = 5.0 Hz); MS ;h/z418.I (M+H).

Example 228

4-((3-fiuoropyridiii-2-yl)nicthyl)-7-(4-(trÎtliioromcthoxy)plicnyl)-3,4dihydrobenzo|t'|| l,4|oxazcpm-5(21I)-onc (Compound 11-164)

312 [0676] Compound II-l 64 was prepared according to the Examples disclosed herein using the appropriate starting materials. ’H-NMR (CD3OD) δ 8.37 (d, IH, 7 = 4.8 Hz),

8.00 (d, IH, J= 2.4 Hz), 7.76 (dd, IH, J= 8.0, 2.4 Hz), 7.72 (d, 2H,7 = 8.8 Hz), 7.61 (t, l H, 7 = 9.2 Hz), 7.38-7.42 (m, l H), 7.34 (d, 2H, J = 8.0 Hz), 7.14 (d, l H, J = 8.0 Hz),

5.07 (s, 2H), 4.45 (t, 2H, J = 4.8 Hz), 3.78 (t, 2H, 7 = 4.8 Hz); MS m/z 433.1 (M+H).

Examplc 229

7-(4-cliloro-3-fluorophcnyl)-4-((3-fluoropyi^,Îdin-2-yl)methyl)-3,4dihydrobcnzo|f|[l,4]oxazepin-5(2H)-one (Compound 11-169)

10677] Compound II-l69 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'l-l-NMR (CD3OD) ô 8.35 (d, IH, J~ 5.2 Hz), 8.00 (s, l H), 7.76 (d, l H.7=8.4 Hz), 7.61 (t, IH, 7= 9.2 Hz), 7.51-7.55 (m, 2H), 7.387.46 (m, 2H), 7.14 (d, l H, 7= 8.0 Hz), 5.07 (s, 2H), 4.46 (t, 2H, 7= 4.8 Hz), 3.78 (t, 2H, 7 = 4.8 Hz); MS m/z 40l.l (M+H).

Examplc 230

7-(2-niiotO-4-(trifhioromcthyl)plicnyl)-4-((3-fluoropyrklin-2-yl)nicthyl)-3,4dihydrobcnzo|f][ l,4|oxazcpin-5(2H)-onc (Compound II-170)

|0678] Compound I1-170 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD3OD) δ 8.37 (d, l H, 7 = 4.8 Hz), 7.99 (s, IH), 7.70-7.74 (m,2H), 7.53-7.63 (m, 3H), 7.38-7.42 (m, III), 7.17 (d, HI,7 = 8.4 Hz), 5.07 (s, 2H), 4.49 (t, 2H,7= 5.0 Hz), 3.80 (t, 2H,7= 4.8 Hz); MS m/z 435.1 (M+H).

313

Example 231

4-((3-fIuoiOpyridin-2-yl)methyl)-7-(4-(tiifluoronicthyl)phenyl)-3,4dîhydrobenzo|f]|l,4]oxazepin-5(2H)-one (Compound 11-176)

[0679] Compound 11-176 was prepared according to the Examples disciosed herein using the appropriate starting materials. ‘H-NMR (CD₃OD) δ 8.36 (d, 1 H, J = 4.4 Hz), 8.06 (s, 111),7.71-7.81 (m, 3H), 7.72 (d,2H,7=8.0 Hz), 7.60 (t, lH,J=9.0Hz), 7.377.41 (m, I H), 7.15 (d, 1 H, J = 8.4 Hz), 5.06 (s, 2H), 4.46 (t, 2H, 7 = 5.0 Hz), 3.78 (t, 2H, J = 4.8 Hz); MS m/z 417.1 (M+H).

Example 232

4-(pyriniidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenylamino)-3,4dihydrobcnzo[l'|[l,4|oxazcpin-5(2H)-onc (Compound XIII-1)

|0680| Compound XIII-1 was prepared according to the Examples disciosed herein 15 using the appropriate starting materials. MS m/z 431.1 (M+H).

Example 233

4-(pyrimidin-2-ylmcthyl)-7-(4-( trifluoromethoxy)plienoxy )-3,4dihydrobenzo|f|| l,4|oxazepin-5(2li)-onc (Compound XI11-2)

314

[0681 ] 233-A (70 mg, 0.21 mmol), 4-(trifluoromethoxy)phenol (45 mg, 0.252 mmol),

K.3PO4 ( 134 mg, 0.63 mmol), Pd(OAc)₂ (3%) and di-tert-butyl(2’4’6’triisopropylbiphenyl-2-yl)phosphine (6%) in toluène (3.5 mL) were put onto microwave at 140 °C for 20 min. The reaction mixture was diluted with EtOAC, filtered through ceilite and washed with EtOAc. The filtrate was concentrated and purifîed by HPLC followed by prep-TLC (EtOAc) to afford Compound XIII-2 ( l .8 mg). MS m/z 432.1 (M+H).

Examplc 234

I0 4-(pyrimidin-2-ylmcthyl)-7-(4-(trinuoromcthyl)plienylamino)-3,4diliydrobcnzo[f|| l,4|oxazepin-5(2H)-one (Compound XIII-3)

|0682| Compound XIII-3 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 415.1 (M+H).

I5

Examplc 235

4-(pyridm-2-y]niethyl)-7-(4-(trifluoromcthoxy)phcnylamino)-3,4dihydrobcnzo[f|| l,4]oxazcpin-5(2H)-one (Compound XIII-4)

Pd_z(dba)₃, (R)-BINAP NaO'Bu, toluene 130°C, 10min, MW

+

f₃co

3I5 [0683] 235-A (70 mg, 0.21 mmol), 4-(trifluoromethoxy)aniline (45 mg, 0.252 mmol),

NaO^lBu (40mg, 0.42 mmol), Pd₃(dba)₃ (3%) and (R)-BINAP (6%) in toluene (3.5 mL) were put onto microwave at 130 °C for 10 min. The reaction mixture was diluted with EtOAC, filtered through ceilite and washed with EtOAc. The filtrate was concentratcd and purified by HPLC to afford Conipound XIII-4 (22.8 mg).

[0684| 'H-NMR (CD₃OD) δ 8.66 (d, l H, 7= 5.2 Hz), 8.23 (t, 1H,7 = 8.0 Hz), 7.78 (d, I H, 7 = 8.0 Hz), 7.68 (t, l H, 7 = 6.4 Hz), 7.41 (s, l H), 7.22-7.40 (m, l H), 7.06-7.13 (m, 4H), 7.01 (d, IH, 7= 8.8 Hz), 5.04 (s, 2H), 4.33 (t, 2H,7= 5.0 Hz), 3.74 (t, 2H,7 = 5.4 Hz); MS m/z 430.1 (M+H).

Exaniplc 236

4-(pyridin-2-ylnietliyl)-7-(4-(trilluoronictliyl)plienylaniino)-3,4diiiydrobcnzo[fj[ l,4|oxazepin-5(2H)-onc (Conipound ΧΠΙ-6)

|06851 Conipound XI11-6 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. ¹ ll-NMR (CD₃OD) Ô 8.52 (d, IH, 7 = 5.2 Hz), 7.84 (t, 111,7= 7.6 Hz), 7.44-7.50 (m, 4H), 7.29-7.36 (m, 2H), 7.10 (d, 2H,7= 8.0 Hz), 7.03 (d, I H, 7 = 8.8 Hz), 4.94 (s, 2H), 4.29 (t, 2H, 7= 5.2 Hz), 3.68 (t, 2H, 7= 5.6 Hz); MS m/z 414.1 (M+H).

Exaniplc 237

7-(nictliyl(4-(trifluoromethoxy)phcnyl)amino)-4-(pyrimidin-2-ylniethyl)-3,4dihydrobcnzo[f|| l,4]oxazepin-5(2H)-onc (Conipound XIII-10)

|0686] Conipound XIII-10 was prepared accordîng to the Examples disclosed herein using the appropriate starting materials. MS m/z 445.1 (Μ+H). J

316

Exaniple 238

7-(niethyl(4-(trifluoroniethoxy)phcnyl)aniino)-4-(pyrÎdin-2-ylmethyl)-3,4dihydrobenzo[f|[l,4|oxaz.epin-5(2H)-one (Conipound XIII-12)

[0687] Conipound XIII-12 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 444.1 (M+H).

Exaniple 239

5-benzyl-8-(4-(ti-ifIuoroniethyl)phcnyl)-41l-benzo|l]iniidazo| 1,2-a | [ l,4|diazepin6(5H)-onc (Conipound X-12)

106881 239-A (0.100g, 0.244mmol), 2, 2-dimethoxycthanamine (lmL, 9.3mmol) were mixed together, the resulting mixture was stirred at 100°C for 4 hours. When the reaction was cooled down, Water was added dropwise until précipitation was finished. The précipitâtes were collected by filtration and washed with water to afford 239-B (0.11 lg, 92%), MS w/z: 498 (M + H)⁺.

|0689] 239-B (0.104g, 0.209mmol), PPTS (0.525g, 2.09mmol) were added to Toluene (5mL). The resulting mixture was stirred at I2OC overnight, concentrated and purified by préparative HPLC to afford Conipound X-12 (0.013g, 14%). MS n\/z\ 434 (MH¹).

317

Example 240

N-(2-(5-oxo-7-(4-(trifluoromcthoxy)phenyI)-2,3-dihydrobenzo|f)|l,4|oxazepm-4(5H)yl)cthyl)pyrimidine-2-carboxamide (Compound II-192)

|0690] Compound II-192 was prepared according to Examples 188 and 195 dîsclosed herein using the appropriate starting materials. MS m/z 473.1 (M⁺).

Examplc 241

7-(5-cyclopropylthiophen-2-yl)-4-(pyrïmidin-2-ylmctliyl)-3,40 dihydrobcnzo[f]|l,4|oxazcpin-5(2H)“Oiic (Compound VI-36)

106911 Compound VI-36 was prepared according to the Examples dîsclosed herein using the appropriate starting materials. 'H-NMR (DMSO) δ 8.77 (d, 2H, J - 5.2 Hz),

7.79 (d, l H, ./=2.4 Hz), 7.68 (dd, IH, J= 8.2, 2.6 Hz), 7.40 (t, IH, J = 5.0 Hz), 7.22 (d,

IH, J= 3.2 Hz), 7.04 (d, IH, J = 8.8 Hz), 6.78-6.79 (m, III),4.95 (s, 2H),4.47 (t, 2H, J =

5.0 Hz), 3.73 (t, 2H, J = 5.0 Hz), 2.07-2.13 (m, IH), 0.96-1.00 (m, 2II), 0.66-0.70 (m,

2H); MS m/z 378 (MHl).

3I8

Example 242

4-(pynmidin-2-ylmethyl)-7-(5-(trinuoromethyl)thiophen-2-yl)-3,4dihydrobenzo|f][l,4|oxazepin-5(2H)-one (Conipound VI-37)

[0692] Conipound VI-37 was prepared according to the Examples disclosed herein using the appropriate starting materials. ¹ H-NMR (DMSO) δ 8.70 (d, 2H, J = 5.2 Hz), 7.72 (d, 1 H, J =2.4 Hz), 7.61 (dd, IH, J = 8.2, 2.6 Hz), 7.30 (t, IH, J =5.0 Hz), 7.12 (d, 1 H, J =3.2 Hz), 7.01 (d, 1 H, J =8.8 Hz), 6.72-6.75 (m, 1 H), 4.91 (s, 2H), 4.42 (t,2H,J = 5.0 Hz), 3.71 (t, 2H, J= 5.0 Hz), 2.07-2.11 (m, IH), 0.94-1.1 (m, 2H), 0.64-0.69 (m, 2H); MS m/z 406 (M+H).

Example 243

4-(pyiimidiii-2-ylmethyl)-7-(4-(tiinuoromethyl)phenethyl)-3,4dihydrobenzo|f'l|l,4|oxazepin-5(2II)-one (Conipound VI11-8)

[06931 Conipound VIII-8 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD₃OD) Ô 8.74 (d, 2H, J= 4.8 Hz), 7.51-7.54 (m, 3H), 7.33-7.37 (m, 3H), 7.26 (dd, IH, J= 8.2, 2.2 Hz), 6.94 (d, IH, J= 8.0 Hz), 5.02 (s, 2H), 4.45 (t, 2H, J= 5.2 Hz), 3.72 (t, 2H, J= 5.2 Hz), 2.91-3.00 (m,4H); MS m/z 428.1 (M+H).

Example 244

4-((3-nuoropyridÎn-2-yl)nicthyl)-7-(4-(triiliioronicthyl)phenethyl)-3,4diliydi*obenzo[f|[ I,4|oxazepin-5(2H)-oiic (Conipound VI11-9)

319 |0694] Compound VIII-9 was prepared according to the Examples disclosed herein using the appropriate starting materials. ’H-NMR (CD₃OD) δ 8.34 (d, I H, J= 5.2 Hz), 7.50-7.60 (m, 4H), 7.33-7.40 (m, 3H), 7.25 (dd, l H, J= 8.4, 2.4 Hz), 6.92 (d, IH, J = 8.0 Hz), 5.01 (d, 2H, J= I.6 Hz), 4.32 (t, 2H, J= 5.2 Hz), 3.66 (t, 2H, J= 5.2 Hz), 2.90-3.00 (m, 4H); MS ro/z 445.1 (M+H).

Example 245

7-(4-(4-fluorophenoxy)phcnyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo(f]|l,4]oxazcpin-5(2H)-one (Compound II-193)

|0695| Compound II -193 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'l-l-NMR (CD₃OD) δ 8.77 (d, 2H, J= 5.2 Hz), 7.97 (d, IH, J= 2.0 Hz), 7.73 (dd, IH, J = 8.8, 2.4 Hz), 7.61 (dd, 2H, J= 6.8, 2.0 Hz), 7.38 (t, I H, J = 4.8 Hz), 7.02-7.14 (m, 7H), 5.07 (s, 2H), 4.56 (t, 2H, J = 5.0 Hz), 3.82 (t, 2H, J = 5.0 Hz); MS m/z 442.1 (M+H).

Examplc 246

7-(4-plienoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f]|l,4]oxazcpin5(2H)-one (Compound 11-194)

|0696] Compound 11-194 was prepared according to the Examples disclosed herein using the appropriate starting materials. 'Η-NMR (CD₃OD) δ 8.77 (d, 2H, J= 5.2 Hz), 7.97 (d, IH, J = 2.4 Hz), 7.74 (dd, IH, J= 8.6, 2.6 Hz), 7.61 (dd, 2H, J = 6.8, 2.4 Hz), 7.35-7.39 (m, 3H), 7.10-7.15 (m, 211), 7.01-7.06 (m, 411), 5.07 (s, 2H), 4.56 (t, 2H, J= 5.2 Hz), 3.82 (t, 2H, J= 5.0 Hz); MS m/z 424.1 (M+H).

320

Examplc 247

7-(3-phenoxyphcnyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo|f]|l,4]oxazepin5(2H)-one (Compound 11-195)

[0697] Compound II-195 was prepared according to the Examples disclosed herein using the appropriate starting materials. ¹ H-NMR (CD₃OD) δ 8.76 (d, 2H, J - 5.2 Hz), 7.96 (d, 1 H, J = 2.4 Hz), 7.71 (dd, 1 H, 7 = 8.2, 2.6 Hz), 7.34-7.44 (m, 5H), 7.23 (t, 1 H, J = 2.0 Hz), 7.10-7.14 (m, 2H), 7.02-7.04 (m, 2H), 6.93-6.96 (m, IH), 5.06 (s, 214),4.56 (t, 2H, 7= 5.0 Hz), 3.81 (t, 214,7= 5.2 Hz); MS m/z 424.1 (M+H).

Examplc 248 (E)-4-bcnzyl-7-(4-(trifluoromcthyl)styryl)-3,4-dihydrobcnzo| f] [ 1,4 |oxazepin-5(2 II)onc (Compound VIII-10)

[0698] Compound VIII-10 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z 424.1 (M+H).

Examplc 249

4-bcnzyl-7-(4-(trifluoromethyl)phcncthyl)-3,4-diliydrobciizo|f|( l,4]oxazepin-5(2II)onc (Compound VIII-11)

|0699] Compound VIII-ll was prepared according to the Examples disclosed herein using the appropriate starting materials. 'H-NMR (CD₃OD) δ 7.53-7.54 (m, 3H), 7.267.37 (m, 814), 6.93 (d, 1 H, 7 = 8.0 Hz), 4.82 (s, 2H), 4.16 (t, 2H, 7 = 5.2 Hz), 3.49 (t, 2H, J = 5.2 Hz), 2.95-3.02 (m, 414); MS m/z 426.1 (M+H).

321

Examplc 250

4-(3-(azetidin-l-ylsulfonyl)propyI)-7-(4-(tnlluoromethoxy)phenyl)-3,4dihydrobenzo|l|[l,4|oxazepin-5(2II)-onc (Compound II-191)

|0700| Compound 250-C was synthesized from Compound 250-A and sultone 250-B following general alkylation procedures. Compound 250-C (84 mg, 0.19 mmol) was treated with thionyl chioride at 60°C ovemiglit. The resulting mixture was concentrated to afford crude Compound 250-1) which was treated with a solution of azetidine (26pL, 2 eq) and triethylamine (250 pL) in DCM, the resulting mixture was stirred at room température for several hours, concentrated and purified with HPLC to afford Compound 11-191 (42 mg). MS m/z: 485 (MH⁺).

