OA16294A

OA16294A - 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds.

Info

Publication number: OA16294A
Application number: OA1201200548
Authority: OA
Inventors: Kerim Babaoglu; Kyla Bjornson; Hongyan Guo; Randall L. Halcomb; John O. Link; Hongtao Liu; Michael L. Mitchell; Jianyu Sun; Randall W. Vivian; Lianhong Xu; James Taylor
Original assignee: Gilead Sciences, Inc.
Priority date: 2010-07-02
Filing date: 2011-07-01
Publication date: 2015-04-24

Abstract

The invention provides compounds of formula (I) :

Description

Human immunodeficiency viras (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type l (HIVl ) encodes three enzymes which are required for viral réplication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and hâve shown effectiveness, particularly when employed in combination, toxicity and development of résistant strains hâve limited their usefiilness (Palella, et al N. Engl. J. Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the réplication of HIV. There is also a need for agents that are directed against altemate sites in the viral life cycle including agents that target the interaction of Lens Epithelial Derived Growth Factor (LEDGF/p75) and HTV-1 integrase.

Summary of the Invention

In one embodimenf the invention provides a compound of the invention which

wherein:

G¹ is N, G² is CR⁸, and the dashed bond is a double bond; or

G¹ îs CR⁵, G² is N, and the dashed bond is a double bond; or

G¹ is CR⁵, G² is NR¹³, the dashed bond is a single bond, and R⁷ is an oxo (=0) group; or

G¹ is CR⁵, G² is NR¹³, the dashed bond is a single bond, and R⁷ and R¹³ together with the atoms to which they are attached form a heteroaryl, wherein the heteroaryl is optionally substituted with one or more (e.g.l, 2,3,4 or 5) Z' groups;

R¹ is R^IaorR^lb;

R² is R²¹ or R^Zb;

R³isR^3a orR^3b;

R³ is R^3a or R^3b ;

R⁴ is R⁴’ or R^4b;

R⁵ is R^5a or R^îb;

R^s is R⁶¹ or R^Éb;

R⁷ is R⁷* or R⁷⁶;

R^sisR^SaorR^gb;

R¹³ is R^13a or R^13b;

R^la is selected from:

a) H, halo, (Ci-C₆)alkyl and (Ci -Côjhaloalkyl;

b) (C2-Cé)alkenyl, (C2-Cé)alkynyl, (C₃-C₇)cycloa]kyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R’¹, -C(=O>O-R' -O-R¹ *, -S-R¹ ’, -S(O)-R¹¹, -SOrR*^l, -(Cj-Cftjalkyl-R¹¹, -(CrC^alkyl-Cf-OyR¹¹, -(CrCejalkyl-CtOj-O-R¹¹, <Cj-C6)alkylO-R, -(Q-CiOaikyl-S-R, -(CpC^alkyl-SiOVR¹¹ and <C1-C6)alkyl-SO2-R¹¹, wherein each R¹¹ is independently selected from H, (C]-C6)alkyl, (C₂-C6)alkenyl, (C₂Cijalkynyl, (Cj-C^haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R¹⁰, -C(^O)-N(R⁹)R¹⁰, -O-C(=O)-N(R⁹)R'°, -SO2-N(R⁹)R^,ü, -(Cj-C^alkyl-NfR^R¹⁰, -(Ci-C6)alkyl-C(=O)-N(R’)R^l0) -(C_rC₆)alkyl-O-C(=0)N(R⁹)R^I(’ and -(Ci-CeJalkyl-SOj-NiR’jR¹⁰, wherein each R⁹ is independently selected from H, (Ci-CsJalkyl and (C3-C7)cycloalkyl, and each R¹⁰is independently selected from Rⁿ,-(C[-C6)alkybR¹¹, -SOrR, -C(=O)-Rⁿ, -C(=O)OR^!1 and wherein each R¹¹ is independently selected from H, (Ci-C₆)alkyl, (C₂-C₆)aikenyl, (C₂> Céjalkynyi. (Ci-C$)haloalkyl, (CrC₇)cycloalkyl, aryl, heterocycle and heteroaryl,

C 3 and wherein any aryl, heterocycle or heteroaryl of R^iais optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups;

R^lb is selected from:

a) -fCi-C6)alkyl-0-(Ci-C₆)alkyl-(C₃-C₇)carbocycle, -(Ci-C₆)alkyi-S-(C]-

C6)alkyl-(CyCCarbocycle, -(Ci-C$)aIkyl-S(O)-(C]-C6)alkyl-(C3-C₇) carbocycle, -(CiC₆)alkyl-SO2-(C_l-C₆)aikyl-(C3-C₇)cajbocycle,-(C₁-C6)alkyl-S02-(C₁-C₆)alkyl-Z¹³,C(O)-(Ci-C6)alkyl-Z^t3, -O-(CrC₆)alkyl-Z¹³, -S-(CrC6)alkyl-Z¹³, -S(O)-(Ci-C6)aIkyl· Z¹³, -SO2-(C,-C6)alkyl-Z^t3, -(CrC6)alky]-Z^!4, -(CrCelalkyl-CÎOJ-tCrCiJalkyl-Z¹³, (CrCÈÎalkyl-QOXOiCi-Côlalkyl-Z¹³,-(C]-C6)alkyl-O-(Ci-C6)alkyl-Z^I3,-(Ci-C6)alkyl10 S-(Ci-C6)alkyl-Z’³, -(C2-C₆)alkenyl-(Ci-C_à)haloalkyl, -(C₂C₆)alkynyl-(CrC6)haloalkyl, -(C3-C₇)halocarbocycle, -NRâSOjNRcRj,

NR_aS0₂0(C₃-C7)carbocycle, -NR_aSO₂Oaryl, -(C₂-Ce)a]kenyl-(C₃-C7)carbocycle, -(C₂-C6)alkenyl-aryl, -(Cî-C^alkenyl-heteroaryl, -(C₂-C6)aIkenyl-heterocycle, -(C₂-C6)alkynyl-(C3-C7)carbocyc!e, -(CrCsJalkynyl-aiyl, -iC₂-Ce)alkynyl-heteroaiyl

-(C₂-C6)alkynyl-heterocycIe, -(C₃-C₇)caTbo<:ycle-Z^! and -halo(Ci-C6)alkyl-Z³, wherein any (Ci-Cô)alkyl, (Ci-CsJhaloalkyl, (C₃-C₇)carbocyc]e, (C₃-C₇)halocarbocycle, (Cî-Cfijalkenyl, (C₂-C<i)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more Z¹ groups (e.g. 1,2,3,4 or 5), wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle, wherein the (C₃-C₇)carbocycle or heterocycle îs optionally substituted with one or more (e.g. 1,2,3,

4 or 5) Z¹ groups;

c) (Ct-Côjalkyl, wherein (Cj-Cijalkyl is substituted with one or more (e.g.

1,2,3,4 or 5) Z groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(C_rC₆)alkyl, -X(C_rC_s)haloalkyl, -X(C2-C₆)alkenyl,

-X(C₂-Cs)alkynyi and -X(C₃-C7)carbocycle, wherein any -X(Ci-C₆)alkyl and -X(Cr

C(,)haloalkyl is substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and wherein any

C

-X(C2-C6)alkenyI, -X(C2-C₆)aIkynyl and -X(C₃-C+/cæbocycle is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g, l, 2, 3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

f) (Ci-Cfi)haloalkyl, (C3-C₇)carbocycle, (Cj-C^alkenyl, and (C₂-Cfi)alkynyl, wherein (Cj-CôJhaloalkyl, (C₃-C7)carbocycle, (CyCôJalkcnyl and (C2-Cs)aikynyl are each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NReRf, -C(O)NReR_f, -OC(O)XKR_f, -S0₂NR_eR_f, -(Ci-C₆)alkyl-NReR_f, <C_rC₆)alkylC(O)-NR_tR_f, -(CrC₆)alkyl-O-C(O)-NReR_f and -(C_rC₆)alkyl-SO2NR_eR_f, wherein any (Ci-Csialkyl, as a part of group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R² is selected from:

a) H, (Ci-C₆)alky! and -OiCrQalkyl;

b) (Cî-Cejalkenyl, (Ci-C^alkynyl, (Cj-C^haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) C(=0)-Rⁿ, -C(=O)-O-R^fl, -S-R¹³, -S(O)-Rⁿ, -SO2-R¹¹,

-(CrCsjalkyl-R¹¹, -(C1-C6)alky]-C(-0)-0-R³ ', ^C^JalkylO-R¹ ^Ci-C^alkyl-S-R¹¹, -(CrC₆)alky 1-5(0)-15¹¹ and -(CrC^alkyl-SOî-R¹¹, wherein each R¹¹ ïs independently selected from H, (C[-C₆)alkyl, (C₂-C_â)alkenyl, (C₂Cg)alkynyl, (Ci-C6)haloalkyl, (C3-C7)cycloaJkyl, aryl and heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups; and

d) -OH, -O(C2-C(,)alkenyl, -O(C₂-C6)aIkynyl, -O(C]-C₆)haloalkyl, -O(C₃C₇)cycloalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl;

e) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R¹⁰, -O-C(=O)-N(R⁹)R’°, -SO₂-N(R⁹)R¹⁰, - (C₁-Ci)alkyl-N(R⁹)R¹⁰, -(Ci-C6)alkyl-C(=O)-N(R⁹)R^ÎC, <Ci-C6)alkyl-O-C(=O)N(R⁹)R¹⁰, and -(Ci*C6)aIkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ îs independently selected from H, (Ci-C$)alkyl and (C3-C7)cycloalkyl, and each R¹⁰ is independently selected

A

from R^-tQ-Csialkyl-R¹¹, -SO2-R'\ -C(-O)-R^1!, -C(=O)OR and C^O^R^R¹¹, wherein each R¹¹ is independently selected from H, (C1-C₆)alkyi, (C₂Ceïalkenyl, (C2-Ce)alkynyl, (Ci-CsJhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^2b is selected from:

a) -(C _t -C₆)alkyl-O-(C] -C₆)alkyl-(C_rC₇)carbocycle, -(Cj-C₆)alkyl-S-(C _rC6)alkyi-(Cj-C₇)caibocycle, -(C i -C6)alkyl-S(O)-(C j -Ci)alkyl-(C₃-C₇)carbocycle, -(Ci C6)alkyl-SO₂-(C₁-C6)alkyl-(CrC₇)carb<^cyc!e, -(C₂-C₆)alkcnyl-(Ci-C₆)haloalkyl. -(C₂C₆)alkynyl-(Ci-C₆)haIoalkyl, XCrCsWl-SOï-iCrQJalkyl-Z¹³, -C(O)-(Ci -C₆)alkyl-

Z¹³, -O-CCj-Cejalkyl-Z¹³, -S-(Cj-C6)alkyl-Z¹³, -SfOXCj-C^kyl-Z¹³, .SOj-fCiC6)alkyl-Z¹³, -(CrC6)alkyl-Z¹⁴, -(C1-C₆)a!kyI-C(O)-(C₁-C₆)alkyl-Z¹³, -(C]-C6)alkylC(O)-O(CrC6)alkyl-Z¹³,-(Ct-C6)alkyl-O-(CrC₆)alkyl-Z¹³,-(CrC6)alkyl-S-(CiCe)alkyl-Zⁱ³, (C3-C7)halocarbocycle, -NRtSOîNRcRd, -NRiSOîOfCj-CiJcarbocycle, NRaSOîOaryl, -(C2-C$)aIkenyl-(Cj-C₇)carbocycle, -(CrC^alkenyl-aryl,

-(C₂-C6)alkenyl-heteroaryl, -(Cî-C^alkenyl-heterocycle, -(C₂-C6)alkynyl(C3-C₇)carbocycle, -(C₂-C6)alkynyl-aryl, -(C₂-Cô)alkyiiy:-heteroaryl, -(Cî-C6)alkynylheterocycle, -(Cj-C^carbocycle-Z¹ and -halo(C]-C6)alkyl-Z³, wherein any (Ci-C^alkyl, (Ci-C^haloalkyl, (C₃-C₇)halocarbocycle,(C3-C₇)carbocycle, (C₂C6)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle îs optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups, and wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle, wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Ci-C₆)alkyl, wherein (C)-C₆)alky! is substituted with one or more (e.g.