Examplc 251

N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromcthoxy)phcnyl)-2,315 dihydrobcnzo[f]|l,4]oxazcpin-4(5II)-yl)piOpanc-l-sulfonamide (Compound 11-190)

107011 Compound 11-190 was prepared according to the Examples disclosed herein using the appropriate starting materials. MS m/z: 485 (MIT¹)

322 [07021 The following compounds were prepared according to the Examples disclosed herein using the appropriate starting materials:

4-(2,2,2-trifluoroethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo|f]|l,4|oxazepin-5(2II)-one (Compound 11-2) MS m/z 406.0 (M+H)

4-(2-(pyrrolidin-l-yl)ethyl)-7-(4-(trifluoronietlioxy)phenyl)-3,4dibydrobenzo[f|[l,4Joxazcpin-5(2H)-one (Compound Π-3) MS m/z 42l.l (M+H)

(2S,I laR)-2-amino-7-(4-(trïfluoi'omethyl)phenyl)-2,3,l t,l la10 tetrahydrobenzoff|pyrrolo|2,l-c||l,4|oxazepin-5(lll)-one (Compound II-20) MS m/z;

363 (MH⁺)

NH₂ (R)“8-(4-(trifhioromethyl)phcnyl)-3,4,l2,12a-tetrahyd!o-lH-benzo[fjpyrazino|2,lc]|l,4]oxazepin-6(2H)-one (Compound 11-26) MS m/z; 363 (MH⁺)

463 (MH⁺)

(S)-8-(4-(trifluoromethyl)phenyl)-3,4,l 2,12a-tctrahydro- ί 11-b en zo| fjpyrazino [2,1c]|l,4]oxazepin-6(2H)-one (Compound 11-28) MS m/z: 363 (MH⁺)

(S)-tert-butyl 6-oxo-8-(4-(trilluoi-omctliyl)phenyl)-3,4,12,12a-tctraliydro-lHbenzo|f|pyrazino|2,l-c]|l,4]oxazepinc-2(6M)-carboxylate (Compound 11-29) MS m/z:

463 (MH⁺)

(2R,1 laR)-2-(pyrimidin-2-ylamino)-7-(4-(trinuoromctliyl)phcnyl)-2,3,l 1,11atctrahydrobenzo|fjpyrrolo[2,l-c]|l,4]oxazepin-5(lll)-one (Compound 11-30) MS m/z:

441 (Mil')

324

4-((l-phcnyl-5-(trifluoroniethyl)-l H-pyrazol-4-yl)niethyl)-7-(4(trifluoromethoxy)phenyl)-3,4-dihydrobenzo|f|[ l,4]oxazepin-5(2H)-onc (Compound

II-32) MS m/z 548.1 (M+H)

(2S,llaS)-2-(pyriniidin-2-ylamino)-7-(4-(trinuoromethyl)phenyl)-2,3,11,1 latetrahydrobenzo[f]pyrrolo|2,l-c||l,4]oxazcpin-5(lH)-one (Compound 11-34) MS m/z:

441 (MH⁺)

7-(4-(trifluoromcthoxy)phenyl)-4-(2-(2,5,5-trimctliyl-l,3-dioxan-2-yl)ctliyl)-3,410 dihydrobenzo[f]|l,4|oxazepin-5(2H)-one (Compound 11-35) m/z: 480.1 (Mil·)

(2R,1 laR)-2-(diethylamino)-7-(4-(triÎluoronietliyl)pliciiyl)-2,3,l 1,1 latctrahydrobenzo[f]pyrrolo|2,l-c][l,4|oxazepin-5(lH)-oiic (Compound 11-36) MS m/z:

419 (MH⁺)

325 (2S,1 laS)-2-(dicthylamino)-7-(4-(trifluoronietliyi)phenyI)-2,3,l 1,11atetrahydrobenzo|fjpyrrolo|2,l-c][l,4|oxazcpin-5(lll)-one (Conipound 11-37) MS m/z:

419 (MH⁺)

(2R,1 laR)-2-aniino-7-(4-(trifluoiOnicthyl)phcnyl)-2,3,l 1,11atetrahydrobenzo|fjpyrrolo[2,l-c]|l,4|oxazcpin-5(lll)-one (Conipound 11-38) MS m/z:

363 (MH⁺)

tert-butyl (2R,1 laR)-5-oxo-7-(4-(tiinuoroniethyl)plicnyl)-l,2,3,5,l 1,1 la10 hexahydrobcnzo[f|pyjTolo[2,l-c|| l,4|oxazcpin-2-ylcai bamatc (Conipound 11-39) MS m/z: 463 (MH⁺)

326

4-((5-(pyrimidin-2-yl)isoxazol-3-yl)methyl)-7-(4-(trifluoromethoxy)phcnyl)-3,4dihydrobenzo[f]| l,4]oxazepin-5(2H)-one (Compound 1I-40) MS m/z 483.1 (M+H)

ethyl 3-((5-oxo-7-(4-(trifIuoromethoxy)plienyl)-2,3-diliydrobenzoJf||l,4]oxazepin5 4(5H)-yl)methyl)benzoate (Compound II-43) m/z: 486.1 (MH⁺)

tert-butyl (2S,1 laS)-5-oxo-7-(4-(trifliioromethyl)phcny 1)-1,2,3-5,11,1 lahexahydrobenzo|f|pyiTolo|2,l-c|| l,4]oxazepin-2-ylcarbamatc (Compound 11-52) MS m/z: 463 (MH^f)

4-((3-cyclopropyl-l-methyl-lll-pyrazol-5-yI)mctliyl)-7-(4-(trifluoiOmcthoxy)phcnyl)3,4-dihydrobenzo[f|| l,4|oxazcpin-5(2H)-one (Compound H-53) MS m/z 458. J (M+H)

4-(4-(tnfluoroniethoxy)berizyl)-7-(4-(tTifliioromcthoxy)phenyl)-3,41 5 diliydiObenzo|f]|l,4|oxazcpin-5(211)-onc (Compound 11-55) MS m/z 498. / (M+H)

327

7-(4-(tiinuoroinethoxy)phenyl)-4-(4-(tiifhioroiiicthyl)bcnzyl)-3,4dihydrobcnzo[f||l,4]oxazepin-5(2H)-one (Compound 11-56) MS m/z 482.1 (M+H)

(2R,l laS)-2-hydroxy-7-(4-(trifluoromethyl)phcnyl)-2,3,l 1,1 la5 tetrahydiObcnzo[f]pyrrolo[2,l-c||l,4|oxazcpin-5(lH)-onc (Compound 11-58) MS m/z:

364 (ΜΙ-Γ)

(R)-7-(4-(trïfiuoroinethyl)phcnyl)-2,3,l 1,1 la-tctraiiydrobcnzo|f|pyrrolo|2,lc||l,4|ox:izcpin-5(lH)-onc (Compound 11-59) MS m/z: 348 (MH⁺)

(S)-7-(4-(triiluoronicthyl)phcnyl)-2,3,l 1,1 la-tctrahydrobenzo|f|pyrrolo|2,lc]| l,4]oxazcpîn-5(l H)-one (Compound 11-60) MS m/z: 348 (MH⁺)

8~(4-(trifluoronictiiyl)plicnyl)-3,4,12,12a-tetraliydi'obciizo|f][ l,4]oxazino[3,415 c][l,4|oxazcpin-6(lH)-onc (Compound 11-63) MS m/z: 364 (Μ1Γ)

328

2-(2-(5-oxo-7-(4-(trifluoromethoxy)plicnyl)-2,3-dihydrobenzo|f|[l ,4|oxazepin-4(5H)yl)ethoxy)pyrimidinc-4-carbonitnlc (Compound II-66) MS m/z471.l (M+H)

4-(2-hydroxyethyl)-7-(4-(trifluoromcthoxy)phenyl)-3,45 dihydrobenzo[f||l,4|oxazcpin-5(2H)-one (Compound 11-71) MS m/z 368.1 (M+H)

(R)-3-ïsopropy!-7-(4-(ti'iiluoronietliyl)phciiyl)-3,4-djliydrobcnzo[f’|| l,4]oxazcpin5(2H)-onc (Compound 11-76) MS m/z: 349 (MH⁺)

(R)-3-isopropyl-4-(pyrÎniÎdin-2-ylniethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobcnzo|f]|l,4|oxazcpin-5(2H)-onc (Compound 11-78) MS m/z: 442 (MH⁺)

(S)-3-isopropyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoronicthyl)phenyl)-3,4dibydiObenzo|f||l,4|oxazcpin-5(2H)-oiic (Compound 11-79) MS m/z; 442 (MH⁺)

329 (S)-2-(2,2,2-trifluoroetliyl)-8-(4-(trinuoromcthyl)phenyl)-3,4,12,12a-tetrahydro-lHbenzol f]pyrazino|2,l-c]|l,4)oxazcpin-6(2H)-one (Compound II-84) m/z: 445 (MH⁺)

7-(4-morpholinopliciiyl)-4-(pyrimidin-2-yhnethyl)-3,4-dihydi'obcnzo|f||l,4|oxazepm5 5(2H)-one (Compound 1I-90) m/z: 417,2 (MH⁺)

7-(4-( nietliylsulfoiiyl)phenyl)-4-(pyrimidin-2-ylniethyl)-3,4dihydrobenzo|f|| i,4|oxazepin-5(2H)-one (Compound 11-93) m/z: 410.0 (MH⁺)

(R)-4-(l-(pyrimidiii-2-yl)ethyl)-7-(4-(ti-iÎluoromethyl)phcnyl)-3,4dihydrobcnzo|i'][ l,4|oxazepin-5(2H)-one (Compound II-95) m/z: 414 (MH⁺)

(S)-4-(l-(pyrimidin-2-yl)ethyl)-7-(4-(trifluoromethyl)phcnyl)-3,4dihydrobenzo|f||l,4|oxazcpin-5(2II)-onc (Compound 11-96) m/z: 414 (MH⁴)

330

7-(4-tert-butoxyplicnyl)-4-(pyriniidin-2-ylmethyl)-3,4-dÎhydrobcnzoJf|| l,4|oxazepin5(2H)-onc (Conipound Π-99) m/z: 404.5 (MH⁺)

(R)-2-niethyl-4-(pyriniidin-2-ylnictiiyl)-7-(4-(trifluoromcthyl)plienyl)-3,45 dihydrobcnzo|f|I l,4|oxazepin-5(2H)-one (Conipound 11-100) m/z: 414 (MH¹)

tert-butyl 4-(5-oxo“4-(pyriniidiii-2-ylnictliyl)-2,3,4,5tetraliydrobenzo|t]| l,4]oxazepin-7-yl)plienylcarbaniate (Conipound 11-103) m/z:

447.1 (MH⁺)

H

N-(4-(5-oxo-4-(pyriniidin-2-ylniethyl)-2,3,4,5-tetraliydrobenzo[f]|l,4|oxazcpin-7yl)phenyl)cyclopropanecarboxaniidc (Conipound 11-112) m/z: 415.2 (MH⁺)

4-((5-(pyridin-3-yl)pyriinïdïn-2-yl)incthyl)-7-(4-(triiluoroniethoxy)plieiiyl)-3,415 dihydrobenzo|l’|| l,4|oxazepin-5(21l)-onc (Conipound 11-114) MS m/z 493.1 (M+H)

331

7-(4-(2-hydroxypropan-2-yl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrohcnzo|f][ l,4]oxazepin-5(21I)-onc (Compound 11-118) m/z: 390.2 (MH⁺)

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trÎfluoroacctyl)plicnyl)-3,45 dihydi'obcnzo[f|[l,4]oxazepin-5(2H)-onc (Compound 11-121) m/z: 428.2 (MH⁺)

4-(pyiimidin-2-ylmcthyl)-8-(4-(h'inuoromcthoxy)phenyl)-3,4dihydrobcnzo|f]|l,4|oxazepiii-5(2H)-one (Compound IV-1) MS m/z 416.0 (M+H)

4-(pyridin“2-ylmethyl)-8-(4-(trinuoromcthoxy)phenyl)-3,4dihydrobenzo[f|| l,4]oxazcpin-5(2H)-one (Compound IV-2) MS m/z 415.1 (M+H)

4-(pyridin-2-ylmctliyl)-8-(3-(trifluoi'omethyl)phcnyl)-3,4dihydrobcnzo|f|| l,4|oxazepin-5(2II)-one (Compound IV-3) MS m/z 399.1 (M+H)

332

4-(pyi'imidin-2-ylmethyl)“8-(3-(trifluoromethyl)plicnyl)-3,4dihydrobenzo|f|[l,4|oxazepin-5(2H)-one (Compound IV-4) MS m/z 400.1 (M+H)

4-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)phenyl)-3,45 dihydrobenzo|f][ l,4|oxazepin-5(2II)-onc (Compound IV-5) MS m/z 400.1 (M+H)

4-(pyridiii-2-ylmethyl)-8-(3-(trifluoromethoxy)phenyl)-3,4dihydrobcnzo|f||l,4|oxazcpin-5(2H)-onc (Compound IV-6) MS m/z4l5.l (M+H)

4-(pynmidin-2-ylmctliyl)-8-(3-(trifluoromcthoxy)phenyl)-3,4dihydrobcnzo|f|| l,4]oxazcpin-5(2H)-onc (Compound IV-7) MS m/z 416.1 (M+H)

333

4-(pyridin-2-ylnicthyl)“8“(4“(trifliioronietliyI)phenyl)-3,4dihydrobenzo|f|[l,4]oxazepin-5(2H)-one (Compound IV-8) MS m/z 399.1 (M+H)

7-(4-tert-butylcyclohex-l-cnyl)-4-(pyrimidin-2-ylmethyl)-3,45 dihydrobcnzo|f|| l,4]oxazepin-5(2H)-onc (Compound V-l) m/z\ 392.2 (MH⁺)

7-cyclopcntenyl-4-(pyt imidïn-2-ylmethyl)-3,4-dihydrobcnzo[f|| Î,4]oxazcpin-5(2H)one (Compound V-2) m/z\ 322.1 (MH¹)

7-(4,4-dimethylcyclohex-l-enyl)-4-(pyrimidin-2-ylmcthyl)-3,4dihydrobenzo|f||l,4|oxazcpin-5(2II)-one (Compound V-4) mte. 364.2 (ΜΡΓ)

7-(bicyclo|3.1.1|licpt-2-cn-3-yl)-4-(pyiiinidin-2-ylmethyl)-3,4dihydrobcnzo|f|[l,4|oxazcpin-5(2II)-onc (Compound V-7) m/z'. 348.1 (MIT¹)

334

7-(2-oxo-l,2-dihydropyridin-4-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f]|l,4|oxazepin-5(2H)-one (Compound VI-1) m/z: 349.1 (MH⁺)

tert-butyl 4-(5-oxo-4-(pyrimidin-2-ylmcthyl)-2,3,4,55 tetrahydrobenzo[f]|l,4|oxazepin-7-yl)-5,6-dihydropyridine-l(2H)-carboxylate (Compound VI-5) m/z: 436.9 (MH⁺)

4-(pyrimidin-2-ylmctliyl)-7-(6-(2,2,2-tnfluoroctlioxy)pyridin-3-yl)-3,4dihydrobcnzo[f|| I,4]oxazcpin-5(2H)-one (Compound VI-6) MS m/z 431.1 (M+H)

4-(pyrimidin-2-ylmethyl)-7-(6-(tiifluoromethyl)pyridm-3-yl)-3,4dihydrobenzo|f]|l,4|oxazcpin-5(2II)-one (Compound VI-8) MS m/z 401.1 (M+H)

7-(6-fluoropyridin-3-yl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f||l,4]oxazepiii15 5(2H)-one (Compound VI-9) MS m/z 351.1 (M+H)

335

4-(pyriniÎdin-2-ylnicthyl)-7-(2-(pyrrolidin-l-yl)pyrimidin-5-yl)-3,4dîhydrobcnzo[f]| l,4|oxazcpin-5(2H)-one (Conipound VI-10) MS m/z 403.1 (M+H)

7-(2-(pipcridin-l-yl)pyriniidm-5-yl)-4-(pyriniidin-2-ylniethyl)-3,45 dihydrobcnzo[f|| l,4]oxazcpin-5(2H)-one (Conipound Vl-11) MS m/z 417.1 (M+H)

7-( l-(cyclopropanecarbonyl)-1,2,3,6-tctrahydropyridin-4-yl)-4-(pyriniidin-2ylincthyl)-3,4“dihydrobenzo[f||l,4|oxazepin-5(2H)-one (Conipound VI-17) m/z‘. 405.2 (ΜΙ-Γ)

7-(pyriniidin-2-yl)-4-(pyriniidin-2-ylnicthyl)-3,4-dihydrobenzo|fl|l,4]oxazcpm5(2H)-one (Conipound VI-18) MS m/z 334.1 (M+H)

4-(pyriniidîn-2-ylmetliyl)-7-(5-(trifluoronicthyl)pyriniidin-2-yl)-3,415 diliydrobcnzo|f][ l,4|oxazcpin-5(2H)-onc (Conipound VI-19) MS m/z 402.1 (M+H)

336

7-(cyclopropylethynyl)-4-(pyrimidin-2-ylmcthyl)-3,4-dihydrobenzo|f][l,4|oxazepin5(2H)-onc (Compound VIII-1) m/z: 320.2 (MH')

7-(3,3-dimethylbut-l-ynyl)-4-(pyrimidin-2-ylmethyl)-3,45 dÎliydrobcnzo|f|(l,4|oxazcpin-5(2II)-one (Compound VIII-2) m/z\ 336.1 (MH¹)

7-((l-mcthyHH-imidazol-5-yl)ethynyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo|f]|l,4|oxazepin-5(2II)-onc (Compound VII1-3) m/z: 360.2 (MH )

4-(imidazo[ l,2-a|pyridin-2-ylmethyl)-7-(4-(trinuoronicthyl)phenyl)-3,4diliyd!Obenzo|f|[l,4|oxazcpin-5(2H)-onc (Compound 11-135) m/z: 438.1 (MH⁺)

7-(3-fluoro-4-(trifliioi-omethyl)plienyl)-4-(pyrimidm-2-ylmethyl)-3,4diliydrobcnzo[f|| l,4|oxazepin-5(2II)-onc (Compound 11-136) m/z: 418.1 (MH¹)

337

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluoi^-oethyI)phenyl)-3,4dihydrobenzo|f|(l,4|oxazepin-5(2H)-one (Compound 11-150) m/z: 459.2 (MH⁺)

4-(pyridin-2-ylmcthyl)-7-(4-(2,2,2-trifluorocthyl)phenyl)-3,45 dihydrobenzo|fj[l,4Joxazepin-5(2H)-one (Compound 11-151) m/z: 458.2 (MH⁺)

cyclopiOpyl(7-(4-(tnfluoiOmcthoxy)phenyl)-2,3-dihydrobenzo|f]| l,4]oxazcpin4(5II)-yl)mcthanone (Compound II1-8) m/z: 378 (MH⁺)

(1 H-pyrazol-4-yl)(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo| f| [ 1,4 |oxazepin4(5H)-yl)methanone (Compound 111-13) m/z: 404 (MH⁺)

(3,5-dimctliyl-lH-pyrazol-4-yl)(7-(4-(ti'ifluoromcthoxy)plienyl)-2,3diliydrobenzo|f|| l,4|oxazcpin-4(5H)-yl)methanonc (Compound III-14) m/z: 432.2

338 (l-methyl-3-(trifluoronicthy])-lH-pyiazol-4-yl)(7-(4-(tiifluoiomcthoxy)phenyl)-2,3dihydrobenzo[fj|l,4joxazepin-4(5H)-yl)methanone (Compound ΠΙ-16) m/z; 486.1

(3-methyl-lH-pyrazol-4-yl)(7-(4-(trifluoiOniethoxy)phenyl)-2,3dihydrobenzo|f||l,4|oxazcpiii-4(5II)-yl)mctlianone (Compound Hl-17) m/z; 418.2

ΙΟ l-morpliolmo-2-(7-(4-(trïfli!oromctliyl)phcnyl)-2,3-dihydrobenzo|f|[l,4|oxazepiii4(5H)-yl)ethanone (Compound III-28) m/z; 421 (MH⁺)

4-(pynmidin-2-ylmethyl)-7-(pyiTolidin-l-yI)-3,4-dihydrobcnzo[f||l,4|oxazepin5(2H)“onc (Compound VI-34) MS m/z 325.1 (M+H)

4-(pyridin-2-ylmethyI)-7-(pyrrolidin-l-yl)-3,4-dihydrobenzo|f|(l,4|oxazepin-5(2iI)one (Compound VI-35) MS m/z 324.1 (M+H)

339

4-ΒεηζγΙ-7-(4-(1πΑυοΓοηιεί1ιοχγ)ρΙΐβηγ1)-3,4-ίϋΗχάΓοργπάο|3,2-Γ|( l,4]oxazcpiii“

5(2H)-one (Compound XII-12) MS m/z 415.1 (M+H)

4-(pyrimidin-2-ylmcthyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[3,25 f][l,4|oxazepin-5(2II)-one (Compound XII-13) MS m/z 417.1 (M+H)

4-(pyridin-2-ylmethyl)-7“(4“(trifluoromctlioxy)plienoxy)-3,4dihydrobenzo|f|| l,4]oxazepm-5(2H)-onc (Compound XIII-5) MS m/z 431.1 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetiahydrobcnzo|f||l,4|oxazepin-7yl)bcnzamidc (Compound ΧΠΙ-7) MS m/z 374.1 (M+H)

4-(pyridin-2-ylmethyl)-7-(4-(trifiiiorometliyl)phenoxy)-3,4diliydrobcnzo|f']| l,4]oxazepin-5(2H)-one (Compound XI11-8) MS m/z 415.1 (M+H)

340

4-(pyrimidin-2-yimethyl)-7-(4-(trifluoromethoxy)benzylamino)-3,4dihydrobenzo[f]|l,4|oxazepin-5(2H)-one (Compound ΧΠΙ-9) MS m/z 445.1 (M+H)

4-(pyridin-2-ylmcthy))-7-(4-(trifluoi-omcthoxy)bcnzylamino)-3,45 dihydrobenzoIf||l,4]oxazcpin-5(2H)-one (Compound XllI-l l) MS m/z 444.1 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydrobenzo|f|| l,4|oxazcpin-7-yl)-4(trifluoromcthyl)benzamide (Compound XIII-13) MS m/z 442.1 (M+H)

7a-(7-(4-(trifluoromethoxy)phenyl)-2,3,4,5-tctraliydrobenzo|f||l,4]oxazcpine-4carbonyl)tetrahydro-l H-pyrrolizin-3(2H)-onc (Compound 111-59) MS m/z 461.4 (M+H)

N-(5-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tctrahydrobcnzo|f][l,4|oxazepin-7-yl)-415 (triiluoromcthoxy)benzamide (Compound XH1-I4) MS m/z 458.1 (M+H)

341

4-(pyridin-2-ylmethyl)-7-(4-(trinuoromethyl)phcncthyl)-3,4dihydrobenzo[f|[ l,4|oxazepin-5(2H)-one (Conipound VI11-7) MS m/z 427.4 (M+H)

10703] Hard gelatin capsules containing the following ingrédients are prepared:

Quant ity ingrédient

Active Ingrédient

Starch (mg/capsule)

30.0

305.0

Magnésium stéarate

5.0 [0704] The above ingrédients are mixed and filled into hard gelatin capsules.

Example 253

A tablet Formula ls prepared using the ingrédients below:	Quantity
Ingrédient Active Ingrédient	(mg/tablct) 25.0

Cellulose, microcrystalline

200.0

Colloïdal silicon dioxide

10.0

Stearic acid

5.0

The components are blended and compressed to form tablets.

Example 254 |0705] A dry powder inhaler formulation is prepared containing the following components:

Ingrédient

Active Ingrédient

Lactose

Weight % |0706] The active ingrédient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. ,χ

342

Example 255

10707] Tablets, each containing 30 mg of active ingrédient, are prepared as follows:

	Quantity
Ingrédient	(mg/tablet)
Active Ingrédient	30.0 mg
Starch	45.0 mg
Microcrystalline cellulose	35.0 mg
Polyvinylpyrrolidone
(as 10% solution in stérile water)	4.0 mg
Sodium carboxymethyl starch	4.5 mg
Magnésium stéarate	0.5 mg
Talc	l .0 mg
Total	I20 mg

|0708| The active ingrédient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the résultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50 °C to 60 °C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnésium stéarate and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weîghing 120 mg.

Example 256

10709] Suppositories, each containing 25 mg of active ingrédient are ruade as follows:

Ingrédient Amount

Active Ingrédient 25 mg

Saturated fatty acid glycerides to 2,000 mg |07l0] The active ingrédient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum beat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. X

343

Examplc 257 (0711| Suspensions, each containing 50 mg of active ingrédient per 5.0 mL dose are ruade as follows:

Ingrédient	Amount
Active Ingrédient	50.0 mg
Xanthan gum	4.0 mg
Sodium carboxymethyl cellulose (11%)
Microcrystalline cellulose (89%)	50.0 mg
Sucrose	1-75 g
Sodium benzoate	lO.Omg
Flavor and Color	q.v.
Purîfied water to	5.0 mL

|0712] The active ingrédient, sucrose and xanlhan guni are blended, passed through a No. 10 mesh U.S. sieve and then mixed with a previously tnade solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

Examplc 258 [0713] A subcutaneous formulation may be prepared as follows:

Ingrédient Quantity

Active Ingrédient 5.0 mg

Corn Oil 1.0 mL

Examplc 259 [0714| An injectable préparation is prepared having the following composition:

Ingrédients	Amount
Active ingrédient	2.0 mg/mL
Mannitol, USP	50 mg/mL
Gluconic acid, USP	q.s. (pH 5-6)
water (distilled, stérile)	q.s. to 1.0 mL
Nitrogen Gas, N F	q.s.

(A

344

Example 260 [07151 A topical préparation is préparée! having the followîng composition:

Ingrédients grams

Active ingrédient 0.2-10

Span 602.0

TweenôO2.0

Minerai oil5.0

Petrolatum0.10

Methyl paraben0.15

Propyl paraben0.05

BHA (butylated hydroxy anisole)0.01

Water q.s. toi00 [07161 Ail of the above ingrédients, except water, are coinbined and heated lo 60°C with stirring. A sufficient quantity of water at 60°C is then added with vigorous stirring to emulsify the ingrédients and water then added q.s. 100 g.

Example 261 |0717] Sustained Release Composition

Ingrédient	Weight Range%
Active ingrédient	50-95
Microcrystalline cellulose (filler)	1-35
Methacrylîc acid copolymer	1-35
Sodium hydroxide	0.1-1.0
Hydroxypropyl methylcellulose	0.5-5.0
Magnésium stéarate	0.5-5.0

|0718| The sustained release formulations of this disclosure are prepared as follows: compound and pH-dependent binder and any optional excipients are intimately mixed(dry-blended). The dry-blended mixture is then granulatcd in the presence of an aqueous solution of a strong base which is sprayed into the blended powder. The granulate is dried, screened, mixed with optional lubricants (such as talc or magnésium stéarate) and compressed into tablets. Preferred aqueous solutions of strong bases are solutions of alkali métal hydroxides, such as sodium or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of water-miscible solvents such as lower alcohols). n/

345 [0719] The resulting tablets may be coated with an optional film-forming agent, l'or identification, taste-masking purposes and to improve ease of swallowing. The film forming agent will typically be présent in an amount ranging from between 2% and 4% of the tablet weight. Suitable film-forming agents are well known to the art and include hydroxypropyl methylcellulose, cationic méthacrylate copolymers (dimethylaminoethyl méthacrylate/ methyl-butyl méthacrylate copolymers - Eudragit E - Rôhm. Pharma) and the like. These film-forming agents may optionally contain colorants, plasticizers and other supplémentai ingrédients.

[0720] The compressed tablets preferably hâve a hardness sufficient to withstand 8 Kp compression. The tablet size will dépend primarily upon the amount of compound in the tablet. The tablets will include from 300 to 1100 mg of compound free base. Preferably, the tablets will include amounts of compound free base ranging from 400-600 mg, 650-850 mg and 900-Il 00 mg.

107211 In order to influence the dissolution rate, the time during which the compound containing powder is wet mixed is controlled. Preferably the total powder mix time, i.e. the time during which the powder is exposed to sodium hydroxide solution, will range from 1 to 10 minutes and preferably from 2 to 5 minutes. Following granulation, the particles are removed from the granulator and placed in a fiuid bed dryer for drying at about 60°C.

Examplc 262 [0722] Activity testing is conducted in the Examples below using methods described herein and those well known in the art.

Sodium carrent screening assays:

[0723] The late sodium current (Late INa) and peak sodium current (Peak INa) assays are performed on an automated electrophysiology platlorm, QPatch 16X (Sophion Bioscience, Copenhagen, Denmark), which uses the whole cell patch clamp technique to measure currents through the cell membrane of up to 16 cells at a time. The assay uses an HEK293 (human embryonic kidney) cell line heterologously expressing the wild-type human cardiac sodium channel, hNaJ.5, purchascd from Millipore (Billerica, MA). No beta subunits were coexpressed with the Na channel alpha subunit. Cells are maintained with standard tissue culture procedures and stable channel expression is maintained with 400 pg/mL Geneticin in the culture medium. Cells isolated for use on QPatch are

346 incubated for 5 minutes in Detachin IX (Genlantis, San Diego, USA) at 37 °C to ensure that 80-90% of the cells are single and not part of a cell cluster. Experiments are carried out at 23-25 °C.

107241 For both the Late INa and Peak INa assays, sériés résistance compensation is set to 100% and sériés résistance and whole-cell compensation are perfomied automatically. Currents are digitized at 25 kHz and low-pass filtered at 12 kHz and 10 kHz for the late and peak INa assays, respcctively. Currents through open sodium channels are automatically recorded and stored in the Sophion Bioscience Oracle databasc (Sophion Bioscience, Copenhagen, Denmark). Analysis is perfomied using QPatch Assay and database software and data are compiled in Excel.

[07251 Compound stocks are routineiy made by the Gilead Sample Bank in plastic vials to 10 mM in dimethyl sulfoxide (DMSO). In some cases, when compounds are not soluble tn DMSO, they are made in 100% éthanol. Stocks are sonicated as necessary. The extracellular solution for screening Late INa is composed of: 140 mM NaCl, 4 mM KCl, I.8 mM CaCh, 0.75 mM MgCB and 5 mM HEPES with pH adjusted to 7.4 using NaOH. The intracellular solution used to perfuse the inside of the cells for both the Late INa and Peak INa assays contains: 120 mM CsF, 20 mM CsCl, 5 mM EGTA, 5 mM HEPES and pH adjusted to 7.4 with CsOH. Compounds are diluted in extracellular solution to l μΜ in glass vials and then transferred to glass well plates beforc robotic addition to the cells. The 0 mM Na extracellular solution (ONa-ECF) used at the end of each experiment for the Late INa and Peak INa assays to measure baseline current contains: 140 mM N-methyl-D-glucamine; 4 mM KCl; 1.8 mM CaCl₂; 0.75 mM MgC^;

mM HEPES and pH was adjusted to 7.4 with HCl.

Late INa Screening Assay:

[0726] For the Late INa assay, sodium channels are activatcd every 10 seconds (0.1 Hz) by depolarizing the cell membrane to -20 mV for 250 milliseconds (ms) from a holding potential of-l 20 mV. In response to a -20 mV voltage step, typical hNaJ .5 sodium currents activate rapidly to a peak négative current and then inactivate nearly completely within 3-4 ms.

[0727] Compounds were tested to détermine their activity in blocking the late sodium current. Late INa was generated by adding 10 μΜ Tefluthrin (pyrethroid) to the extracellular solution while recording Na currents. To confirm the block of late In»

347 observed using the automated screening method, a second late In» enhancer (ATX-II) and the manual patch clamp method were used. ATX-II and tefluthrin occupy distinct, nonovcrlappîng binding sites and modify Na⁺ channel function differently to increase late In.?. Compounds tested hâve been found generally to inhîbît the enhanced late In_u caused by either late In;i enhancer. For the purposes of the screening, late INa is defined as the mean current between 225 ms and 250 ms after stepping to -20 mV to activate Na channels. After establishing the whole cell recording configuration, late INa activator is added to each well 4 times over a I6-17 minute period so that the late component of the Na current reaches a stable value. Compounds were then added (typically at l μΜ), in the presence of the late INa activator, with 3 additions over the course of 7 or 8 minutes. Measurements were made at the end of exposure to the third compound addition and values were normalizcd to the current level when ail Na⁺ was removed from the extracellular solution after two additions ofONa-ECF.

10728| Results are reported as percent block of late INa. When tested in the assay disclosed above with 10 μΜ Tefluthrin activating late INa, for example Compounds II105 inhibited (or reduced) the late sodium current by 45% (see Table l for additional compound data). The inhibition of Late INa of the cardiac isoform hNa_v i.5 support the use of the compounds of this disclosure to treat atrial arrhythmias, ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal's (variant) angina, stable angina, unstable angina, exercise induced angina, congestive heart disease, ischemia, récurrent îschemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, pulmonary hypertension and intermittent claudication.

Peak INa Screening Assay:

[07291 Compounds were also evaluated for their effect in several other assays, including their effect on Peak INa. Good séparation between the concentrations of test compound to reduce late and peak Inu is bénéficiai to enable séparation of the desired effect to reduce late lua-mduced electrical and mechanical dysfunction from the undesired effect to reduce peak 1n₀, which can lead to slowing or block of conduction of electrical excitation in the heart. It is contcmplated that the compounds of Formula I avoid significant block of peak INa. Since the peak INa in the cells used herein can be very large, introducing artifacts in the recording, the concentration of Na* in the batli can be reduced to 20 niM and a nonpermeant cation added to compensate for the Na* that was removed to maintain the

348 osmolarity and ionic strength of the solution (see solution details below). Analysis of peak INa generally requires correction for rundown before determining the % block of peak current by the tested conipound.

[0730] A separate Peak INa screening assay was developcd to allow assessment of the effect of compounds on peak INa at both low and high stimulation frequencies in order to identify compounds that are highly sélective for block of late INa but do not block peak INa. A low stimulation frequency of 0.1 I-lz was used to détermine the effect of the test compound when the channel spent most of the time in the resting (closed) state and provides information about Tonie Block (TB). A higlier stimulation frequency (3Hz) was used to measure block of the channel when it spent more time in the activated and inactivated states and provided a measure of Use-Dependent Block (UDB). Usedependent block refers to the accumulation of block with increased frequency of channel activation. Block of cardiac peak lN_n by compounds of this disclosure is increased with an increase in the frequency of stimulation from O.l to i-5 Hz (frequencies encountered either in the normal hearl or during tachycardia). It is therefore expected that réduction of peak 1n_;) by compounds of this disclosure will be greater at high heart rates, such as those during tachyarrhythmias, than at normal heart rates. As a conséquence, compounds of this disclosure may reduce Na⁺ and Ca²⁺ ovcrload due to late INa and abnormal elcctrical activity and electrical conduction in myocardium thaï is arrhythmic, especially during ischemia.

[07311 The -l 00 mV holding potential and the 3 Hz stimulation frequency were chosen so that the benchmark compound would bave a small but détectable effect under experimental conditions, allowing for direct comparison of new compounds with the benchmark. The extracellular solution for screening Peak INa is composed of: 20 mM NaCl, 120 mM N-inethyl-D glucamine, 4 mM KCI, 1.8 mM CaCl₂,0.75 mM MgCl₂ and 5 mM HEPES with pH adjusted to 7.4 using HCl. The intracellular solution used for the Peak INa assay is the saine as outlined for the Late INa assay (see above).

10732J For the peak INa assay, Na⁺ channels were activated by depolarizing the cell membrane to 0 mV for 20 ms from a holding potential of -100 mV. Aller establishing the whole cell recording configuration, channels were stimulated to open with low frequency stimulation (0.1 Hz) for 7 minutes so that the recording can be monotered and the extent to which the recording bas stabilized can be assessed. Aller this stabilization period the stimulation frequency was increased to 3 Hz for 2 minutes and then returned to 0.1 Hz. d

349

Since 3 Hz stimulation causes a small decrease in the peak current even in the absence of compound, this internai control was used for each cell, when no compound is présent, to correct the results from 3 Hz stimulation when compound is présent. Following 3 Hz stimulation under control conditions, the cell is allowcd to recover for 200 seconds betbre compound is added. The test compound tested at l or 3 μΜ (depending on the % block of late INa at l pM) was added 3 times at 60 second intervals, while stimulating the channels to open at 0.1 Hz to monitor the progression of TB. Aller the third compound addition, a 320 second wait period was imposed to allow for équilibration before the second period of 3 Hz stimulation begins. TB was measured before the second period of 3

Hz stimulation. Both TB and UDB were analyzed by incorporating rundown correction for the peak INa and UDB as calculated by compensating for the small use-dependent effect of the stimulation protocol on peak INa in the absence of compound. Compound 11-105 exhibited peak INa TB of 9% and peak INa UDB of 11%, both measured at l pM.

10733] The above data demonstrates the selectivity of Compound II-105 to block late

INa compared to peak INa (45% versus 9% for peak INa TB; and 45% versus 11% for peak INa UDB) and suggests that Compound II-105 should show minimal to no effects on conduction through the heart (which is driven by peak INa) at concentrations that effectively block late INa.

h ERG Screening Assay:

107341 Compounds were also tested for their effect to block the hERG K⁺ channel. At least a 3-5-fold séparation, preferably 10 fold séparation, of IC50 values for compounds to inhibit late In» (more potent) and hERG (less potent) indicates that a compound is unlikely to cause QT prolongation and/or proarrhythmic effects at concentrations nceded to reduce late l_Na.

|0735j Compounds were screened to test their activity in biocking the hERG potassium channel at AVIVA Biosciences (San Dcigo, CA, USA). The hERG channel is heterologously expressed in a CHO (Chinese Hamster Ovary) cell line. Cells were maintained with standard tissue culture procedures and stable channel expression was maintained with 500 pg/mL G418 in the culture medium. Cells were harvested for testing on the PatchXpress 7000A automated patch clamp with Accumax (Innovative Cell Technologies, San Diego, CA) to isolate single cells. A

350 [07361 The following solutions were used for electrophysiological recordings. The extemal solution contained: 2 mM CaCl₂; 2 niM MgCl₂; 4 mM KCl; 150 mM NaCl; 10 mM Glucose; 10 mM HEPES (pH 7.4 with IM NaOH; osmolarity, -3I0 mOsm). The internai solution contained: 140 mM KCl, 10 mM MgCI₂, 6 mM EGTA, 5 mM HEPES, 5 mM ATP (pH adjustcd to 7.25 with KOH; osmolarity, —295 mOsm).

[0737] hERG channeis were activated when the voltage was first stepped to -50 mV for 300 ms from the -80 mV holding potential and then stepped to +20 mV for 5 seconds. At +20 mV the channeis open and then largely inactivate, so the currents are relatively small. Upon returning to -50 mV from +20 mV, hERG currents transiently become much larger as inactivation is rapidly removed and then the channel closes. The first step to -50 mV for 300 ms was used as a baseline for measuring the peak amplitude during the step to -50 mV after channel activation. The peak tail current at -50 mV was measured both under control conditions and after addition of compound, each cell serving as its own control.

[0738] Ail compounds were prepared as 10 mM DMSO stocks in glass vials. Stock solutions were mixed by vigorous vortexing and sonication for about 2 minutes at room température. For testing, compounds were diluted in glass vials using an intermediate dilution step in pure DMSO and then further diluted to working concentrations in extemal solution. Dilutions were prepared no longer than 20 minutes bcforc use.

10739] For the electrophysiological recordings, aller achieving the whole-cell configuration, cells were monitored for 90 seconds to assess stability and washed with external solution for 66 seconds. The voltage protocol described above was then applied to the cells every 12 seconds and throughout the whole procedure. Only cells with stable recording parameters and meeting specified health criteria were allowed to enter the compound addition procedure.