1,2,3,4 or 5) Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 or 30 5) Z¹ groups;

d) -X(Ci-C6)alkyl,-X(Cj-C6)haloalkyl, -X(C₂-C6)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle, wherein any-X(Ci-Cô)alkyl and -X(Ci-

C ’ 6

Côjhaloalkyi is substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups, and wherein any -X(C₂-Cs)a[kenyl, -X(C₂-C6)alkynyi and -X(C₃-C₇)carbocycle is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1, 5 2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaiyl, -Xheteroaryl and -Xheterocycle; wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1, 2, 3,4 or 5) Z^s groups and optionally substituted with one or more Z¹ groups;

f) (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C2-C_s)alkenyl, and (C₂-C₆)alkynyl, wherein (Cj-C^haloalkyl, (C3-C7)carbocycle, (C₂-C6)alkenyl and (C₂-C_g)alkynyl are each substituted with one or more (e.g. 1,2, 3,4 or 5) Z^s groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5} Z¹ groups; and

g) -NReRf, -C(O)NReR_f, -OC(O)NR,R_f, -S0₂NR_<R_f, -(Ci-C₆)alkyl-NKR_f, 15 -(C₁-C₆)alkylC(O)-NR_eR_fi -(Cj-CiJalkyl-O-C^Î-N^Rt and -(C₁-C₆)alkyl-SO₁NR_ÎR_ftwherein any (Ci-Ci)alkyl, as a part of group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R³* is (Ci-C₆)alkyl, (C|-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, -(C_rC6)alkyl-(C3-C7)cycloalkyl, -(Ci-C₆)a]kyl-aryl, -(Ci-CeJalkyl-heterocycle, 20 -(C j-Côfalkyl-heteroaryl, -O(C ]-C<;)alkyl, -O(C i-CsJhaloalkyl, -O(C₂-C₆)alkcay],

-O(C₂-C_g)alkynyl, -O(C₃-C₇)cycloaikyl, -Oaryl, -O(Ci-C₆)alkyl-(C3-C7)cycloalkyl, -O(Ci-C₆)alkyl-aryl, -0(C_rC6)alkyl-heterocycle or -CXCj-C^alkyl-hcteroaryl, wherein any (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynvl of R³¹, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2 or 3) 25 groups selected from -O(Ci-C6)alkyl, halo, oxo and -CN, and wherein any (C3-C7)cycloalkyl, aryl, heterocycle or heteroaryl of R³’, either alone or as part of a group, is optionally substituted with one or more groups selected from (Ci-C6)aikyl, -O(C]“C6)alkyl, halo, oxo and -CN; and R³* is H;

R^3b is -(C₇-Ci4)alkyl, (C₃-C7)carbocycle, aryl, heteroaryl, heterocycle,

-(Ci-C₆)alkylOH, -(CrCsJalkyl-O-iCj-CiJalkyl-Z¹², -(Ci-C6)alkyl-O-(C2C6)alkenyl-Z¹², -(C2-C6)alkyl-O-(CrC6)alkynyl-Z^,z, -(C;-C₆)alkyl-S-(CrC6)alkyl-Z¹²,

-(Ci-CsIalkyi-S-fCî-CeJalkenyl-Z¹²,-(C1-C6)alkyl-S-(C2‘C6)alkynyl-Z^,2J -(Ci-C₆)âlkyl16294

S(O)-(C₃-C₆)alkyl-Z^l2, -(Ct-C6)alkyI-S(O)-(C2-C6)alkenyl-Z^!2, -(CrQalkyl-SfOXGC6)alkynyl-Z^l2, -(Cj-C6)alkyl-SO2-(Ci-C6)aikyl-Z¹², -(C|-C6)alkyl-SOr(C₂C₆)alkenyl-Z¹², -(0₁-ϋ₆)οΙ!α·μ50₂-(σ₂<₆)&^ντΛ1-Ζ¹\-(C.-C^alkyl-N^Rt.

-(CrCejalkylOCfOJ-NRcR^-(Cj-Céjalkyl-NRa-CiOyORb,

-(C_]-C₆)alkyl-NR_a-C(O)-NR_aR_b, -(Ci-C_t)alkyl-SO₂(C|-C₆)alkyl, -(C_rC₆)alkylSOaNFLRd, -(GCÈ^kyl-NKSOjNRJG -(C_rC₆W-WO₂O(C₃-C₇)carbocycle, -(Ci-C₆)alkyl-NR.SO₂OaiyI, -(C_l-C₆)aikyl-NR₁-SO₂-(C_t-C₆)alkyl, -(C_rC₆)alkyl-NR_<-S0₂-halo(C_l-C₆)alkyl, -(Ci-C^lkyl-NRrSOz-tCz-C^alkenyl, -(Ci-Cejalkyl'NRvSOrfCrCéjalkynyl, -(Cj-C6)alkyl-NRe'SO2-(C₃-C₇)carbocycle,

-(Ci -C6)alkyl-NR_a-SO₂-halo(C₃-C₇)carbocyc]e, -(C i-C^alkyl-NRe-SOz-aryl,

-(Cj-Cejalkyl-NRa-SOî-heteroaryl, -(Cj-Csjalkyl-NRa-SC^ -heterocycle, -O(C₇C_H)alkyl, -O(Ci-C_i)alkyl-NR_tR_b, -O(Ci-C₆)alkylOC(0)-NR_<R_d, -OiCi-Ce^Ikyl-NRf QOFORb, -O(C₁-C₆)alkyl-NR_s-C(O)-NR₁R_b> -O(C₁-C_s)alkyl-NR_e-SO₂-(Ci-C₆)alkyl, -O(C_t-C6)alkyl-NR_a-SO₂-halo(Ci-C₆)alkyl,-O(Ci-Ci)3]kyl-NR_e-SO₂-(C₂-C₆)alkenyl₎