[07401 Extemal solution containing 0.1 % DMSO (vehicle) was applied to the cells first to establish the control peak current amplitude. After allowing the current to stabilize for 3 to 5 minutes, 1 μΜ and then 10 μΜ test compounds were applied. Each compound concentration was added 4 tiines and cells were kept in test solution until the effect of the compound reached steady state or for a maximum of 12 minutes, After addition of test compound, a positive control ( I μΜ Cisapride) was added and must block >95% of the current for the experiment to be considered valid. Washout in the extemal solution compartment was performed until the recovery of the current reached steady state. Data _r

351 were analyzcd using DataXpress software and its associated SQL server database, Clampfit (Molecuiar Devices, Inc., Sunnyvale, USA) and Origin 7 (Originlab Corp.) When tested in the assay disclosed above, Compound II-105 inhibited (or reduced) the activity of the hERG potassium channel by <10% at l μΜ (see Table l for additional 5 compound data).

|074l] Compounds were tested using the above described assay methods. Data are obtained by testing the listed compounds at l μΜ concentration in the late and peak INa assays (and other concentrations as needed) and at l μΜ and ΙΟ μΜ for the hERG channel assay.

Table l : Late I_Nil Assay results

No.	Late I_NaΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
U-l	25
II-3	15
II-4	30
Il-5	26
Π-6	16
II-7	34
11-8	21
11-10	43	9	2
II-II	23
11-12	21
11-13	18
11-14	47	7	6
11-15	48	8	8
11-16	19
H-17	59	47	46
11-19	21

352

No.	Late l_NnΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
II-21	18
II-22	30
II-23	25
11-24	23
11-25	25
11-31	51	9	8
11-33	46	10	13
11-35	25
Π-39	16
11-41	17
11-42	34
11-43	23
11-44	39
11-45	27
11-46	25
11-47	60	13	45
11-48	47	13	53
11-49	63	28	44
11-50	48	5	19
11-51	20
H-54	51	13	20
11-57	55	50	41
11-59	15
11-61	41
11-62	49	10	14

353

No.	Late Ijîi, ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
11-64	55	12	19
11-65	19
11-67	22
11-68	17
11-69	33
11-70	37
11-71	12
11-72	60	22	34
11-73	42
11-74	12
11-75	68	45	59
11-77	21
11-83	31
11-87	22
11-88	41
11-89	28
11-91	54	8	11
11-92	34
11-95	19
11-97	36
11-98	39
11-102	21
11-104	21
11-105	45	9	11
11-106	18

354

No.	Late I_NnΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
11-107	18
11-110	35
11-113	27
11-115	21
11-117	37
11-122	19
11-123	21
11-124	17
11-129	33
11-133	23
11-134	69	38	34
11-135	32
11-136	30
11-137	54	28	26
11-13«	47	16	23
11-139	31
Π-140	32
11-141	73	40	40
11-142	19
11-143	65
11-144	68	34	41
11-145	19
11-146	36
11-147	54	13	6
11-148	17

355

No.	Latc l_NnΙμΜ	Peak TB ΙμΜ	Pcak UDB ΙμΜ
II-150	27
II-lSl	51	13	14
II-152	23
1I-153	56	15	13
II-154	25
11-155	38	13	11
11-156	48	23	13
11-157	43	13	16
11-15«	58	34	26
11-159	28
11-160	48
11-162	20
11-163	28
11-164	75
11-165	56	15	30
Π-166	53	20	34
11-167	56	20	25
11-168	44	36	47
11-169	65	23	23
II-170	66	36	31
11-171	24
11-172	33
11-174	48	7	18
11-175	53	21	16
11-176	68	45	44

356

No.	Latc 1^_η ΙμΜ	Peak TB ΙμΜ	Pcak UDB ΙμΜ
II-177	22
II-178	19
11-179	21
11-186	55	20	30
11-187	62	9	21
11-189	53	23	28
11-190	18
11-191	25
11-192	15
11-193	70
11-194	63
11-195	66
III-l	33
111-4	35
III-10	29
111-11	20
111-12	39	10	17
Iïl-15	50	19	18
ΠΙ-23	26
111-24	17
111-29	48	11	14
II1-30	16
111-32	22
II1-33	37
111-37	41

357

No.	La te l^_nIgM	Pcak TB IgM	PcakUDB IgM
I1I-38	28
III-40	22
III-50	24
III-58	26
IV-4	14
V-l	24
V-3	23
V-5	49	5	5
VI-4	36
VI-ll	19
VI-26	28
Vl-30	40
VI-3I	61	50	42
VI-32	66	28	26
VI-36	47
Vl-37	48
VIII-4	61	12	19
Vil 1-5	32
VII1-6	38
Vil 1-7	59
VIII-8	47
VIII-9	50
VII1-10	25
VIII-11	42
IX-2	22

358

No.	Late ΙμΜ	Peak TB ΙμΜ	Peak UDB ΙμΜ
IX-3	27
X-8	50	6	10
X-ll	48	17	20
X-12	26
X1I-1	53	25	21
XII-2	57	45	64
XII-3	44	51	79
XII-5	25
XII-8	36
XI1-9	22
XII-10	45	13	20
Xll-11	55	25	24
XI1-14	26
XII1-1	16
XIII-2	19
XIII-3	17
XIII-4	51	8	9
XIII-6	60	8	8
XIII-10	22

10742] The assay results shown in the above table establishes thaï compounds tested sliowed activity as modulators of late sodium current, for example by inhibiting (or rcducing) the late sodium cuncnt.

10743] In some embodiments the effects of a conipound of Formula I are spécifie for the late sodium current and show little or no activity with respect to one or more other ion channels. Thus, in some embodiments, a conipound having an activity of reducing late Λ

359 sodium current will also exhibit little or no activity with regard to the peak sodium current. In particular embodiments, a compound having an activity of reducing late sodium current will also exhibit little or no activity with regard to the hERG potassium channel.

10744] Table 2 is a summary comparing compound II-73 and ranolazine abilîty to block late and peak hNa_v l .5 Na⁺ current and hERG K^μ current. The data in Table 2 were obtained in similarbut not necessarly contemporaneous experiments.

Table 2

	IC_5Ü μΜ	IC₅o Ratio (fold)
Late INa	Peak INa	hERG	Peak INa/Late INa	hERG/Late INa
II-73	0.6±0.l	52 ±5	5.7 ± 0.6	87	10
Ranolazine	6.7 ± 1.4	428 ± 33	13.4 ±0.5	64	2

107451 The above data suggests that the compound of Example U-73 exhibits comparable or improved properties with respect to the tested paramaters.

L-type Ca2+ Channel Assay — ChanTest:

[0746| Selected compounds were screened for block of the cardiac L-typc Ca“* channel (hCav l .2, encoded by the human CACNAIC gene and coexpressed with the beta 2 subunit, encoded by the human CACNB2 gene and alpha2deltal, encoded by the CACNA2D1 gene). The Ca²⁺ channel is heterologously expressed in a CHO (Chinese Hamster Ovary) cell line. Cells are maintained following standard tissue culture procedures and stable channel expression is maintained with appropriate sélection antibiotics in the culture medium. Cells arc harvested for testing on the PatchXpress automated patch clamp (Model 7000A, Molecular Devices, Sunnyvale, CA) by washing twice with Hank’s Balanced Sait Solution, treating the cells with trypsin and resuspending cells in culture medium (4-6 xlO⁶ cells in 20 mL). Cells in suspension are allowed to recover for 10 minutes in a tissue culture încubator set at 37°C in a humidilied 95% air, 5% CO₂ atmosphère.

360 [0747] The following solutions are used for electrophysiological recordtngs. The extemal solution contains (mM): 137 NaCl, 4 K.C1, 1.8 CaCl₂, I MgCl₂, 10 Glucose, 10 HEPES (pH 7.4 with NaOH). The internai solution contains (mM): 130 Cs Aspartate, 5 MgCI₂, 10 EGTA, 4 ATP, 0.5 GTP, 10 HEPES, (pH adjusted to 7.2 with N-methyl-Dglucamine).

(07481 Vehicle is applied to naive cells (n > 2, where n = the number cells), for a 5-l 0 minute exposure interval. Each solution exchange is performed in quadruplicate. At the end of each experiment, a saturating concentration of nifedipine (10 μΜ) is added to block hCavl .2 current. Leak current is digitally subtractcd from the total membrane current record.

107491 Test compound stock solutions are prepared by addition of dimethyl sulfoxide (DMSO) and stored frozen. Each test compound DMSO stock is sonicated (Model 2510/5510, Branson Ultrasonics, Danbury, CT), at ambient room température for at least 20 minutes to facîlitate dissolution. Test compound concentrations are prepared fresh daily by diluting stock solutions into the standard extracellular physiological saline solution (see above). The maximum percent of DMSO added with compound is 0.1 %. Ail test compound and control solutions arc placed in a glass-lined 96-well compound plate before loading on PatehXpress.

|0750| Two concentrations (l, 10 μΜ) of each test compound are applied at fîvc (5) minute intcrvals via disposable polyethylene micropipette tips to naïve cells (n > 2, where n = the number cells/concentration). Each test compound concentration is added to the cell in quadruplicate. Total duration of exposure to each test compound concentration is 5 minutes.

[0751] Onset and steady state block of hCavl .2 (α1Ο/β2/α2δί J channels is measured using a stimulus voltage pattern consisting of a depolarizing test puise (duration, 200 ms; amplitude, 10 mV) at 10s intcrvals from a -80 mV holding potential. Peak current is measured during a step to 10 mV.

|07521 When tested in the assay disclosed above, Compound 11-73 blocked the hCavl .2 late current by 14% and peak current by 32% at 1 μΜ concentration. At 10 μΜ concentration the compound 11-73 blocked the hCavl.2 late current by 47% and the peak current by 79%.

361

Example 263

107531 Compounds of this disclosure that block cardiac late Im may also médiate UDB of other Na⁺ channel isoforms including the major Na⁺ channel isoforms in pcripheral nervous System pain fibers, Nayl.7 and 1.8. Compounds of this disclosure that block these channels inay also be uscful to decrease neuropathie pain.

[0754| In particular embodiments, a compound will exhibit a high selectivity for the late sodium current modulatory activity as compared to the activity in one or more other ion channels. The selectivity of a compound may be determined by determining the percentage réduction in late sodium currcnt due to the compound, as measured by the assay described above. The percentage réduction in one other ion channel activity, such as the hERG potassium channel, due to the compound is determined as described above. The selectivity is determined by taking the ratio of (percentage réduction in late sodium current) to (percentage réduction in one other ion channel activity). The assays conducted to measure activities in this regard should be performed as described above, with the compound at a concentration of 10 μΜ (or at the upper limit of solubility, if less). In particular embodiments, the selectivity of a compound of the disclosure will bc at least 5:1, e.g. at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 12:1, al least 15:1, at least 20:1, or at least 25:1, when comparing the percentage réduction in late sodium current versus percentage réduction of one of the peak sodium current. the hERG potassium channel current. Selectivity data can be calculated based on the values provided in the Examples above.

10755] Evidence supports a rôle for the tetrodotoxin-sensitive Na_vl .7 in the pathogenesîs of pain. In this assay, using whole-cell patch-clamp technique, the effects of compounds of the disclosure on hNa_v1.7 (hNa_v 1.7+β l subunits) peak Na* current ( !n_u) are tested as described previously (Rajamani et al, 2009). Cells are continuously maintained using MEM (Gibco-lnvitrogen, Carlsbad, CA) supplcmented with 10% beat inactivated fêtai bovine sérum, 1% penicillin-streptomycin, 600 pg/mL gcneticin (Gibco-lnvitrogen), 2 pg/mL blastocydin (Calbiochem, NJ, USA), and are incubatcd at 37C in an atmosphère of 5% CO₂ in air. For recording hNavl.7 Ins, HEK293 cells are superfused with an extracellular solution containing (in mM): 140 NaCI, 3KC1, 10HEPES, 10 glucose, I MgCI₂, 1 CaCl₂, pH 7.4 (with NaOH). Patch pipettes are filled with an internai solution containing (in mM): 140 CsF, 10 NaCI, 1 EGTA, 10 I IEPES, pl i 7.3 (with CsOH). /

362

X [0756) Whole-cell I^a are recorded as described previously (Rajamani et al, 2009) using an Axopatch 200B amplifier (Molecular Devices, Sunnyvale, USA). Signais are filtered at 5 kHz and sampled at 20 kHz. Patch pipettes are formed using borosilicate glass (World Précision Instruments, Sarasota, USA) using a micropipette puller (Dagan Corporation, Minneapolis, USA). The offset potential is zeroed before the pipette is attached to the cell and the voltages are not corrected for the liquid junction potential. In ail recordings, 7580% of the sériés résistance compensation will be achieved, thus yielding a maximum voltage error of~5 mV and leak currents are cancelled by P/4 subtraction. pCLAMP 10.0 software (Molecular Devices) will be used to generate voltage clamp protocols and acquire data. The membrane potential is held at -100 or -120 mV and the cell dialyzed with the pipette solution for 5-7 minutes before current is recorded, to avoid timedependent shifts in Na⁺ channel gating within the first several minutes after patch rupture. In ail experiments, the température of experimental solutions will be maintaincd at 20±I^l’C using a CL-I00 bipolar température controller (Warner Instruments, Hamden, USA).

10757) Data are analyzed using Clampfit and Mîcrocal Origin (MicroCal, Northampton, USA) software.

)0758] When tested in the assay disclosed above, Conipound II-73 blocked the hNa_v l .7 sodium channel isoform with IC50 of 5.2 μΜ at a frequency of 10 Hz. Compound II-73 blocked the hNa_v 1.8 sodium channel isoform with a IC50 of > 10 μΜ at a l() Hz frequency. At higher frequency of 25 Hz, compound H-73 blocked both hNa_v 1.7 and hNa_v 1.8 isoforms with IC50 of l.l and 1.5 μΜ respectively. The inhibition of either hNa_v 1.7 and hNa_v 1.8 isoforms or the inhibition of both channels when stimulatcd at these frequencies support the use of compounds of this disclosure to decrease neuropathie pain.

Example 264

Expression of hit mu h Nayl.I cl)NA

10759) Ail experiments with human Nayl. I are conducted as described (Kahlig, et al., PNAS, 105: 9799-9804). Briefly, expression of hNavl.l is achieved by transient transfection using Qiagen Superfect reagent (5.5 pg of DNA is transfected at a plasmid mass ratio of 10: l : l for «i :βι :β₂). The human βι and β₂ cDNAs are cloned into plasmids

363 containing the marker genes DsRcd (DsRed-IRES2-hpi) or eGFP (eGFP-IRES2-hp₂) flanking an internai ribosome entry site (1RES).

Electrophysiology [0760] Whole-cell voltage-clamp recordings are used to measure the biophysical properties of WT and mutant Navl.l channels, as described previously (Kahlig, 2008). For recording hNavl. 1 1ν₁₍, HEK293 cells are superfused with solution containing (in mM): 145 NaCl, 4 KC1, 1.8 CaCI₂, 1 MgCi₂, 10 dextrose, 10 HEPES, with a pH of 7.35 and osmolarîty of’310 mOsmol/kg. The pipette solution contains (in mM): 110 CsF, 10 NaF, 20 CsCl, 2 EGTA, 10 HEPES, with a pH of7.35 with an osmolarîty of 300 mOsmol/kg. Cells are allowed to stabilize for 10 min after establishment of the whole-cell configuration before current is measured. Sériés résistance is compensated 90% to assure that the command potential is reached williin microseconds with a voltage error <2 mV. Leak currents are subtracted by using an online P/4 procedure and ail cuncnts are lowpass Bessel filtered at 5 kHz and digitized at 50 kHz.

|07611 For use-dependent studies, cells are stimulated with depolarizing puise trains (-10 mV, 5 ms, 300 puises, 10 and 25Hz) from a holding potential of-120 mV. Currents are then normalized to the peak current recorded in response to the first puise in each frequency train. For tonie block studies, peak and persistent (late) currents are evaluated in response to a 200 ms depolarization to -10 mV (0.2 Hz) following digital subtraction of currents recorded in the présence and absence of 0.5 μΜ tetrodotoxin (TTX). The sodium current termed Late INa in the periphery is commonly called persistent INa in the CNS. Persistent current is calculated during the final 10 ms of the 200 ms step. Data analysis is performed using Clampfit 9.2 (Axon Instruments, Union City, CA, U.S.A), Excel 2002 (Microsoft, Seattle, WA, U.S.A.), and OriginPro 7.0 (OriginLab, Northampton, MA, U.S.A) software. Results are presented as mean ± SEM.

In vitro Pharmacology (0762] A stock solution of 1 OmM compound of Formula I is prepared in 0.1 M HCl or DMSO. A fresh dilution of the compound of Formula I in the bath solution is prepared every experimental day and the pH is readjusted to 7.35 as necessary. The final DMSO concentration was kept at 0.1% in ail solutions. Direct application of the perfusion X

364 solution to the clamped cell is achieved using the Perfusion Pencil system (Automate, Berkeley, CA). Direct cell perfusion is drivcn by gravity at a flow rate of 350 pL/min using a 250 micron tip. Tliis system sequesters the clamped cell within a perfusion stream and enables complété solution exchange within l second. The clamped cell is perfused continuously starting immediately after establishing the whole-cell configuration. Control currents are measured during control solution perfusion. Where appropriate, concentration inhibition curves are fit with the Hill équation: ~ l/[l + lO^A(logICso-I)*k], where IC50 is the concentration that produces half inhibition and k is the Hill slope factor.

[07631 Solutions containing the compounds of the disclosure are perfused for three minutes prior to current recordings to ailow cquilibrium (tonie) drug block. Tonie block of peak current is measured from this steady-state condition. Use-dependent block of peak current is measured during puise number 300 of the puise train, (-10 mV, 5 ms, 300 puises, 10Hz) from a holding potential of-120 mV. Two sequential puise train stimulations are averaged to obtain mean current traces for each recording condition.

/11 vivo pharmacology [0764] Jugular vein cannulated male Sprague Dawley rats (250 - 350g, Charles River Laboratories, Hollister, CA) are used to study brain pénétration of the compounds of the disclosure in vivo. Animal use is approved by the Institutional Animal Care and Use Committee, Gilead Sciences. Three rats per group are infused intravcnously with the compound of the disclosure in saline at 85.5 pg/kg/min. After 1,2.5 or 5 h the animais are sacrificed for plasma and brain collection, and concentrations of the compound of the disclosure are measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Brain tissue is homogenated in 1% 2N HCl acidified 5% sodium fluoride (final homogenate is diluted 3-fold). Plasma and brain homogenate samples (50 μΙ) are precipitated along with deuterated D3-Formula 1 as an internai standard, vortexed and centrifuged. The supernatant (50 pL) is transferred and diluted with water (450 pl) prior to injection (10 pl). High performance liquid chromatography wasperformed using a Shimadzu LC-1OAD liquid chromatograph and a Luna Cl8(2), 3 pin, 20 x 2.0 mm column with a mobile phase consisting of water containing 0.1 % formic acid (solution A) and acetonitrile (solution B) carricd out under isocratic conditions (75% solution A, 25% solution B; flow rate 0.300 ml/min). Mass spectrométrie analyses are performed using an API3000 mass spectromelcr (Applied Biosystems, Foster City, CA)

365 operating in positive ion mode with MRM transition 428.1 > 98. Brain-to-plasma ratios are calculated for each sample as ng compound/g brain divided by ng compound/ml plasma.

Examplc 265

Expression of Ituntan ΝαιΊ.2 cDNA [0765] Wild-type (WT) cDNA stably transfected in Chinese hamster ovary (CHO) cells is used to record Iwa· Unless otherwise noted, ail reagents are purchased from SigmaAldrich ( St Louis, MO, U.S.A.).

Electrophysiology

107661 Whoie-cell voltage-clamp recordings are uscd to measure the biophysical properties of WT. Briefly, the pipette solution consists of (in mM) 110 CsF, 10 NaF, 20 CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 and osmolarity of 300 mOsmol/kg. The bath (control) solution contains in (mM): 145 NaCI, 4 KCl, I.8 CaCI₂, I MgCl₂, I0 dextrose, 10 HEPES, with a pH of 7.35 and osmolarity of 3I0 mOsmol/kg. Cells are

I5 allowed to stabilise for 10 min after establishment of the wholc-cell configuration belore current is measured. Sériés résistance is compensated 90% to assure that the command potential is reached wilhin microscconds with a voltage errer <2 mV. Leak currents arc subtracted by using an online P/4 procedure and ail currents are low-pass Bessel filtered at 5 kHz and digitized at 50 kHz.

|<J767| For clarity, représentative ramp currents are low pass filtered off-line at 50 Hz.

Spécifie voltage-clamp protocole assessing channel activation, fast inactivation and availability during répétitive stimulation are uscd. Results arc présentée! as mean ± SEM„.

[0768| Tonie block of peak currcnt is measured using a step to -l OmV (20ms) from a holding potential of -!20mV (0.2Hz). Use-dependent block of peak current is measured during puise number 300 of a puise train (-10 mV, 5 ms, 300 puises, 10Hz or 25Hz) from a holding potential of-120 mV. Two scquential puise train stimulations are averaged to obtain mean current traces for each recording condition, which are then used for offline subtraction and analysis.

|0769] For use-dependent studies, cells are stimulatcd with depolarizing puise trains (10 mV, 5 ms, 300 puises, K) and 25Hz) Irom a holding potential of — 120 mV. Currents

366 are then normalized to the peak current recorded in response to the first puise in each frequency train. For tonie block studies, peak current is evaluated in response to a 20 ms depolarization to -l 0 mV (0.2 Hz). Data analysis is performed using Clampfit 9.2 (Axon Instruments, Union City, CA, U.S.A), Excel 2002 (Microsoft, Seattle, WA, U.S.A.), and OriginPro 7.0 (OriginLab, Northampton, MA, U.S.A) software. Results are presented as mean ± SEM.

lit vitro Pharmacology [0770] A stock solution of lOmM compound of Formula I is prepared in 0.1 M HCl or DMSO. A fresh dilution of the compound of Formula I in the bath solution is prepared every experimental day and the pH is readjusted to 7.35 as necessary. The final DMSO concentration was kept at 0.1% in ail solutions. Direct application of the perfusion solution to the clamped cell is achicved using the Perfusion Pencil system (Automate, Berkeley, CA). Direct cell perfusion is driven by gravity at a flow rate of 350 pL/min using a 250 micron tip. This system sequesters the clamped cell within a perfusion stream and enables complété solution exchange within l second. The clamped cell is perfused continuously starting immediately after establishing the whole-cell configuration. Control currents are measured during control solution perfusion.

[07711 Solutions are perfused for three minutes prîor to current recordings to allow equilibrium (tonie) drug block. Tonie block of peak currents is measured from this steady-state condition. Three séquentiel current traces are averaged to obtain a mean current for each recording. The mean current traces are utilized for offline analysis. Usedependent block of peak current is measured during puise number 300 of the puise train, (-10 mV, 5 ms, 300 puises, 10Hz) from a holding potential of-120 mV. Two sequential puise train stimulations are averaged to obtain mean current traces for each recording condition, which are then used for offline subtraction and analysis Where appropriate, concentration inhibition curves are fit with the Hill équation: I/l_m(W = l/[l + 10^A(loglC5ol)*k], where IC50 is the concentration that produces half inhibition and k is the Hill slope factor.

Results |(I772| Using the above methods it may be demonstrated that the compounds of the disclosure are sélective for inhibiting cardiac Late Ina current without inhibiting peak and low frequency currents of brain isoforms NaV 1.1 and 1.2. The compounds of the

367 disclosuremay inhibît the very liigh frequency firingof Na_vl.l and Na_vl.2 or demonstrate voltage dépendent block of mutant Navl l and Nay l .2 observed with epilepsy patients. In addition compounds of this disclosure may show activity for inhibition of a panel of Nayl .1 mutant channels associated with the epilepsy and headache (migraine) syndromes 5 GEFS+, SMEI and FHM3 suggesting the ability of the compounds of the disclosure to preferentially block the abnormal increased persistent current carried by these mutant channels. disclosure

107731 When tested in the assay disclosed above for hNa_v 1.1 and hNa_v 1.2 sodium channei isoforms, Compound 11-73 blockcd the hNa_v 1.1 sodium channei isoform peak

INa with 1C₅₍₎ value of > 100 pM at a frequency of 10 I-Iz and the hNa_v 1.2 sodium channei isoform peak INa with IC50 value of > 30 pM at the same frequency. At higher frequency of 25 Hz the compound 11-73 blocked both hNa_v 1.1 and hNa_v 1.2 isoforms with IC50 of 3.4 pM and 10.1 pM respectively. The inhibition ofeithcrhNa_v 1.1 and hNa_v 1.2 isoforms or the inhibition of both channels when stimulatcd at these frequencies support the use of compounds of this disclosure to treat patients with epilepsy.

Table 3: Late I_Nn Assay results

No.	La te 1n«*	ΝΑ V 1.1* UDB-I0HZ	NAV1.2* UDB-IOIIZ	hERG	RIIE ART MAPD90 ATX*
II-7	34	0	13		-10
11-10	43	-4	9
11-14	47	16	19
11-17	59			<10
11-22	30	3	15	16
11-42	34	2	12		-27
11-46	25	2	16
11-61	41	9	25	<10	-62
11-73	42	10	19	18	-56
11-75	68	35	52
11-83	31	_2	10	21

368

No.	Latc I_Nn*	NAVl.l* UDB-10HZ	NAV1.2* UDB-10HZ	11ERG	RIIEART MAPD90 ATX*
11-88	41	-10	-1	26	-69
11-91	54	-9	-3
11-98	39	-1	-8	<10	-50
11-105	45	-17	1	<10
11-110	35	-4	-2	26
11-117	37	-Il	-18	<10
H-129	33	8	7	17	-49
11-138	47	21	40
11-143	65	29	44
11-156	48				-23
III-1	33	-1	-3	<10	-47
V-5	49	-18	3
VII1-4	61	5	18	30	-25
VII1-6	38	6	20	<10	-49
X-8	50	-12	-14	<10
XII-1	53	-1	-4
XI1-8	36	11	11		-34

* % Inhibition at l uM

Examplc 266

Ischemia-indnced ST segment élévation in anesthetized rahhits [0774] This study was undertaken to déterminé the anti-ischeinic effects of compounds of the présent disclosure in an in vivo rabbit model.

Methods:

10775] Female New Zealand rabbits (3.0-4.0 kg) were purchased from Western Oregon Rabbitry. Animais were housed on a 12-h light and dark cycle and received standard

369 laboratory chow and water. Ali experimcnts were perfonned in accordance with the Guide for the Care and Use of Laboratory Animais published by The National Research Council and with the experimental protocol approved by the Institutional Animal Care Committee of Gilead Sciences, Inc.

|0776| Rabbits were anesthetizcd with ketamine (35 mg/kg) and xylazine (5 mg/kg) intramuscular injection (im). A tracheotomy was perfonned and the trachea was intubated with an endotrachéal tube. The animal was ventilated with room air supplementcd with oxygen using a pressure control animal ventilator (Kent Scientific Corp., Torrington, CT) at a respiratory rate of 40 strokes/min and peak inspiration pressure of 10 mmH₂O, which was adjusted to keep blood gases and pH within the physiological range (iSTAT clinic analyzer, lleska Corp.; Waukesha, Wl). The left fémoral artery was cannulated for the measurement of blood pressure (BP). Blood samples were also withdrawn from fémoral artery. The right extcrnal jugular vein was cannulated for drug/vchicle administration. Needle électrodes were inserted subcutaneously into the limbs for recording of the surface electrocardiogram (ECG). The heart was exposed via an incision in the 4^lh intercostal space (4^lb and /or 5^1h ribs were eut for a clear surgical vision). The chest was opened and a pericardial cradle was formed using 4 retractors. A eoronary artery occluder, comprised of a snare made of 5 cm PE-10 tubing with a 6-0 Prolene polypropylene suture in it, was placed loosely around the left anterior descending artery (LAD) at its origin. Two unipolar électrodes, made with teflon coated silver wire attached to a small patch of filter paper, were attached on the surface of the ischémie and normal régions of the left ventricle to record epicardial electrocardiogram. Référencé électrodes were placed in the open incision of the neck. The body température of the animal was monitored via a rectal thermometer and maintained at 37-40°C by adjusting the surface température of the surgical table. Régional ischemia ( 15 min) was înduced by ligating the LAD followed by 15 min of reperfusion caused by releasing the ligation. The heart was excised at the end of the experiment and the LAD was rc-ligated. The ischémie area was visualized by perfusîng the heart with 1% Evans blue in saline and calculated as a percentage of total ventricular weight. Rabbits with ischémie area less than 10% or larger than 25% were excluded from the analysis. Animais were randomly assigned to vehicle and test compound groups. Test compounds was dissolved in 5% NMP, 30% PG, 45% PEG 400 and 20% de-ionized water (dH₂O). Test compound was given as an iv bolus at 0.1,0.2

370 and 0.4 mg/kg. After 30 min of dosing, the heart was subjected to 15 min of ischemia followed by 15 min of reperfusion.

Results:

10777J The compound of Example II-61 dose-dependently prevented the ischcmia5 induced ST élévation. The area under curve (AUC) for the ST segment height was reduced (vs. control) by 38% and 88% at 0.28 and 0.52 μΜ plasma concentration of compound of Example II-61. At the plasma concentration levels studied, compound of Example I1-61 had no significant effect on blood pressure (BP), heart rate (HR) and ECG intervals prior to the ischemia. The data suggests the compound of Example II-6I prevents ischemia-induced 10 myocardial electrical dysfonction in a dose-dependent manner.

10778] Simiiarly, compound of Example I1-73 dose-dependently prevented the ischemiainduced ST élévation. The area under curve (AUC) for the ST segment height was reduced (vs. control) by 55% and 93% at 0.25 and 0.5 pM respective plasma concentration of compound of Example ll-73. At the plasma concentration levels studied, compound of

Example I1-73 had no significant effect on blood pressure (BP), heart rate (HR) and ECG intervals prior to the ischemia. The data suggests the compound of Example II-73 prevents ischemia-induced myocardial electrical dysfonction in a dose-dependent manner.

Claims

What is claimed is:

l. A conipound of Formula IA:

wherein:

Cy is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

Q is a covalent bond, -O-C0.2 alkylene, -NR^II-Co.₂ alkylene, C2 alkylene,

C₂ alkenylene or C₂ alkynylene;

m is 0, l, 2 or 3;

n is 0, l, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -C(O)N(R^2O)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R^2,), -S(O)2-N(R²⁰)(R²²), C,.6 alkyl, C₂ut alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said Cm alkyl, C₂.₄ alkenyl, C₂-₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cj-î, alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cri, alkylcne-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵or -Cm, alkylene-L-C|.(, alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NI 1S(O)₂-, -S(O)₂NH-, -C(O)NH- or -NIIC(O)-; provided that when R is -L-R' or -L-C|.(, alkylene-R , then L is not -O-, -S-, -NHS(O)₂- or -N HC(O)-; and (£

372 each R³ is independently hydrogen, deutérium, Cm alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected

7Ω 79 from the group consisting of halo, -NO₂, -N(R“ )(R ), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O- or R² and onc of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Cm» alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

J «s?

each R is independently hydrogen, deuterium, Cm alkyl, -C(O)-OR , -C(O)-N(R^2î’)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

373

-N0₂, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycioalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, Cm alkyl, aralkyl, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycioalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁵ is cycioalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycioalkyl, aryl, heteroaryl or heterocyclyl arc optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Cm alkyl, cycioalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cr, alkyl, cycioalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰; X

374

R¹⁷ is halo, -O-R²⁰ or C,._s alkyl;

jn ·!>

R. antl R are in each instance independently selected from the group consisting of hydrogen, C|.₍, alkyl, C₂.e alkenyl, C₂.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.6 alkenyl, C₂.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂₁ -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

Trt Τ') Tfl 'J'I when R and R are attached to a commun nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R^2f', -CN, Cm alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof;

provided that when each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl, Q is a bond and Cy is phcnyl or morpholinyl, then n is l, 2, 3, 4 or 5. ρζ

375
2. A compound of Formula II:

wherein:

m is 0, l or 2;

n is 0, l, 2,3,4 or 5;

each R^lü is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R^2O)(R²²), -N(R^2,,)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Ci.6 alkyl, C₂.₄ alkenyl, C₂4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said C|.& alkyl, C₂m alkenyl, C₂.4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl arc optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylcne-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkyiene-L-R⁵ or -Cm alkylene-L-C).6 alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -N1IS(O)₂- or -NHC(O)-;

each R³ is independently hydrogen, deuterium or C|.₆ alkyl optionally substituted with heteroaryl;

each R⁴ is independently hydrogen, deuterium or Cm alkyl optionally substituted with heteroaryl;

c

R is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from

376 the group consisting of Cm alkyl, C₂.j alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2i,)(R²²), -CN, oxo and -OR²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally lurther substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²° and -O-R²⁰;

R¹⁷ is halo, -O-R²⁰ or C m alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂.e alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.6 alkenyl, C₂.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, -OCI I₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally lurther substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2. -S(O)2R^2il, -CN, C1 _3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and

377 each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

whereîn the C1.4 alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceuticaily acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

<* £
3. The compound of claim l or 2, wherein R is -Cm alkylene-R or -C|.6 alkyleneL-R⁵.
4. The compound of claim l or 2, wherein R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, halo, cycloalkyl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-OR^Z0, -CN and -O-R²⁰;

wherein said C_t.₆ alkyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, Cm alkyl and aryl; and wherein said C |alkyl is optionally further substituted with one, two or three halo.
5. The compound of claim I, wherein R² and one of R³ can join together with the atom to which they arc attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, -O-R²⁰, -N(R²⁰)(R²²) and -C(O)-OR²⁰; and wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting 0f halo and heteroaryl. c4

378
6.

1 » 1 » t

Cl

1 , fit

3Ί9 or
7. The compound of claim 2, wherein n is I, 2 or 3; and each R^l(> is independently selected from the group consisting of halo, -O-R²⁰, -OS(O)2-R²⁰, Cm alkyl and cycloalkyl; and wherein said alkyl and cycloalkyl arc optionally substituted with one, two or three halo or -CN; and

R²⁰ is independently selected from the group consisting of Cialkyl, cycloalkyl and aryl; and tA

380 wherein the alkyl and aryl are optionally substituted with one, two or three halo or cycloalkyl.
8. The compound of claim 2, wherein n is l, 2 or 3; and each R¹⁰ is independently 2-fluoro, 3-fiuoro, 4-fluoro, 2-chloro, 4-chloro, 2-methyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-difluoromethyl, 4-trilluoromethyl, 4-cyclopropyl, 4-isobutoxy, 4-difluoromethoxy, 4-trifluoromethoxy, 4-(2,2,2-trifluoroethoxy), 4-tri fl uoromcthylsu I foxyl, 4-(2,2,2-tri fluoroethyl), 4-cycl opropoxy, 4-cyclobutylmethoxy, 4-fluorophenoxy, 4-phenoxy or 3-phenoxy.
9. The compound of claim 1 or 2, wherein R and R are in each instance independently selected from the group consisting of hydrogen, C|._(> alkyl and heteroaryl.
10. The compound of claim 2, wherein each R³ is independently hydrogen, deuterium, methyl, isopropyl or pyridin-2-ylmethyl;

m is 0 or 1 ; and

R¹⁷ is halo.
11. The compound of claim 1 or 2, wherein the compound is represented by Formula IIB:

wherein:

n is 0, 1,2 or 3;

each R¹⁰ is independently selected from the group consisting of halo, -NO?, -CN, -SF₅, -Sî(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)NiR^XR²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)?-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)?-N(R^2ü)(R²²), Cm alkyl, C?.₄ alkenyl, C?m alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said Cm alkyl, C7.4 alkenyl, C?^ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo,

381

-N0₂, aryl, heterocyclyl, heteroaryl, Cm alkyi, C|.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2U)(R²²), -CN and -O-R²⁰;

R² is -C|_6 alkylene-R^s;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyi, C₂_i alkynyl, halo, -NO₂, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)-C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)N(R²⁰)(R²²), -CN, oxo and -O-R²⁰; and wherein said Cm alkyi is optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R and R are in each instance independently selected from the group consisting of hydrogen, Cm alkyi, C₂.(, alkenyl, C₂.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and wherein the Cm alkyi, C₂.₆ alkenyl, C₂.₍₁ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selectetl from the group consisting of hydroxyl, halo, Cm alkyi, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, -OCH₂CF₃ and -C(0)-NH₂; or when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclîc or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyi, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂.