-O(C₁-C₆)alkyI-NR_a-SO₂-(C_rC₆)alkynyl, -OtCrCejalkyl-NRa-SOHCî-CTjcarbocycle, -O(C i -C6)alkyl-NR*-SO₂-haIo(C₃-C7)carbocycle, ~O(Ci-C₆)alky!-NR_!l-SO2-aryl, -0(Cj“Cs)alkyl-NR*-S0₂-heteroary3,0(Ci-C₆)alkyl-NR_a-SO_rheterocyc!e, -O(C i-C₆)alkyl-NR_a-SO₂-NR_aR_bî -O(C i -Cijalkyl-NRrSOrfCî^jcarbocycle, 0(C₎-C6)aJkyl-NR_J-S0₂-halo(C3-C₇)carbocycle, -OfCi-CsJalkyl-NRa-SOraryl, -O(Ci20 Cfijalkyl-NRjSOîNRcRd, -OÎCi-C6)alkyl-NR_aSO₂O(C3‘C₇)caTbocycle, -OfCi-CsjalkylNRjSO₂Oaryl, -Oheteroaiyl, -Oheterocycle, -Sheteroaryl, -Sheterocycle, -S(O)heteroaryI, -S(O)heterocycle, -S0₂heteroaryl or -S0₂heterocycle, wherein any (Ci-C₆)alkyl, -(C₇-Ct4)alkyl, (C₂-Ce)alkenyl, (C₂-C6)alkynyl, aryl, (C₃-C₇)carbocycle, heteroaryl or heterocycle of R^3b, either alone or as paît of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and R^3b is H, (Ci-C6)alkyl or -O(CrC6)alkyl; or R^3b and R^3b together with the carbon to which they are attached form a heterocycle or (C3-C7)carbocycle which heterocycle or (C3-C₇)carbocycle of R^3band R^3b together with the carbon to which they are attached is optionally substituted with one or more (e.g. 1, 2,3,4 or 5) Z¹ groups;

R⁴® is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁴® is optionally substituted with one or more (e.g. 1,2,

3,4 or 5) groups each independently selected from halo, (Ci-C$)alkyl, (C₂-C6)alkenyl, (CrCjIhaloalkyl.rCî-Cife'cloalkvl.-Otl.OfCrC.jalkjl -SH,-SIC.-CfJalkyi,-NHi, NH(Ci-C6)alkyl and -N((Cj-C6)alkyl)₂, wherein (Cj-CôJalkyl is optionally substituted with hydroxy, -O(CrC6)alkyl, cyano and oxo;

R^4b is selected from;

a) (Ci-C₆)alkyl, (C₂-C₆)aikenyl and (Cj-C^alkynyl, wherein (C_;-CJalkyl_: (C2-C₆)alkenyl and (CrCeJalkynyl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) (C3-C_I4)carbocyeie, wherein (C₃-C ₁₄)carbocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃C₇)carbocyc!e or heterocycle;

c) spiro-heterocycle and bridged-heterocycle, wherein spiro-heterocycle and bridged-heterocycle are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle; and

d) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fiised-heterocycle and bridgedheterocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁷groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; or

R⁴ and R³ together with the atoms to which they are attached form a macroheterocycie or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R⁴ and R³ together with the atoms to which they are attached may be optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z’ groups; and R³ is H, (Ci-C₆)alkyl or -O(Ci-C₆)alky!;

R^ia is selected from:

a) halo, nitro and cyano;

b) R¹¹, -C(=O)-R, -C(=O)-O-R”, -O-R^lt, -S-R”, -S(O)-Rⁿ, -SO2-R¹¹, (Ci-Cé)alkyl-R¹¹, -(CrC6)alkyl-C(=O)-R”, -(CrC6)alkyl-C(-O)-O-R^!1, -(Ci-C6)alkylO-R¹¹, -(Ci-C6)alky[-S-R^!l. -(CrC₆)alkyl-S(O)-R¹¹ and-(Cpt^alkyl-SCh-R¹¹, wherein each R¹¹ is independently selected from H, (C 1 -Ce)alky 1, (C₂-Ci)alkenyl, (C₂C6)alkynyl, (Cj-C^Jhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl,

wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups; and

c) -N(R⁹)R¹⁰, -C(=0)-N(R’)R^!0, -O-C(=O)-N(R⁹)R^!0, -SO2-N(R^?)R^:c, -(CjC6)alkyl-N(R⁵)R¹³, -(C !-C0)a)kyl-C(=O)-N(R⁹)R^lù, -(CrC₆)aIkyl-O-C(=O)-N(R⁹)R^lû, and -(Cr0/)aIkyTSO2-N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (Cj-C6)alkyl and (C3-C7)cycloalkyl, and each R^l0is independently selected from Rⁿ,(Ct-C₆)alkyl-Rⁿ, -SO2-Rⁿ, -C(=O)-R¹¹, -C(=0)ORⁿ and -C(=O)N(R⁹)R^U, wherein each R¹¹ is independently selected from H, (Ci-C6)alkyl, (C₂-C6)alkenyl, (C₂CeÎalkynyl, (Cj-C6)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^Sb is selected from:

a) -(Ci-Cé)alkyl-O-(Ct-C6)alkyl-(CrC₇)carbocycIe, -(Ci-C6)alkyl-S-(Ci-C6)alkyl-(C3-C7)carbocycle, -(Ci-C₆)alkyiS(0)-(C_l-C₆)alkyl-(C3-C_è)caibocyde, -(Ci-C6)alkylSO₂(CrC6)aIkyl-(C3-C7)carbocycle, -(^-CsJalkenyl-fCi-C^haloalkyl, (C₂-C6)alkynyl-(Ci-C6)haloalkyl, - (C₃-C7)halocarbocycle, -NRaSOzNRçRj, NRaSO₂O(C3-C7)carbocycle, -NR^SOjOaryl, -(C₂-C6)alkenyl-(C3-C7)carbocycle, -(C₂-C₆)alkenyl-aryl, -(C₂-C6)alkeny!-heteroaryl, -(C₂-C₆)alkenyl-heterocyc]e, -(C2-Cft)alkynyl-(C3-C7)carbocycle,-(C2-C6)alkynyl-aryl, -(Cï-C_É)alkynyl-heteroaryl, -(C₂-Cs)alkynyl-heterocycIe, -(C3-C₇)carbocycle-Z^,and -halo(Ci-C6)alkyl-Z³, wherein any (CpCJalkyl, (Ci-C₆)haloalkyl, (C₃-C₇)halocarbocycle, (C3-C₇)caibocycle, (C₂-Cé)alkenyl, (C₂-Cs)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C3-C₇)carbocycle or heterocycle, wherein the (C₂C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

c) (Ci-C6)alkyl, wherein (Ci-CT)alkyl is substituted with one or more (e.g.

1,2, 3,4 or 5) Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(C|-C6)aikyl, -X(C|-C₆)haioaIky'i, -X(C₂-C6)alkenyl, -X(C₂-Ci)alkynyl and -X(C₃-C₇)carbocycle, wherein any -XfCj-CJalkyl and -X(CjC₆)haloalkyl is substituted with one or more (e.g. 1, 2. 3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups, and wherein any -X(C₂-C6)alkenyI, -X(C₂-C6)alkynyl and -X(C₃-C7)caTbocycle is substituted with one or more (e.g. 1,2, 3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z^! groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryi and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z^s groups and optionally substituted with one or more (e.g. I, 2, 3,4 or 5) Z^! groups;

f) (C i -C₆)haloalkyl, (C₃-C7)carbocycle, (C₂-C₆)alkenyl, and (C₂-C6)alkynyl, wherein (C|-C₆)haloalkyl, (C₃-C₇)carbocyclc, (C₂-C$)alkenyl and (C₂-C6)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NRJlf, -C(O)NReR_fl -0C(0)NR^₆ -SOiNR^Rf, -(G-C^alkyl-NReRf, -(Ci-C₆)alkyIC(O)-NReR_r, -(C_rC₆)alky l-O-CtO-NIUr and -(CrQalkyl-Si^NKR,-, wherein any (Ci-Ce)alkyl, as part of a group, îs optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

r6.

is selected from:

a) H, halo, (C rCejalkyl, and (C i-C^haloalky];

b) (C₂-Ce)alkenyl, (C₂-C6)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-Rⁿ, -C(=O)-O-Rⁿ, -O-R¹¹, -S-R¹¹, -S(O)-R^U, -SOz-R¹¹, -(CrC6)alkyl-Rⁿ, -(CrC^alkyl-^OJ-R”, XCrCeW-CWO-R¹¹, -(Ci-QjalkylO-R¹¹, -(CrGjalkyl-S-R, -(C)-C6)alkyl-S(O)-R¹¹ and -(CrQalkyl-SO^R¹¹, wherein each R¹¹ is independently selected from H, (Cj-CÉ)alkyl, (C₂-Cg)alkenyl, (C₂Cfi)alkynyl, (CpCsJhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R‘°, -C(=O)-N(R⁹)R’°, -0-C(=O)-N(R⁹)R¹⁰, -SO2-N(R’)R¹⁰, <CrC₆)alkyl-N(R⁹)R¹⁰,-(CrG)alkyl-C( -O)-N(R⁹)R^lc,-(CrC6)alkyl-O-C(=O)N(R⁹)R¹⁰ and -(Ci-C6)alkyl-SO2-N(R⁹)R^l0 ₎ wherein each R⁹ is independently selected

from H, (Cj-Cé)alkyi and (C3-C₇)cycloalky], and each R ⁰ is independently selected from R, -(Ci-Cgjalkyl-R¹¹, -SO2-R^h, -C(-O)-R^i;, -C(=O)OR¹¹ and -C^OjNtR⁹)^¹, wherein each R¹¹ is independently selected from H, (Ci-Csjalkyl, (Cj-C^alkenyl, (C2Céjalkynyl, (Ci-C^haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

and wherein any aryl, heterocycle or heteroaryl of R⁶¹is optionally substituted with one or more (e.g. 1,2 or 3)Z¹⁰ groups;

R⁶** is selected from:

a) -(Ci-C₆)aIkyl-O-(Ci-C₆)alkyl-(Cj-C₇)carbocycle, -(C_rC₆)alkyl-S-(CiC₆)alkyl-(C3-C₇)carbocycle, -(C_rC₆)dkyl-S(0)-(CyC6)alkyl-(C}-C7)carbocycie, -(CiC^alkyl-SOi-fCrCelalkyUCî-CîXarbocycle,-(Cî-C6)alkenyl-(Ci-Ce)haloalkyl, -(C₂Csialkynyl-CCi-CsJhaloalkyl, halo(C3-C₇)carbocycle, -NR_eSO₂NR_cR_d, -NR₁SO₂O(C₃C₇)carbocycle, -NR_aSO₂Oaryl, -(C₂-Cé)alkenyl-(C3-C₇)carbocycle, -(C₂-C6)alkenylaryl, -(Ci-CeJalkenyl-heteroaryl, -(C₂-Ce)alkenyl-heterocycle, -(C₂-C6)alkynyl-(C3-C₇)carbocycle₎ -(CrCé/alkynyl-aryl, -(Cî-Csjalkynyl-heteroaiyl, -(C₂-C6)alkynyl-heterocycle,-(C3-C₇)carbocycle-Z^l and -halo(Ci-C6)aIkyl-Z³, wherein any (C|-C6)alkyl, (Ci-C6)haioalkyl, (€3-C₇)carbocycle, (C₂-C&)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fosed-bicyclic carbocycle and bridgedbicyclic carbocycle, wherein any spiro-bicyclic carbocycle, ftiscd-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z^! groups, wherein two Z¹ groups together withthe atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

c) (Cj-Cfilalkyl, wherein (Cj-C6)alkyl is substituted with one or more (e.g. 1, 2,3,4 or 5) Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(Ci-C₆)alkyl, -X(Ci-C₆)haloalkyl, -X(C₂-C₆)alkeny), -X(C₂-Cc)alkynyI and -X(C3-C₇)carbocycle, wherein any -X(Ci-C₆)aJkyl and -X(Cr Cô)haloalkyl is substituted with one ot more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups, and wherein any -X(C₂-C6)alkenyl, -X(C₂-C₆)alkynyl and -X(Cj-C₇)carbocycle is substituted with one or