—S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃ and -OCF₃; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyi, aryl and cycloalkyl;

wherein the Cialkyi, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

382 or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
12. A compound selected from the group consisting of: 4-((3-methyloxctan-3-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazcpin-5(2H)-one (II -1 );

4-(2-(pyrrolidin-l-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f|[ l ,4]oxazepin-5(2H)-one (II-3);

4-((5-cyclobutyl-l,3,4-oxadiazol-2-yl)mcthyl)-7-(4-(trifluoromethoxy)phenyl)-

3,4-dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (H-4);

4-((2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl )-7-(4-(tri II uoromethoxy)phenyl)-

3,4-dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-5);

4-(quinolin-2-ylmethyl)-7-(4-(tri iluoromethoxy)phenyl)-3,4dîhydrobenzo[f|[l,4]oxazepin-5(2H)-one (11-7);

(R) -2-(pyrimidin-2-ylmcthyl)-8-(4-(trifluoromethyl)phenyl)-3,4,l2.l2atetrahydro-lH-benzo[f]pyrazino[2,l-c][ l ,4]oxazepin-6(2H)-one ( 11-8);

4-(cyclopropylmcthyl)-7-(4-(trifluoiOmethoxy)phenyi )-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2I l)-one (II-10);

(S) -3-methyl-4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (11-12);

(R)-3-methyl-4-(pyrimidin-2-yImethyl)-7-(4-(trifluoromethyl)phenyl )-3,4dihydrobcnzo[f][l,4]oxazepin-5(2l·I)-one (11-13);

6- ((5-oxo-7-(4-(trilluorometlioxy)phenyi)-2,3-diliydrobcnzo[I]|l,41oxazepin-

4(5H)-yl)methyl)picoIinonitrile (11-14);

7- (4-(trifluoromethoxy)phenyl)-4-((6-(trifluoiOmethyl)pyridin-2-yl)mcthyl)-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-15);

7-(4-(trinuoromethoxy)phenyl)-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3,4dihydrobenzo[t][l,4]oxazcpin-5(211)-one (II-16);

4-((6-methylpyridin-2-yl)methyl)-7-(4-(trifluorometlioxy)phenyl)-3,4dihydrobenzo[f|[ l,4]oxazepin-5(2H)-one (11-17);

(2R,1 laS)-2-amino-7-(4-(trilluoromethyl)plienyl)-2,3,l 1,1 latetrahydrobenzo[f]pyrrolo[2,l-c][ 1,4]oxazepin-5( 1 H)-one (11-21 );

(R)-2-(2,2-difluoroethyl )-8-(4-(tri fluoromethyl)phenyl )-3,4,12,12a-tetrahydiO-l 11benzo[f]pyrazino[2,l -c][ 1,4]oxazepin-6(2H)-one (11-22); o/

383 (R) -2-ethyl-8-(4-(trifluoroniethyl)phenyl)-3,4,12,12a-tetraliydro-1Hbenzo[f]pyrazino[2, l -c][ l ,4]oxazepin-6(2H)-one ( ll-23);

(S) -2-(2,2-difluoroethyl)-8-(4-(trifluoiOmethyl)phenyl)-3,4,12,12a-tetrahydro-1Hbenzo[f]pyrazino[2, l -c][ l ,4]oxazepin-6(2H)-one ( 11-24); (S)-2-etliyl-8-(4-(trifluoromethyl)phenyl)-3,4,12,12a-tetrahydro-1 IIbenzo[f]pyrazino[2, l-c][l,4]oxazepin-6(2H)-one (I1-25); 4-(pyrazin-2-ylmethyl)-7-(4-(trifluoromethoxy)pheiiyl)-3,4dihydrobenzof f][ l ,4]oxazepin-5(2H)-one (Il-3 i );

4-((5-niethyloxazol-2-yl)niethyl)-7-(4-(trifluorometlioxy)phenyl)-3,4dihydrobenzo[f][ I,4]oxazepin-5(2H)-one (II-33);

7-(4-(trifluoroinethoxy)phenyl)-4-(2-(2,5,5-trimetliyl-1,3-dioxan-2-yl)ethyl )-3,4dihydrobcnzo[f][l,4]oxazepin-5(2H)-one (Il-35);

tert-butyl (2R,l laR)-5-oxo-7-(4-(trifluoromethyl)phciiyl)-1,2,3,5,11,11ahexahydrobenzo[t]pyrrolo[2,l-c][l,4]oxazepin-2-ylcarbainate (11-39);

4-((5-(pyridin-2-yl)isoxazol-3-yl)mcthyl)-7-(4-(tri lluoromethoxy)phenyl)-3,4diliydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-41 );

4-((4,6-diinethoxypyrimidin-2-yl)inetliyi)-7-(4-(trinuoroniethoxy)phenyl)-3,4dihydrobcnzo[f][1,4]oxazepin-5(2H)-one ( H-42);

ethyl 3-((5-oxo-7-(4-(trifluoiOincthoxy)phenyl)-2,3dihydrobenzo[f][ 1,4]oxazepin-4(5H)-yl)mcthyl)benzoate (11-43);

4-(2-(pyriniidin-2-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-44); 4-(3,4-difluorobenzyl)-7-(4-(tritluoroinethoxy)phenyl)-3,4dibydrobenzo[f|[l,4]oxazepin-5(2H)-one (11-45); 4-(2-chloiObenzyl)-7-(4-(trifluoromctlioxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-47);

4-(2,6-dichlorobenzyl)-7-(4-(trifluoiOmethoxy)plienyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2I I)-one ( 11-48);

4-(2,6-ditluorobeiizyl)-7-(4-(trifluoiOmethoxy)plienyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-49);

4-(2-( 1 H-pyrazol- l-yl)etliyl)-7-(4-(trifluorometlioxy)phcnyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-50);

384 (2S,l laS)-2-amino-7-(4-(trifluoromethyl)phcnyl)-2,3,l l,l latetrahydrobenzo[f]pyrrolo[2,1 -c][ l ,4]oxazepin-5(l H)-one ( 11-51 );

4-(2-(pyridin-2-yl)ethyl)-7-(4-(trilluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (1I-54);

4-(2-iluorobenzyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[fj[ 1,4]oxazcpîn-5(2H)-one (H-57);

(R)-7-(4-(trifluoroniethyl)phenyl )-2,3,11,11 a-tetrahydrobenzo[f]pynOlo[2,lc][ 1,4]oxazepin-5( lH)-one (11-59);

4-(pyrimidin-2-ylmethyl)-7-(4-(tri fluoromethyl)phenyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-61);

4-(4-fluorobenzyl)-7-(4-(trifluoiO!nethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-62);

4-((l-methyl-IH-pyrazol-3-yl)niethyl)-7-(4-(trifluoiOincthoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazcpin-5(2H)-one (11-64);

4-((5-chloropyrimidin-2-y1)methyl)-7-(4-(tri 11 uoromethoxy)phenyl )-3,4dibydrobenzol l’][ 1,4]oxazepin-5(2H)-one ( H-65);

4-(pyridin-4-yhnetliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4diliydiObenzo[f|[ 1,4]oxazcpin-5(2H)-one (11-67);

4-((5-cyclopropyl-l,3,4-oxadiazol-2-yl)niethyl)-7-(4-(trifluoroniethoxy)phenyl)-

3,4-dihydrobcnzo[f][l,4]oxazepin-5(2H)-one (11-68);

4-(2-(pyrimidin-2-yloxy)ethyl)-7-(4-(lritluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-69);

4-(pyridin-3-ylmethyl)-7-(4-(trifluoiOmethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-70);

4-(pyridin-2-ylmethyI)-7-(4-(triHuoiOmethoxy)phenyl)-3,4diliydrobenzo[f][l,4]oxazepin-5(2H)-one (11-72);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoiOmethoxy)phenyl)-3,4diliydrobenzo[i][l,4]oxazepin-5(2H)-one (11-73);

4-((3-methylpyridin-2-yl)methyl)-7-(4-(trifluoroniethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (11-75);

(R)-2-(2,2,2-trifluorocthyl)-8-(4-(tiïiluorornethyl)phenyl)-3,4,12,12a-tetrahydro1 H-benzo[f]pyrazino[2,l-c][l,4]oxazepin-6(2H)-one(11-83);

385

4-(pyrimidin-2-ylmethyl)-7-p-tolyl-3,4-dihydiObenzo[f][l,4]oxazepin-5(2I-I)-one (II-87);

7-(4-chlorophenyi)-4-(pyrimidin-2-ylînelhyi)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-88);

7-(4-isopropylphenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobcnzo[f][ l,4]oxazepin-5(2H)-one (H-89);

7-(4-ethyiphenyl)-4-(pyrimidin-2-ylmethyI)-3,4-dibydrobenzo[f][l,4]oxazepin5(2H)-onc (II-91);

7-(4-cyclopropylphenyl)-4-(pynmidin-2-ylmethyl)-3,4diliydrobenzo[f][1,4]oxazcpin-5(2H)-one (I1-92);

(R)-4-(l-(pyriinidiii-2-yl)etbyl)-7-(4-(trilluoromethyl)phenyl)-3,4dihydrobenzo[f][l,4|oxazepin-5(2H)-one (I1-95);

7-(4-isobuloxypbenyl)-4-(pyrimidin-2-ylmetbyl)-3,4dihydrobenzo[f][ l,4]oxazcpin-5(2H)-oiie (II-97);

7-(4-tert-bu tyl phcn yl )-4-( py ri midi n-2-yl m ethyl )-3,4dibydiobcnzo[f][l,4]oxazepin-5(2H)-one (I1-98);

7-(4-cyclopiOpoxyphenyl)-4-(pyrimidin-2-ylmetliyl)-3,4dihydrobcnzo[f][],4]oxazepin-5(2l-l)-one (II-102);

7-(4-fluorophenyl)-4-(pyrimidin-2-ylmelhyl)-3,4-dihydrobenzo[f][ l ,4]oxazcpin5(2H)-one (II-l 04);

7-(2-fluoro-4-(triiluoi'omctliyl)phenyl)-4-(pynmidin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazcpin-5(2l I)-one (II-105);

7-(3-fluoro-4-(2,2,2-triil uoroethoxy)pbenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-I06);

4-(pyrimidin-2-ylmethyl)-7-(4-(2,2,2-trifluorocthoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazcpin-5(2H)-one (11-107);

7-(2-chloro-4-(trifluorometbyl)pheiiyl)-4-(pyrimidin-2-ylmcthyl)-3,4diliydrobenzo[f][l,4]oxazepin-5(2H)-one(ll-l I0);

7-(4-(trifluoiOmethoxy)plienyl)-4-((4-(lriiluoiOmetliyl)pyrimidm-2-yl)methyl)-

3,4-diliydrobenzo[f][1,4]oxazepin-5(2H)-one (II-l 13);

7-(4-(trifluoromethoxy)phenyl)-4-((5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin2-yl)inethyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one(II-l 15); ¢/

386

7-(4-chloro-2-fluorophenyI)-4-(pyrimidin-2-yhncthyl)-3,4diliydrobenzo[f][l,4]oxazepin-5(2H)-one (II-117);

l-(4-(5-oxo-4-(pyrirnidiii-2-ylmethyl)-2,3,4,5-tetraliydiObenzo[f][l,4]oxazepin-7yl)phenyl)cyclopentanecarbonitrile (II-122);

7-(4-ethoxyphcnyl)-4-(pyrimidin-2-ylmetbyl)-3,4-diliydiObenzo[f][ l,4]oxazepin5(2H)-one (II-123);

7-(4-(difluoromethyl)phenyl)-4-(pyriniidin-2-ylniethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-124);

4-(imidazo[l,2-a]pyiidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4dihydrobenzo[fj[l,4]oxazepin-5(2H)-one (11-129);

4-((4-inoipholinopyrimidin-2-yl)metliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydiObenzo[t][ 1,4]oxazepin-5(2H)-one (II-133);

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydiObcnzo[f|[l,4]oxazepin5(2H)-one (11-134);

4-(imidazo[ l,2-a]pyridin-2-ylmcthyl )-7-(4-( tri fluorometliyljphenyl )-3,4diliydrobenzo[lj[l,4]oxazepin-5(2H)-one (11-135);

7-(3-tluor0-4-(trifluoroinethyl)phenyl)-4-(pyrimidiii-2-ylmethy1)-3,4dihydrobenzo[f|[l,4]oxazepin-5(2H)-one (11-136);

4-((4-m ethoxypyriinidin-2-yl)methy])-7-(4-(trifluoromethoxy)pheiiyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-oiic (11-137);

4-((4-inethylpyriniidin-2-yl )metliyl)-7-(4-(trifluoromethoxy)phenyl )-3,4diliydrobenzo[f][ l,4]oxazepin-5(2H)-one (II-138);

4-((4-(piperidin-l-yl)pyrimidin-2-yl)niethyl)-7-(4-(triiluoroniethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2I-l)-one (II-139);

4-((4-(dimethylamino)pyrimidin-2-yi)metliyl)-7-(4-(trifluoromethoxy)pheiiyl)-

3,4-di hydrobenzo[ f][ 1,4}oxazepin-5(2H)-one ( 11-140);

4-benzyl-7-(4-(trifluorometliyl)phenyl)-3,4-diliydrobenzo[fJ[ 1,4]oxazcpîii-5(2H)one (11-141);

4-((3-niethoxypyridin-2-yl)methyl)-7-(4-(tritluoroinetlioxy)phenyl )-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-oiie (11-143);

7-(4-(cyclobutyliiietlioxy)phenyl)-4-(pyrirnidin-2-ylmetliyl)-3,4dihydrobenzo[FJ[l,4]oxazepîn-5(2H)-one (11-144);

387

7-(2-mcthyl-4-(tiifluoromethyl)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-145);

7-(2-niethyl-4-(trifluoiOinethoxy)phenyl)-4-(pyrirnidin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-146);

4-((l-(difluoromethyl)-lH-pyrazol-3-yl)mcthyl)-7-(4-(trifiuororncthoxy)phenyl)-

3.4- dihydrobenzo[f][ l,4]oxazepîn-5(2H)-one (II-147);

7-(4-( trifluoromethoxy)phenyl)-4-((3-(tritluorornethyl)-lll-pyrazol-l-yl )methy])-

3.4- dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-148);

4-(pyriinidin-2-ylmetliyl)-7-(4-(2,2,2-trifluoroethyl)phenyl)-3,4diliydrobenzo[f|[l ,4]oxazepin-5(2H)-one (II-150);

4-(pyridin-2-ylmethyl)-7-(4-(2,2,2-trifluoroetbyl)phenyl)-3,4dihydrobcnzo[f][l,4]oxazepin-5(2H)-one (1I-151);

4-(( l-cyclopentyl-IH-pyrazol-3-yl)metliyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (11-152);

4-((I-ethyl-IH-pyrazol-3-yl)niethyl)-7-(4-(lrifluoromethoxy)phenyl)-3,4dihydrobenzo[t][ l ,4]oxazcpin-5(2H)-one (II-153);

4-(( l-methyl-1 H-imidazol-4-yl)methyl)-7-(4-(ti‘ifluoroniethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-154);

4-((4-methyl-l H-pyrazol-l-yl)methyl)-7-(4-(tiït1uoiOmethoxy)phenyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-onc (11-155);

4-((4-cbloro-lH-pyrazol-l-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (11-156);

7-(4-(difluoromethyl)phenyl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2II)-one (Il-l 57);

7-(4-cbloro-3-fluoropbenyl)-4-(pyridin-2-ylniethyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-158);

7-(4-(dilluoiOmetlioxy)plieiiyl)-4-(pyridin-2-ylmetliyI)-3,4dihydiObcnzo[f][ 1,4]oxazepin-5(2H)-one (II-159);

4-((1-methyl-l Il-pyrazoI-4-yl)methyl)-7-(4-(trifluoiOniethoxy)pheiiyl)-3,4dihydrobcnzo[f][ 1,4]oxazepin-5(2H)-one (II-160);

4-(pyrimidin-2-ylmcthyl)-7-(2,3,4-trifhiorophenyl)-3,46ί1^ΓθΙιβηζο[ί]|Ί,4]οχΒζερϊη-5(21Ι)-οη€ (11-162);

388

7-(3,4-di fluorophenyl )-4-(pyrimid i n-2-ylmethyl )-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (II-163);

4-((3-fluoropyridiji-2-yl)methyl)-7-(4-(trifluoroniethoxy)phenyI)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-164);

4-benzyl-9-fluoro-7-(4-(trifluoroinethoxy)phenyl)-3,4diliydrobenzo[f][l,4]oxazepin-5(2H)-one (II-165);

4-benzyl-9- fl uoro-7-(4-(tri fl uoromethyl )phenyl)-3,4diliydrobenzo[t][l,4]oxazepin-5(2H)-one (II-166);

4-benzyl-8-fluoro-7-(4-(tiifluoromethoxy)phcnyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-167);

4-benzyl-8-fluoro-7-(4-(tritluoromethyI)phenyl)-3,4dihydrobcnzo[f][l,4]oxazcpin-5(2H)-one (11-168);

7-(4-chloro-3-fluoroplienyl)-4-((3-fluoropyridin-2-yl)methyl)-3,4dihydiObcnzo[f][l,4]oxazepin-5(2H)-one (11-169);

7-(2-fluoro-4-(trifluorometliyl)phenyl)-4-((3-fIuoropyridïn-2-yl)nielhyl)-3,4dihydiObenzo[f][ 1,4]oxazepin-5(21I)-one (II-170);

4-(5-oxo-4-(pyriinidin-2-ylmethyl)-2,3,4,5-tetrahydrobcnzo[f][l,4]oxazepin-7yl)phenyl trifluoroinethanesulfonate (11-171);

4-((5-niethylpyrazin-2-yl)methyl)-7-(4-(tiifluorornethoxy)phenyl)-3,4dihydiObenzo[f][l,4]oxazepin-5(2H)-one (11-172);

2,2,3,3-tetradeutero-4-(pyrimidin-2-ylniethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (II-174);

4-((6-methylpyrazin-2-yl)niethyl)-7-(4-(trifluoromethoxy)plienyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2II)-one (11-175);

4-((3-tluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyI)phenyl )-3,4dihydrobenzo[fj[ 1,4]oxazepin-5(2H)-one (11-176);

N-(2-(5-oxo-7-(4-(tiifluoromethoxy)phenyl )-2,3-dihydiObenzo[f][l,4]oxazepin4(5H)-yl)ethyl)benzenesulfonamide (11-177);

N-(2-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3-dihydiObenzo[Ij[l,4]oxazcpin4(51 l)-yl)ethyl)cyclopiOpanesulfbnamide (11-179);

4-((l-niethyl-lH-imidazol-2-yl)methyl)-7-(4-(trifluoiOinethoxy)phenyl)-3,4diliydiObeiizo[fj[l,4]oxazepin-5(2H)-one (11-186);

389

4-((l-benzyl-lH-imidazol-2-yl)methyl)-7-(4-(triiluoromethoxy)phenyi)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (II-187);

4-(irnidazo[l,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (Π-189);

N-cyclopropyl-3-(5-oxo-7-(4-(trifluoromethoxy)phenyl)-2,3dihydiObenzo[f][l,4]oxazepin-4(5H)-yl)piOpane-l-sulfonamide (II-190);

N-(2-(5-oxo-7-(4-(triiluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)ethyl)pyrimidine-2-carboxamide (II-I92);

7-(4-(4-fluoiOphcnoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazcpin-5(2H)-one (U-193);

7-(4-phenoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (H-194); and

7-(3-phcnoxyphenyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ I,4]oxazepin-5(2H)-one (II-195);

or a phamiaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
13. A compound of Formula V;

wherein:

A is cycloalkenyl;

n is 0, l, 2, 3, 4 or 5;

each R^l(l is independently selected from the group consisting of halo, -NO?, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R^2O)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, CM alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂m alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, X

390

-NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R^2ü, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylcne-L-CM alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-0R²°, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R“ )(R ), -C(O)-R²⁰, -C(0)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm, alkyl, C₂.(, alkenyl, C'₂.f, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, Cm alkenyl, C₂.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, o/

391 halo, Cm alkyl, acylamino, oxo, -NO_2i -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF3, -OCFI₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci-4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C |_3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
14.

T

The compound of claim 13, wherein R is
15. The compound of claim 13, wherein A is cyclohex-1 -enyl;

n is 0 or l; and

R^l() is 4-methyl or 4-tert-butyl.
16. A compound selected from the group consisting of:

7-(4-tert-butylcyclohex-1 -enyl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[f][ l,4)oxazepin-5(2H)-one (V-l);

7-cyclohexenyl-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (V-3); and

7-(4-methylcyclohex-l-enyl)-4-(pyrimidin-2-ylmethyI)-3,4dihydrobcnzo[f][ l ,4]oxazepin-5(2H)-one (V-5);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

392
17. A compound of Formula VI:

wherein:

B is heterocyclyl or heteroaryl;

n is 0, l, 2, 3, 4 or 5;

each R^l() is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2.₄ alkenyl, C₂.₄ alkynyl, cycioalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, Cm alkynyl, cycioalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, Cj.₃ haloalkyl, cycioalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -C|.(, alkylene-R⁵, -L-R⁵, -L-Cm alkylcne-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylene-L-C|.f, alkylcne-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NIIC(O)-;

R⁵ is cycioalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycioalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cr, alkyl, Cm alkynyl, halo, -NO₂, cycioalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²; A

393 wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)?-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂.₆ alkenyl, C₂._& alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂, -S(O)?R²⁶, -CN, C1.3 alkoxy, -CF₃, -OCF3, -OCH?CF3, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or wlien R“ and R are attached to a common nitrogen atom R and R mayjointo form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO?. -S(O)?R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

394 or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
18. The compound of claim 17, wherein B is heteroaryl.
19. The compound of claim 17, wherein B is 2-oxo-l,2-dihydropyridin-4-yl, pyridin-4-yl, pyridin-2-yl, thiazol-4-yl or thiophen-2-yl.
20. The compound of claim 17, wherein R is
21. The compound of claim 17, wherein n is l ;

R^lü is cycloalkyl, -O-R²⁰ or Cm alkyl;

wherein said C|.₄ alkyl is optionally substituted with one, two or three halo; and

R²⁰ is Ci-6 alkyl.
22. The compound of claim 17, wherein B is 2-oxo-l,2-dihydropyridin-4-yl, pyrîdîn4-yl, 5-(trilluoromethyl)pyridin-2-yl, 2-isopropylthiazol-4-yl, 5(trifluoromethyl)thiophen-2-yl or 5-cyclopropylthiophen-2-yl.
23. A compound selected from the group consisting of: 7-(2-tert-butoxypyridin-4-yl)-4-(pyridîn-2-ylmcthyl)-3,4- dihydrobenzo[ij[ 1,4]oxazepin-5(2H)-one (Vl-4);

7-( l -methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (VI-12);

4-(pyridin-2-ylmethyl)-7-(5-(trifluoiOmethyl)pyridin-2-yl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (Vl-26);

7-(2-isopropylthiazol-4-yl)-4-(pyridin-2-ylmethyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2ll)-one (Vl-30);

4-(pyridin-2-ylmethyl )-7-(5-( tri 11 uoromethyl)thiophen-2-yl )-3,4dihydrobenzo[f]| 1,4]οχ3ζερίη-5(2Η)-οηε (VI-31 );

7-(5-cyclopropylthiophen-2-yl)-4-(pyridin-2-ylmethyl )-3,4dihydrobcnzo[f]| 1,4]oxazepin-5(2H)-one (Vl-32);

7-(5-cyclopropylthiophen-2-yl)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzof f][ 1,4]oxazepin-5(2H)-one (Vl-36); and

395

4-(pyrimidin-2-ylmethyl)-7-(5-(trifluoromethyl)thiophen-2-yl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (Vl-37);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
24. A compound of Formula VIII:

wherein:

n is 0, l, 2, 3, 4 or 5;

represents a single, double or triple bond;

each R^lü is independently selected from the group consisting of halo, -NO?, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)?-N(R²⁰)(R²²), Ci_6 alkyl, C₂m alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.& alkyl, C₂.4 alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R² is -C].₍, alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵or -Cm alkylcne-L-CM alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or-NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from

396 the group consisting of Cm alkyl, C₂y alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²)(R²²), -CN, oxo and -OR²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C[.(, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -NfR^XR²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected front the group consisting of hydrogen, C|.6 alkyl, C₂_6 alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C|.₆ alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|.4 alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, Ct.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cy alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R* and R“ may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Ci.4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and ol

397 each R²⁶ is independently selected from the group consisting of hydrogen, Cj_4 alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.

The compound of claim 24, wherein R² is or
25.
26. The compound of claim 24, wherein n is 0 or l ; and R¹⁰ is 4-trifluoromethyl or 4trifluoromethoxy.
27. A compound selected from the group consisting of:

4-(pyrimidin-2-ylmethyl)-7-((4-(trifluoromethoxy)phenyl)ethynyl)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(2H)-one (VIII-4);

7-(phenylethynyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (V1II-5);

4-(pyrimidin-2-ylmethyl)-7-((4-(tri fluoromethyl)phenyl)ethynyl )-3,4dihydrobenzo[f][ l,4]oxazepin-5(2H)-one (VII1-6);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2FI)-one (VII1-7);

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobcnzo[f][l,4|oxazepin-5(2H)-one (VI11-8);

4-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenethyl)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (VII1-9);

(E)-4-benzyl-7-(4-(triiluoiOmethyl)styryl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (VllI-10); and

4-benzyl-7-(4-(trifluoromethyl)phenethyl)-3,4-dihydrobenzo[f|[ l,4]oxazepin5(2H)-one(VIII-l I);

398 or a pharmaceuticafly acceptable sait, ester, stereoisonier, mixture of stereoisomers or tautomer thereof.
28. A compound of Formula X:

wherein:

n is 0, I, 2,3,4 or 5;

R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFj, -SÎ(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R^2î\ -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)3-N(R²⁰)(R²²), Cm alkyl, C^ alkenyl, C2^ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C).₆ alkyl, C₂4 alkenyl, C₂.4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, C|*& alkyl, C|.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R“). -CN and -O-R²⁰;

R² is -C|.6 alkylene-R⁵, -L-R⁵, -L-Cm aikylene-R⁵, -Cm alkylcne-L-R⁵ or-Cm alkylene-L-C|.6 alkylene-R⁵;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

each R⁴ is independently hydrogen, deutérium, Cm, alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected lrom the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

399 wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cm alkyi, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NiR²⁰)^²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.₆ alkyi, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO?,

-NiR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R⁴ together with the carbon atom to which they are attached form an oxo; R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|.₍, alkyi, Cm alkynyl, halo, -NO?, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)?-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -O- wherein said Cm alkyi, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?,

Cm alkyi, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C i_6 alkyi, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)?-R²⁰ and -O-R²⁰; t?

400

R⁶ is hydrogen or Cm alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂.₆ alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.6 alkenyl, C₂.(, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂, -S(O)₂R^2Û, -CN, Cm alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R“ and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂. -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen. Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
29.

The compound of claim 28, wherein R² is or
30. The compound of claim 28, wherein R¹ is 4-trifluoromethyl or 4 trifluoromethoxy.

401
31. The compound of claim 28, wherein each R⁴ is independently hydrogen, deuterium or Cm alkyl optionally substituted with heteroaryl, or two R⁴ together with the carbon atom to which they are attached form an oxo.
32. The compound of claim 28, wherein R^û is hydrogen or methyl.
33. A compound selected from the group consisting of:

4-(2-(benzyloxy)ethyl)-1 -methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-lHbenzo[e][l,4]diazepine-2,5-dione (X-7);

4-benzyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lH-benzo[e][1 ,4]diazepine2,5-dione (X-8);

4- benzyl-1-methyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydro-lH- benzo[e][l,4]diazcpine-2,5-dione (X-l I); and

5- benzyi-8-(4-(trifluoromethyI)phenyl)-4H-benzo[f|imidazo[ l,2-a][ 1,4]diazepin-

6(5H)-one(X-12);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
34. A compound of Formula XIII:

O

XIII wherein:

Q is a -O-Cq.2 alkylene- or -NR¹ '-Co.₂ alkylene-;

n is 0, 1,2, 3,4 or 5;

R¹⁰ is halo, -NO2, -CN, -SF5, -Si(CII3)3, -O-R²¹’, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R^2ü)(R²²), -N(R^2ü)-C(O)-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)S(O)2-R^2f>, -S(O)2-R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm, alkyl, CM alkenyl, C₂.4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm, alkyl, C₂.4 alkenyl, C₂_4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cj-6 alkyl, C|.₃ haloalkyl, cycloalkyl,

-N(R²ⁱ’)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

402

R² is -Cm alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -C|_g alkylene-L-R⁵ or -Cm alkylene-L-CM alkylene-R⁵;

L is -O-, -S-, -C(0)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Cm> alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci-* alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2l’)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R¹¹ is hydrogen or Cm alkyl;

R²⁰ and R²² are in eacli instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂.₍, alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.& alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl,

403 halo, Ct-4 alkyl, acylamino, oxo, -NO₂, -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycioalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycioalkyl; or

70 77 7Ω 77 when R and R are attached to a common nitrogen atom R and R may join to form a helerocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, C'i-3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycioalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycioalkyl;

wherein the Cm alkyl, aryl and cycioalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
35.

The compound of claim 34, wherein R² is
36. The compound of claim 34, wherein R¹⁰ is 4-trifluoromethoxy.
37. A compound selected from the group consisting of:

4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoiOmethoxy)phenylamino)-3,4dihydrobenzo| T][l,4]oxazepin-5(2H)-one (X1II-1);

4-(pyrimidin-2-ylmethy1)-7-(4-(trifluoromethoxy)phenoxy)-3,4dihydrobenzo[f][ 1,4]oxazcpin-5(2H)-one (XlII-2);

4-(pyrimidin-2-ylmethyl)-7-(4-(tri nuoromethyl)phenylainino)-3,4dihydrobenzo[f][l,4]oxazepin-5(2H)-one (XII1-3);

4-(pyridin-2-ylmethyl)-7-(4-(trifluoiOmethoxy)phenylamino)-3,4dihydrobenzo[f][ 1,4]oxazepin-5(21 l)-one (X111-4);

4-(pyridin-2-ylmethyl )-7-(4-( trifluoromethyl)phenylamino)-3,4dihydrobenzo[f|[l,4]oxazcpin-5(2H)-one (XIII-6); and X

404

7-(methyl(4-(lrifluoromethoxy)phenyl)amino)-4-(pyrimidin-2-ylmethyl)-3,4dihydrobenzo[fJ[l,4]oxazepin-5(2H)-one (XIII-10);

or a phannaccutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
38. A compound selected from the group consisting of:

4-(2,2-difluoroethyl)-7-(4-(trifluoiOmethoxy)phenyl)-3,4dihydrobenzo[t][l,4]oxazepin-5(2H)-one (ll-6);

4-(2-methoxyethyi)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydrobenzo[f][l ,4]oxazepin-5(2H)-one (II-11 );

(R) -3-methyl-7-(4-(trifluoiOmethyl)phenyl)-3,4-dihydrobenzo[f][l,4]oxazepin5(2H)-one (II-19);

4-methyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[t][l,4]oxazepin5(2H)-one (I1-46);

(S) -3-isopropyl-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobcnzo[f][l,4]oxazepin5(2IT)-one (II-77);

3'(pyridin-2-yhnethyl)-7-(4-(trilluoiOmethoxy)phenyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-onc ( 11-142);

N-(2-(5-oxo-7-(4-( tri fluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)ethyl)ethanesulfonamide (II-178); and

4-(3-( azetidin-l-ylsulfonyl)propyl)-7-(4-(trifluoromcthoxy)phcnyl)-3,4dihydrobenzo[f][ l ,4]oxazepin-5(2H)-one (l l-191 );

or a phannaccutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
39. A compound of Formula I:

wherein:

405

1 0 “j

Z and Z are each independently selected from the group consisting of CR and

N;

Z and Z are each independently selected from the group consisting of CR , C-QR¹ and N, provided that one of Z³ and Z⁴ is C-Q-R¹ and the other of Z³ and Z⁴ is CR⁷ or N and further provided that only one of Z¹, Z² and Z⁴ is N;

X is -O- or-NR⁶-;

Y is -C(O)-;

Q is a covalent bond, -O-Co-2 alkylene-, -NR^H-Co.₂ alkylene-, C₂ alkylene-,

C₂ alkenylene- or C₂ alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of halo, -NO₂, -CN, -SF5, -Si(CH₃)₃, -O-R², -S-R²⁰, -C(O)-R^2<), -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R^2o)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R^2ü)-S(O)2-R²⁶, -S(O)2-R^2ü, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, Cm alkenyl, C_Malkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂.4 alkenyl, C₂-4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, C|.& alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)N(R²”)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-C|.₆ alkylcne-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylene-L-C|.(, alkylene-R⁵;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of C2.4 alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2o)(R²²), -N(R²⁰)-S(0)₂-R²⁰, cycloalkyl, aryl, heteroaryl or

406 wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of C|.& alkyl, C₂.₄ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NIIC(O)-; provided that when R² is -L-R⁵ or -L-Cm alkylcne-R⁵, then L is not -O-, -S-, -NHS(O)₂- or -NHC(O)-; and

I each R is independently hydrogen, deuterium, Cm alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm alkyl is optionallysubstituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

or R and one of R can join together with the atom to which they are attached to form a heterocyclyl;

407 wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Ci_(, alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, deuterium, Cj.& alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Ci_6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atom to which they are attached form an oxo;

R⁵ îs cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂.4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)

408

C(O)-R²², -C(O)-R^Z“, -C(O)-OR²⁰, -C(O)-N(R²)(R²²), -CN, oxo and -O- wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²),

-C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO?, -CF₃, -N(R²⁰)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)?-R²⁰ and

R⁶ is hydrogen, C|.₍, alkyl or cycloalkyl;

wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, -N(R^2ü)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and

R⁷ is hydrogen, halo, -O-R²⁰ or Cm alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂.₆ alkenyl, C?.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.f, alkenyl, C?.f, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|..| alkyl, acylamino, oxo, -NO?. -S(O)₂R²⁶, -CN, C[.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH?, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with

C|_4 alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with

409 one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyi, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2i-S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF3, aryl, heteroaryl and cycloalkyl; and each R is independently selected from the group consisting of hydrogen, Cm alkyi, aryl and cycloalkyl;

wherein the Cm alkyi, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF3;

or a phannaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof;

provided that when X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which they are attached fonn a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstitutcd phenyl or morpholinyl.
40. The compound of daim 39, wherein R¹ is aryl, cycloalkyl, cycloalkenyl or heteroaryl;

wherein said aryl, cycloalkenyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -O-R²⁰, -C(O)-R²⁰, -C(O)-OR^2ü, -N(R^2o)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(0)OR²², -S(O)2-R²⁰, -O-S(O)₂-R²⁰, Cm alkyi, cycloalkyl and heterocyclyl; and wherein said Cm> alkyi or cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting ol’halo, -CN and -O-R²⁰.
41. The compound of claim 39, wherein each R³ is independently hydrogen, deuterium or Cm alkyi.
42. The compound of claim 39, wherein each R⁴ is independently hydrogen, deuterium or Cm, alkyi.
43. The compound of claim 39, wherein R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group

410 consisting of Cm alkyl, halo, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN, oxo and -O-R²⁰;

wherein said Cm> alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally lurther substituted with one, two or three substituents independently selected from the group consisting of halo, Cm alkyl, aryl, heterocyclyl and heteroaryl; and wherein said Cm alkyl is optionally further substituted with one, two or three halo.
44.

The compound of claîm 39, wherein R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, -O-R²⁰, -N(R²⁰)(R²²) and -C(O)-OR²⁰; and wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl.
45.

A compound of Formula I:

wherein:

Z^l and Z² arc each independently selected from the group consisting of CR⁷ and N;

3 4 7

Z and Z are each independently selected from the group consisting of CR , C-QR¹ and N, provided that one ofZ³ and Z⁴ is C-Q-R¹ and the other ofZ³ and Z⁴ is

CR or N and further provided that only one of Z , Z and Z is N;

X is -O- or -NR⁶-;

Y is -C(0)-, -C(R)₂- or -S(0)₂-;

411

Q is a covalent bond, -O-C0.2 alkylene, -NR¹ '-Co-2 alkylene, C2 alkylene,

C₂ alkenylene or C₂ alkynylene;

R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CN, -SF5, -SifCFhJj, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -OS(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C|.₆ alkyl, C₂.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said C|.₍, alkyl, C₂^ alkenyl, C₂^i alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.₃haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is -Cm alkylene-R⁵, -L-R⁵, -L-Cm alkylene-R⁵, -Cm, alkylene-L-R⁵or-C|-6 alkylene-L-C|.(, alkylene-R⁵;

wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of Qm alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)NfR^’XR²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂-4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(0)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -C(O)-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH-, or -NHC(O)-; provided that

412 when Y is -C(R' ')₂-, then R² is -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkyleneL-R⁵or -Cm alkylene-L-Cm alkylene-R⁵ and L is not -C(0)-; and when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NHS(O)₂or-NHC(O)-;

each R³ is independently hydrogen, deuterium, Cm alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR^2ü, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|._f, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Calkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

or when Y is -C(O)-, then R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR^2ü and -C(O)-OR²⁰; and wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; q/

413 each R⁴ is independently hydrogen, deuterium, Cj.₆ alkyl, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R²⁶), cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cm alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CNI and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atom to which they are attached form an oxo;

R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, alkynyl, halo, -NO2, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)2-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, oxo and -OR²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, 0/

414

C |_6 alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF₃, -N(R^2O)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

R⁶ is hydrogen, Cm alkyl or cycloalkyl;

wherein said Cm alkyl is optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R⁷ is hydrogen, halo, -O-R²⁰ or Cm alkyl;

R¹¹ is hydrogen or Cm alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂.6 alkenyl, C₂._f) alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂.& alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionaily substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO_2i -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionaily further substituted with Cm alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionaily substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂, -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and X

415 each R²⁶ is independently selected front the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected front the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof;

provided that when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R² and R³ together with the atom to which tliey are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phcnyl or morpholinyl; and that when Y is -S(O)₂-, X is -O-, R² is benzyl, each R³is hydrogen, Z⁴ is C-Q-R¹, Q is a bond and R¹ is aryl or heteroaryl, then both R⁴are hydrogen.
46. The compound of claim 45, wherein the compound of Formula I is represented by Formula II:

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C|.6 alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said C|.<, alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.jhaloalkyl, cycloalkyl, -NfR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²°XR²²), -CN and -O-R²⁰; c/

416

R¹⁷ is halo, -O-R²⁰ or Cm alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂-6 alkenyl, C₂.(> alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, C₂_6 alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂, -S(O)₂R²⁶, -CN, Ci.3 alkoxy, -CF3, -OCF3, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂. -S(O)₂R²⁶, -CN, C1.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
47. The compound of claim 45, wherein the compound of Formula I is represented by Formula 111:

R² is -L-R⁵, -L-Cm alkylene-R⁵, -Cm alkylene-L-R⁵ or -Cm alkylene-L-Cm> alkylene-R⁵;

417 wherein each -Cm alkylene is optionally substituted by one substituent independently selected from the group consisting of C₂^ alkynyl, halo, -NO₂, -CN, -O-R²⁰, -N(R^2o)(R²²), -C(O)-R²⁰, -C(O)-OR²⁶, -C(O)N(R^2o)(R²²), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl; and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyi, C₂.4 alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

L is -O-, -S-, -NHS(O)₂-, -S(O)₂NH-, -C(O)NH- or -NHC(O)-, provided that when R² is -L-R⁵ or -L-Cm alkylene-R⁵, then L is not -O-, -S-, -NI 1S(O)₂- or -NI ÎC(O)-; R⁵ is cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyi, Cm alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -N(R²⁰)-S(O)₂-R²⁰, -N(R²⁰)C(O)-R²², -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R), -CN and -O-R²⁰;

wherein said C|.g alkyi, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyi, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyi, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, aryl, -NO₂, -CF3, -N(R^2O)(R²²), -C(O)R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -O-R²⁰;

n is 0, I, 2, 3, 4 or 5;