C - 12 more (e.g. 1,2, 3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

f) (Ci-C6)haloalkyl, (CrC?)carbccyck, (C2-C6)alkenyl, and (C^-Céjalkynyl, wherein (Cj-CsJhaioalkyi, (C₃-C₇)carbocyde, (C₂-C₆)alkenyl and (CrCbJalkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5)

Z⁶groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) ZI groups; and

g) -NR«Rf, -C(O)NR_eR_f, -OCtOlNR^Rf, -SOjNILRf, -(Ci-C₆)alkyl-NR_tR_f, -(Ci-CslalkylQOl-NKRf, -(CrCeJaikyl-O-CiOXNRJif and -(Ci-QJalkyl-SOiNRRf wherein any (Ci-Côjalkyl, as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R⁷* is selected from:

a) H, halo, (C,-C₆)alkyl and (Q-Cejhaloaikyl;

b) (Cj-Cslalkenyl, (C₂-C₆)alkynyl, (Cî-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -CiO^R¹¹, -C(K))-0-R, -O-R'¹, -S-R¹¹, -S(O)-R^1], -SOrR¹¹,

-(Ci-C₆)alkyl-Rⁿ, -(Cj-C^alkyl-Ct^-R¹¹, -(Cj-C^alkyl-C^O-R¹¹, -(C1-C6)alkylO-R¹¹, -(Ci-C6)alkyl-S-R¹¹, -(C|-C6)alkyI-S(O)-Rⁿ and -(Ci-C6)alkykSO2-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-C^alkyl, (CE-C^alkenvl, (C2C(,)alkynyl, (CrCgJhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R’)R'°, -C(=O)-N(R⁹)Rⁱ°, -O-C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰,

-(Ci-C₆)alkyl-N(R⁹)R¹⁰, -(CrCôJalkyl-CfOXNtR^R’ViCi-CiJalkyl-O^O)N(R⁹)R¹⁰ and -(Ct-C6)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (CfCôJalkyl and (C3-C₇)cycloalkyl, and each R¹⁰ is independently selected from Rⁿ,-(Ci-C«)alky!-R^Il,-SOrR¹¹, -C(=O)-R, -CLO)OR^!1 and -C(=O)N(R⁹)R^U, wherein each R¹¹ is independently selected from H, (Ci-C₆)alkyl, (C2-C6)alkenyl, (C₂Csialkynyl, (Ci-Cô)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl of R ^ais optionally substituted with one or more (e.g. 1,2 or 3) Z*° groups;

R⁷¹’ is selected from:

a) -(C_I-C₆)alkyl-SO₂-(C_l-C₆)alkyl-Z^iJ, -CiO/iCj-C^alkyl-Z¹³, -O-(CiC6)alkyl-Z^!3, -S-(CrC₆)alkyl-Z¹³, -S(O)-(Ci-C6)alkyI-Z¹³, -SOrtCi-C^alkyl-Z¹³, -(Cj-C^alkyl-Z¹⁴, -(CÎ-C₆)alkyl-C(O)-(C₁-C_Î)alkyl-Zⁿ,-(Ci-C6)a]kyl-C(O)-O(C1CsJalkyl-Z¹³, -(CrC^alkyl-O-fCrCéW-Z¹³, -(CrC^alkyl-S-iCrCéJalkyl-Z¹³, -(CjC6)alkyl-0-(Ci-C₆)alkyl-(C3-C₇)carbocycle, -(Ci-C₆)alkyl-S-(CiC6)alkyl-(C₃-C₇)carbocycle, -(C]-C6)aikyl-S(0)-(C]-C6)alkyl-(C3-C₇)carbocycle, -(Ci· C₆)alkyl-S0₂-(C_rC₆)alkyl-(C₃-C₇)carbocycle,-(C₂-C₆)alkenyl-(Ci-C₆)haloalkyl, -(C₂Cs)alkynyl-(Ci-C6)haIoalkyI, (C₃-C₇)halocarbocycle, -NR»SO₂NR«Rj, -NR*SO₂O(C₃C₇)carbocycle₎ -NRaSO₂Oaryl, -(C₂-CÎ)alkenyl-(Cj-C₇)carbocycle, -(CrCéJalkenylaryl, -(C₂-C6)alkenyl-heteroaryl, -(CrCejalkenyl-hcterocycle, -(C₂-C_fi)alkynyl-(C₃-C₇)carbocycie, -(C^C^alkynyl-aryl, -(C₂-C₆)alkynyl-heteroaryl, -(C₂-C6)alkynyI-heterocycle, -(C₃-C₇)carbocycle-Z^l and -halo(Ci-C6)alkyl-Z³, wherein any (C_t-Cs)alkyl, (Cj-C^haloalkyi, (C₃-C₇)carbocycle,(C3-C₇)halocaibocycle, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bîcyclic carbocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C3-C₇)carbocycle or heterocycle, wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (C|-C₆)alkyl, wherein (CpC^alkyl is substituted with one or more (e.g.