418 each R¹⁰ is independently selected from the group consisting of halo, -NO?, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C,.6 alkyl, Cm alkenyl, C₂^ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, Cj.₃ haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cru alkyl, C₂-u alkenyl, C₂-u alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cris alkyl, C₂-u alkenyl, C?-|₅ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)?R²⁶, -CN, Ci.₃alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R²⁰ and R²² are attached to a comrnon nitrogen atom R²⁰ and R²² may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO?, -S(O)2R²ⁱ’, -CN, C|.3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C_ualkyl, aryl and cycloalkyl; and 7

419 wherein the Cm alkyl, aryl and cycloalkyl may bc further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF3 and -OCF3;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
48. A compound selected from the group consisting of: pyrimidin-2-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[fJ[l,4]oxazepin4(5H)-yl)methanone ( II l-1 );

phenyl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f|[l,4]oxazepin-4(5H)yl)methanone (I1I-4);

(l-methylcyclopropyl)(7-(4-(trifluoiOmcthoxy)phenyl)-2,3di hydrobenzo [f] [ 1,4]oxazepi n-4( 5 H )-yl )methanone ( 111 -10); (3,3-difluorocyclobutyl)(7-(4-(trilluoromethoxy)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (lll-l l);

( l -methyl-1 H-pyrazol-4-yl)(7-(4-(tri fl uoromethoxy)phenyl )-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (lll-l 2);

( I H-pyrazol-3-yl)(7-(4-(trifluoromethoxy)phenyl )-2,3dihydrobenzo[f][ l ,4]oxazepin-4(5H)-yl)methanone (III-15);

pyrazin-2-yl(7-(4-(trifluoromethoxy)phcnyl)-2,3-dihydrobcnzo[f][l,4]oxazepÎn4(5H)-yl)methanone (III-23);

pyridazin-3-yl(7-(4-(trifluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazcpin4(5H)-yl)methanone ( III-24);

2-(pyridin-2-yl)-l-(7-(4-(trifluoromethyl)phenyl )-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)ethanone (IH-29);

2-(pyrimidin-2-yl)-l-(7-(4-(trinuoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazcpin-4(5H)-yl)ethanone (II1-30);

( l-methyl-1 H-imidazol-5-yl)(7-(4-(trifIuoromethyl)phenyl )-2,3dihydrobcnzo[f][ l ,4]oxazcpin-4(5H)-yl)methanone ( 111-32);

( l H-imidazol-2-yl)(7-(4-(trifluoromethyl)phenyl)-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (1II-33);

( l-methyl-1 H-imidazol-2-yl)(7-(4-(tri fluoromethyl)phenyl )-2,3dihydrobcnzo[f][1,4]oxazepin-4(5H)-yl)methanone (IU-37); c/

420 (R)-(2-methyl-7-(4-(tritluoromethoxy)phenyl)-2,3-dihydrobenzo[f][l,4]oxazepin4(5H)-yl)(pyrimidin-2-yl)methanone (Hl-38);

tert-butyl 2-(7-(4-(trifluoromethyl)phenyl)-2,3,4,5tetrahydrobenzo[f][l,4]oxazepine-4-carbonyl)-5,6-dihydiOimidazo[l,2a]pyrazine-7(8H)-carboxyiate (III-40);

( l H-1,2,4-tri azo I-3-y I )(7-(4-(tri fluoromethyl)phenyl)-2,3dihydrobenzo[f][ l ,4]oxazepin-4(5H)-yl)methanone (III-5O); and ( l ,5-di incthyl -1 H-pyrazol -3-y I )( 7-(4-(tri fl uoromethox y)phenyl )-2,3dihydrobenzo[f][l,4]oxazepin-4(5H)-yl)methanone (III-58);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
49. The compound of claim 45, wherein the compound of Formula l is represented by Formula V:

(R¹⁰),

A is cycloalkenyl;

n is 0, 1, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)NtR^’XR²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰XR²²), Cm alkyl, C2.₄ alkenyl, C₂.₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said Cm alkyl, C₂_4 alkenyl, C₂_4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm, alkyl, Ci.₃ haloalkyl, cycloalkyl, -N(R^2OXR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2üXR²²), -CN and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂.(, alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

421 wherein the C|.& alkyl, C₂-6 alkenyl, C₂-6 alkynyl, cycloalkyl, heterocyclyl, aryl antl heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|.4 alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, Cj.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH2, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

20 22 20 22 when R and R are attached to a common nilrogen atom R and R may jointe form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|.₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO2, -S(O)₂R²⁶, -CN, C|.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C|.4 alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, C|.₄ alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
50. The compound of claim 45, wherein the compound of Formula I is represented by Formula VI:

B is heterocyclyl or heteroaryl;

n is 0, I, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²¹’, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(_R ²«)(R22), -N(R²⁰)-C(0)-R²², -N(R²⁰)-C(O)-OR²², -N(R^2I))-S(O)2-R^2î’, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C|.₍, alkyl, C₂m alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

422 wherein sait! Cm alkyl, C’2.4 alkenyl, C₂..| alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, Ci.jhaloalkyl, cycloalkyl, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR^2ü, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, C₂.& alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO_2- -S(O)₂R²⁶, -CN, Cm alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or ηη 17 T?

when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂. -S(O)₂R²⁶, -CN, C1 _3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, C1-4 alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof. qI

423
51. The compound of claim 45, wherein the compound of Formula I is represented by Formula VIII:

=-=-= représente a single, double or triple bond;

n is 0, l, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO?, -CN, -SFs, -Si(CHj)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R²⁰)(R“), -N(R²⁰)-C(O)-R²², -N(R^2g)-C(O)-OR²², -N(R²⁰)-S(O)?-R²⁶, -S(O)?R²⁰, -O-S(O)2-R²⁰, -S(O)?-N(R²⁰)(R²²), Cm alkyl, C₂₄ alkenyl, C₂₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said Cm alkyl, C₂.₄ alkenyl, C?_4 alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, aryl, heterocyclyl, heteroaryl, Cm alkyl, Cm haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R^2ü)(R²²), -CN and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, C|._f) alkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C] .<, alkyl, C₂.f, alkenyl, C₂.₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cj-₄ alkyl, acylamino, oxo, -NO₂. -S(O)?R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCFj, -OCH₂CF₃, -C(O)-NH?, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or

70 77 20 27 when R and R““ are attached to a common nitrogen atom R and R ” may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of

424 hydroxyl, halo, C1.4 alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2>-S(O)₂R²⁶, -CN, Ci-3 alkoxy, -CFj, -OCF3, aryl, heteroaryl and cycloalkyl; and each R is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF3;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
52. A compound selected from the group consisting of:

2-((pyrimidin-2-yl)methyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2Hbenzo[b][l,4,5]oxathiazepin-sulfone(IX-2); and

2-((5-chloropyrimidin-2-yl)mcthyl)-8-(4-(trifluoromethyl)phenyl)-3,4-dihydro2H-benzo[b][ l ,4,5]oxathiazepin-sulfone (lX-3);

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
53. The compound of claim 45, wherein the compound of Formula I is represented by Formula X:

n is 0, I, 2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFs, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R^2O)(R²²), -C(O)N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)-OR²², -N(R²⁰)-S(0)3-R²⁶, -S(O)₂R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), C|.6 alkyl, C₂.₄ alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said C|.₍, alkyl, C₂-4 alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, J

425

-N0₂, aryl, heterocyclyl, heteroaryl, Cm alkyl, C|.₃haloalkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

7Π 77

R and R are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, Cm alkenyl, C₂.6 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionaily substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂. -S(O)₂R²⁶, -CN, Cj_₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NII₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionaily further substituted with Cm alkyl or cycloalkyl; or

2Ü 72 70 22 when R and R* are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionaily substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2>-S(O)₂R²⁶, -CN, C[_₃ alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the C m alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
54. The compound of claim 45, wherein the compound of Formula I is represented by Formula XII:

Z¹ and Z² are each independently selected from the group consisting of CR⁷ and

N;

426

Z'¹ is CR⁷ or N; provided that only one of Z¹, Z² and Z⁴ is N;

n is 0, 1,2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SF5, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R^2o)(R²²), -N(R^2ü)-C(O)-R²², -N(R^2tl)-C(O)-OR~, -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²⁰, -O-S(O)2-R²⁰, -S(O)2-N(R²⁰)(R²²), Cm alkyl, C2.₄ alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Ci.3 haloalkyl, Cm alkyl, cycloalkyl, -N(R^2t’)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²)(R²²), -CN and -O-R²⁰;

R is hydrogen, halo or Cm, alkyl;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyl, Ci.₆ alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyl, Cm alkenyl, Cm alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, acylamino, oxo, -NO₂, -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF3, -OCH₂CF₃, -C(O)-NI1₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyl or cycloalkyl; or when R and R are attached to a common nitrogen atom R“ and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, Cm alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO₂. -S(O)₂R²⁶, -CN, C].₃ alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl; X

427 wherein the Cm alkyl, aryl and cycioalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
56. The compound of claim 54, wherein n is 0 or l ; and R¹⁰ is 4-trifiuoromethyl or 4trifluoromethoxy.
57. A compound selected from the group consisting of:

4-benzyl-7-(4-(trifluoromcthoxy)phenyl)-3,4-dihydropyrido[4,3-f][l,4]oxazepin5(2H)-onc (X1I-1);

4-benzyl-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[2,3-f][l,4]oxazepin5(2H)-one (XI1-2);

4-benzyl-7-(4-(trî iluoromethyl)phenyl)-3,4-dihydropyrido[2,3-f][l,4]oxazepin5(2H)-one (XII-3);

4-(pyrimidin-2-ylmethy])-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3l][l,4]oxazepin-5(2H)-one (XII-5);

4-((4-methylpyrimidin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrîdo[4,3-f][ 1,4]oxazepin-5(2H)-one (XII-8);

4-(cyclopropylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydropyrido[4,3f][l,4]oxazepin-5(2H)-one (XI1-9);

4-((3-methoxypyridin-2-yl)methyl)-7-(4-(trifluoromethoxy)phenyl)-3,4dihydropyrido[4,3-f][l,4]oxazepin-5(2H)-one (XII-10);

4-((3-fl uoropyridin-2-yl)methyl )-7-(4-(tri fl uoromethoxy)phenyl )-3,4dihydropyrido[4,3-f][ 1,4]oxazepin-5(2H)-one (XII-11); and

4-((4-methoxypyrimidin-2-yl )methyl)-7-(4-( tri tluoromethoxy)phenyl )-3,4dihydropyrido[4,3-f|[ 1,4]oxazepin-5(2H)-one (XII-14); ol

428 or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stéréo isomers or tau to mer thereof.
58. The compound of claim 45, wherein the compound of Formula l is represented by Formula XIII:

Q is a -O-Co-2 alkylene or -NR¹ ’-Co-₂ alkylene;

n is 0, 1,2, 3, 4 or 5;

each R¹⁰ is independently selected from the group consisting of halo, -NO2, -CN, -SFj, -Si(CH3)3, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)N(R^2O)(R²²), -N(R^2ü)-C(O)-R²², -N(R^2ü)-C(O)-OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2R²¹', -O-S(O)2-R²⁰, -S(O)₂-N(R²⁰)(R²²), Cm alkyi, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;

wherein said Cm alkyi, Cm alkenyl, Cm alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, aryl, heterocyclyl, heteroaryl, Cm alkyi, C|.₃haloalkyl, cycloalkyl, -NfR^’XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R²⁰ and R²² are in each instance independently selected from the group consisting of hydrogen, Cm alkyi, C₂.(, alkenyl, C₂-& alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the Cm alkyi, C₂.₍₎ alkenyl, C₂_₆ alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl arc optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|-4 alkyi, acylamino, oxo, -NO_2- -S(O)₂R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, -OCII₂CF₃, -C(O)-NI 1₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with Cm alkyi or cycloalkyl; or

429

9Λ 99 ΤΑ when R and R are attached to a common nitrogen atom R and R may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, -NO_2t-S(O)₂R²⁶, -CN, C1.3 alkoxy, -CF₃, -OCF₃, aryl, heteroaryl and cycloalkyl; and each R²⁶ is independently selected from the group consisting of hydrogen, Cm alkyl, aryl and cycloalkyl;

wherein the Cm alkyl, aryl and cycloalkyl may be further substituted with from l to 3 substituents independently selected from the group consisting of hydroxyl, halo, Cm alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
59. A compound of Formula IB:

wherein:

R¹ is aryl, cycloalkenyl, heterocyclyl or heteroaryl;

wherein said aryl, cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CN, -SF₃, -Si(CH₃)₃, -O-R²⁰, -S-R²⁰, -C(O)-R²⁰, -C(O)-OR²⁰, -N(R²⁰)(R²²), -C(O)-N(R²⁰)(R²²), -N(R²⁰)-C(O)-R²², -N(R²⁰)-C(O)OR²², -N(R²⁰)-S(O)2-R²⁶, -S(O)2-R²⁰, -S(O)2-N(R^2ü)(R²²), Cm alkyl, Cm alkenyl, C2_4 alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein said Cm alkyl, C₂__t alkenyl, C₂m alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, phenyl, heterocyclyl, heteroaryl, Cm alkyl, cycloalkyl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

R² is hydrogen, CM$ alkyl, -C'(O)-R²⁰, -C(O)-OR²⁶, -C(O)-N(R²⁶)(R^2K), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

430 wherein said Cms alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with one, two or three substituents independently selected from the group consisting of Cm alkyl, C₂^ alkynyl, halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cj.(, alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -CF₃, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN, -S(O)₂-R²⁰ and -OR²⁰;

Q is a covalent bond or C₂ alkynylene;

Y is -C(O)-, -CH₂-, -C(NR⁵)- or -S(O)₂-;

Xis-O- or-NR⁶-;

each R³ is independently hydrogen, Cm; alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cms alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selectcd from the group consisting of halo, -NO₂, C|.(, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²),-CN and -O-R²⁰; and

431 wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O- or R² and one of R³ can join together with the atom to which they are attached to form a heterocyclyl;

wherein said heterocyclyl is optionally substituted with one, two or three substituents independently selected from the group consisting of C|.|$ alkyl, -O-R²⁰, -N(R²⁰)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Ci45 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl;

each R⁴ is independently hydrogen, C145 alkyl, Cm alkoxy, -C(O)-OR²⁶, -C(O)-N(R^2f,)(R²⁸), -N(R²⁰)-S(O)₂-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Cj.is alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,

-NfR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said C|.₍, alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, are optionally further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂₎

432

-N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or two R³ or two R⁴ together with the carbon atom to which they are attached form an oxo;

R⁵ is hydrogen, C|.)5 alkyl, CM alkoxy, -C(O)-O-R²⁶, -C(O)-N(R²⁶)(R²⁸), -N(R²⁰)-S(O)2-R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said C|_ 15 alkyl is optionaily substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, C|.6 alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NfR^XR²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R~), -CN and -O-R²⁰; and wherein said C|,₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionaily further substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, -NO₂, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

or R² and R⁵ can join together with the atom to which they are attached to form a heterocyclyl or heteroaryl;

wherein said heterocyclyl or heteroaryl is optionaily substituted with one, two or three substituents independently selected from the group consisting of Cms alkyl, cycloalkyl, heteroaryl, -O-R²⁰, -N(R^2O)(R²²), -N(R²⁰)-C(O)-OR²⁰ and -C(O)-OR²⁰; and wherein said Cms alkyl is optionaily substituted with one, two or three substituents independently selected from the group consisting of halo and heteroaryl; X

433

R⁶ is hydrogen, C|.i; alkyl, -C(O)-R²⁰, -C(O)-OR²⁶, cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein said Ci.15 alkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -O-R²⁰;

wherein said cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO?, Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(R²⁰)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(0)-N(R²⁰)(R²²), -CN and -O-R²⁰; and wherein said Cm alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally further substituted with one, two or three substituents independently selected from the group consisting of halo, -NO₂, -N(R^2O)(R²²), -C(O)-R²⁰, -C(O)-OR²⁰, -C(O)-N(R²⁰)(R²²), -CN and -OR²⁰;

R and R are in each instance independently selected from the group consisting of hydrogen, Ci-15 alkyl, C₂-i5 alkenyl, C₂-is alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

wherein the C₍-|₅ alkyl, C₂-|5 alkenyl, C₂-i5 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl, halo, C|.₄ alkyl, acylamino, -NO?. -S(O)?R²⁶, -CN, C|.₃ alkoxy, -CF₃, -OCF₃, -OCH₂CF₃, -C(O)-NH₂, aryl, cycloalkyl and heteroaryl; and wherein said heteroaryl is optionally further substituted with C|₄alkyl or cycloalkyl; or

2ij 22 2 7 when R“ and R are attached to a common nitrogen atom R~ and R ~ may join to form a heterocyclic or heteroaryl ring which is then optionally substituted with one, two or three substituents independently selected from the group consisting of 0/

434 hydroxyl, halo, C|.₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino, -NO?, -S(O)₂R²⁶, -CN, C,.3 alkoxy, -CF3, -OCF3, aryl, heteroaryl and cycloalkyl; and R²⁶ and R²⁸ are in each instance independently selected from the group consisting of hydrogen, Ch alkyl, aryl and cycloalkyl; and wherein the Ch alkyl, aryl and cycloalkyl may be further substituted with from I to 3 substituents independently selected from the group consisting of hydroxyl, halo, Ch alkoxy, -CF₃ and -OCF₃;

or a pharmaceutically acceptable sait, ester, hydrate, solvaté, stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or prodrug thereof.
60. The compound of claim 59, wherein when Y is -C(O)-, X is -O-, each R⁴ is hydrogen, R and R together with the atom to which they are attached form a piperazine which is optionally substituted with tert-butoxycarbonyl and Q is a bond, then R¹ is not unsubstituted phenyl or morpholinyl; and that when Y is -S(O)?-, X is -O-, R is benzyl, each R is hydrogen, Z is C-Q-R , Q is a bond and R¹ is aryl or heteroaryl, then both R⁴ are hydrogen.
61. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of the compound of any one of daims 1 to 60 or a pharmaceutically acceptable sait, thereof.
62. A method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of reducing late sodium current, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of any one of daims 1 to 60.
63. The method of claim 62, wherein the disease state is a cardiovascular disease selected from one or more of atrial arrhythmias, ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetafs (variant) angina, stable angina, unstable angina, exercise induced angina, congestive heart disease, ischcmia, récurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, pulmonary hypertension and intermittent claudication.
64. The method of 62, wherein the disease state is diabètes or diabetic peripheral neuropathy.

435
65. Tlie method of 62, wherein the disease state results in one or more of neuropathie pain, epilepsy, migraine, seizures or paralysis.
66. Use of a compound according to any one of ciaims l to 60 in therapy.
67. Use of a compound according to any one of ciaims I to 60 in the manufacture of a médicament for treating one or more diseases selected from atrial arrhythmias, ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal’s (variant) angina, stable angina, unstable angina, exercise induced angina, congestive heart disease, ischemia, récurrent ischemia, reperfusion injury, myocardîal infarctîon, acute coronary syndrome, peripheral arterial disease, pulmonary hypertension and intermittent claudication, ç/