1,2,3,4 or 5) Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(CrC₆)alkyl, -X(C_rC₆)haloaIkyl, -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C3-C₇)carbocycle, wherein any -X(C]-C6)alkyl and -X(C]Ci)haloalkyl Îs substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and wherein any

-X(C₂-Cé)aIkenyl, -X(C₂-C6)alkynyl and -X(C3-C₇)carbocycle is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1, 2,3,4 or 5) Z¹ groups;

f) (C^CsJhaloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)aikenyl and (C₂-C₆)alkynyl, wherein (Ci-Ceihaloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C6)alkynyl are each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NR^Rf, -CiOJNReRf, -OQOlNKRf, -SChNKRf, -(Cj-Cslalkyl-NR^, -(Ci-C₆)alkylC(O)-NR_€R_f, -(Ci-C₆)alkyl-O-C(O)·^!^ and -(Ci-C₆)alkyl-SO₂NR_cR_f, wherein any (Ci-C₆)alkyl, as a part of group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R⁸* is selected from:

a) halo, nitro and cyano;

b) R¹¹,-CCOJ-R¹¹,-0(=0)-0-^¹.

(Ci-C₆)alkybRⁿ, -(C^alkyl-C^J-R¹ -(CrC^alkyl-C^OyO-R, -(Cj-C^alkylO-R¹¹, -(Ci-C6)alkyl-S-R, -(C|-C6)aIkyl-S(O)-R“ and-(CI-C6)alkyl-SO2-Rⁿ, wherein each R¹¹ is independently selected from H, (C]-C6)alkyl, ((^-CeJalkenyl, (C₂C_è)alkynyl, (Ci-C₆)habalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups; and

c) -N(R⁹)Rⁱ⁰, -C(=O)-N(R’)R^l°, -O-C(=O>N(R⁹)R¹⁰, -SO7-N(R⁹)R¹⁰, -(CiC6)alkyl-N(R⁹)R¹⁰, -(CJ-C6)aïkyl-C(=O)-N(R⁹)R^l°, -(CI-C_fi)alkyl-0-C(=0)-N(R⁹)R^lûand -(Ci-C6)alkyI-SO2-N(R⁹)R^m, wherein each R⁹ is independently selected from H, (Ci-C6)alkyl and (C3-C₇)cycloalkyl₎ and each R¹⁰ is independently selected from R¹¹, -(Cj-C6)alkyl-R”, -SO2-R¹¹, -C(=O)-R^U, -C(=O)OR^U and -0(=0)1^11¹¹. wherein each Rⁿ is independently selected from H, (Cj-OeJalkyl, (C2-C(>)alkenyl, (C₂C6)alkynyl, (Ci-Csjhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl,

L * ’5 wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Zⁿ groups;

R*^b is selected from:

a) -(Ct-Cs^Ikyl-SO^Cj-C^alkyl-Z¹³, -C(OHCrC6)alkyl-Z^l3, -O-(Cr

C₆)alkyl-Z¹³, -S-(CrC6)alkyl-Z¹³, -S(O)-(Ci-C6)alkyl-Z’³, -SO2-CCrCÊ)alkyl-Zⁿ, -(Ci-C6)alkyl-Z¹⁴, -(CrCJalkyl-CCOMCrCftialkyl-Z^.-ÎCi-C^aikyl-CiO^OiCiC6)alkyl-Z^f3, -(CvCsJalkyl-O-iCrC^alkyl-Z¹³, -(C^C^alkyl-S-fC^C^alkyl-Z'³, -(Cr Ce)alkyl-O-(C i -Cfi)alkyi-(C₃-C₇)carbocycle, -(C) -C_é)alkyl-S-(CiCs)aikyl-(CrC7)carbocycIe, -(C|-C₆)aJkyi-S(0)-(Ci-C6)alky!-(.'C3-C?)carbocyck, -(Ct10 CiJalkyl-SOi-tCrC^alkylXC^-CjXarbocycle, -(C₂-C₆)alkenyl-(C_rC₆)habalkyl, -(C_r

C^alkynyHCj-C^haloalkyl, halo(C₃-C₇)carbocycle, -NRaSOzNRcRd, -NRaSO₂O(C₃-C₇)carbocycle, -NRaSO₂Oaryl, -(C₂-C6)alkenyl-(C₃-C₇)carbocycle, -(C₂-Cô)alkenyl-aryl, -(C₂-C₆)alkenyl-heteroaryl, -(C₂-Ci)alkenyl-heterocycle, XCrC6)alkynyl-(C₃-C₇)carbocycle, -(C2-C₆)alkynyl-aryi, -(C₂-C6)alkynyl-heteroaryl,

-(C₂-C6)alkynyl-heterocycle, -(C₃-C₇)carbocycle-Z¹ and -halofCi-C^Jalkyl-Z³, wherein any (Ci-Cejalkyl, (Ci-CéJhaloalkyl, (C₃-C₇)carbocycle, (C₂-Ci)alkenyl, (C₂-Cs)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1,2,3, or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3,

4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl, wherein (C|-C₆)alkyl is substituted with one or more (e.g.

d) -X(CrC₆)alkyl, -X(Ci-C_fi)haloalkyl, -X(Cî-C₆)alkeny],

-X(C2-C<i)alkynyl and -X(C₃-C₇)carbocycle, wherein any -X(C_rC₆)alkyl and -X(CiC₆)haloalkyl is substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and wherein any

-X(C₂-Cs)alkenyI, -X(C₂'Cs)aikynyl and -X(C3-C₇)carbocycle is substituted with one or more (e.g. I. 2, 3, 4 or 5) Z⁴ groups and optionally substituted with one or more (e.g.

1,2, 3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

(Ci-Cejhaloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-Ce)alkynyl, wherein (Ci-C₆) haloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkcnyl and (C₂-C₆)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NR<Rf, -C(O)NReRf, -OC(O)NR,Rf, -SO₂N'R«Rf, -(CrCsjaîkyl-NReRf, -(Ci-CôJalkylCtOj-NR^Rf, -(CrCeJalkyl-O-CÎOj-NKRt and -(C₁-C₆)alkyl-SO₂NR_<R_i-, wherein any (Ci-Cs)alkyl, as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R^l3a is selected from:

a) Rⁿ, -C(=O)-Rⁿ, -C(=O)-O-R.ⁿ, -O-R¹', -S-R¹¹, -S(O)-Rⁿ, -SO2-R^]I, (Ci-Cÿ)alkyl-R¹¹, -(Cj-C^kyl-CÎ^R¹¹, -(C1-C₆)albl-C(=O)-O-R¹ \ -(C,-C6)alkylO-R¹’, -(Ci-Cejalkyl-S-R¹¹, -(Cj-C^lkyl-StOfR¹¹ and -(C1-C₆)alkyl-SO₂-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-C₆)alkyl, (C^Csjalkenyl, (C₂C₆)alkynyl, (CrC₆)haIoalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. l,2or3)Z^u groups; and

b) -C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(CrCs)aUcyl-N(R⁹)R^l°, -(Cr

C₆)alkyl-C(=O)-N(R⁹)R¹⁰, -(C, -C6)alkyl-O-C(-O)-N(R^R¹⁰ and -(C]-C6)alkyl-SO₂·

N(R⁹)R¹⁽⁾, wherein each R⁹ is independently selected from H, (Ci-Cô)alkyl and (C3C7)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, -(Ci-Csjalkyl-R¹¹, -SO2-R^h, -C(=O)-R, -C(=O)OR^h and -C^ORR^R¹¹, whereineach R¹¹ is independently selected from H, (Ci-C₆)alkyl, (Cb-C^alkcnyl, (C₂-C6)alkynyl, (Cj30 Cfijhaloalkyl, (C3-C₇)cycloalkyl, -(Ci-Cijalkylaryl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

C - I7

R^,3b is selected from:

a) -(Ci-C6)alkyl-SO2-(CrC₆)alkyl-Z¹³, -C(O)-(Ci-C6)alkyl-Z¹³, -O-(CiC6)alkyl-Zⁱ³, -S-(Ci-C6)alkyl-Z¹³, -S(O)-(Ci-C6)alkyl-Z¹³, -SO2-(C:-C6)alkyl-Zⁱ³: -(C_rC₆)alkyl-Z¹⁴, -(CrC5)alkyl-C(OXC_rC₆)a]kyl-Zⁱ³, -(C,-C6)alkyl-C(O)-O(C]-

C^alkyl-Z¹³, -ÎC!-C6)aIkyl-O-(CrC6)alky]-Z¹³, -(Cj-^alkyl-S-iCi-Ceialkyl-Z¹³, -(Cr C6)alkyl-O-(Ci-C6)alkyI-(C₃-C7)carbocycle, -(C i-Câ)alkyl-S-(C_rC₆)alkyl-(C3-C7)carbocyde₎ -(Ci-C6)alkyl-S(O>(Ci-C6)alkyl-(C3-C₇)carbocyck -(CjC6)aDiyl-SO₂-(Ci-C6)alkyl-(C₃--C₇)carbocyc]e, -(C₂-Ci)alkenyl-(Ci-C6)haloalkyl, -(C₂C6)alkynyl-(Ci-C₆)haioalkyl, -halo(C3-C₇)carbocyçle,

-(C₂-C6)aikenyI-(C3-C7)carbocycie, -(C₂-C6)alkenyl-aryl, -(C₂-C₆)alkenyl-heteroaryl, -(CrCôJalkenyl-heterocycle, -(C₂-Cfi)a]kynyl-(C3-C7)carbocycle, -(C₂-C6)alkynyl-aryl, -(C₂-C₆)aIkynyl-heteroaryI, -(Cj-C^alkynyl-heterocycle, -(Q-Cyjcarbocycle-Z¹, halo(Ci-C6)alkyI-Z³, -NR_aSO₂NRcR<i, -NR_tS0₂0(C3-C7)carbocycle and -NRaSChOaryl, wherein any (Cj-Cé)alkyl, (Cj-CsJhaloalkyl, (Ca-C₇)carbocycle, (C₂-C6)alkenyl, (C₂15 Csjalkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bndgedbicyclic carbocycle, wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C3-C?)carbocycle or heterocycle wherein the (C3-C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (C i-Céialkyi, wherein (C i -C^Jalkyl is substituted with one or more (e.g,

1,2,3,4 or 5) Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 ot

5) Z¹ groups;

d) -X(C_rC₆)alkyl, -X(Ci-C₆)haloalkyl, -X(C₂-C_s)alkenyl, -X(C₂-Ci)alkynyl and -X(C3-C₇)carbocycle, wherein any -X(Cj-Câ)alkyl, -X(CiCé)haloalkyl, is substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and wherein any -X(Cî-C6)alkenyl, -X(C₂-C6)alkynyl and -X(C₃-C₇)carbocycle, is substituted with one *

or more (e.g. 1,2, 3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g.

1,2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z* groups;

f) (Ci-Cslhaloalkyl, (Ci-C₇)carbocycle, (C₂-Cs)alkenyl and (C₂-C₆)alkynyl, wherein (Ci-C^haloalkyl, (Cj-Cjjcarbocycle, (C₂-C6)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z^É groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -C(O)NRcRf, -SO₂NR,R_f, -(CrC^alkyl-NReRf, -(C_rC₆)alkylC(O)NRcRf, -(Ci-C6)aIkyl-O-C(O)-NR<Rf and -(CpCfiJaikyl-SC^NRcRf, wherein any (CrCe)alkyl, as part of a group, is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

or any of R^5a and R^6a, R*⁴ and R^7a, R^7a and R^Sa, R¹ and R*, R¹ and R² or R¹ and

R¹³ together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or the 4,5,6 or 7-membered heterocycle is optionally substituted with one or more (e.g. 1,2 or 3) substituents each independently selected from halo, (C|20 C₆)alkyl, (C₂-C_s)alkenyl, (Ci-Cejhaloalkyl, (C3-C₇)cycloalkyl, -OH, -O(Ci-C6)alkyl, SH, -S(Ci-C6)aikyl, -NH₂, -NH(C|-C₆)alkyl and -NKCrCûalkylh;

or any of R⁵ and R⁶, R⁶ and R⁷ or R⁷ and R⁸, together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5,6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or the 4,5,6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1,2 or 3) Z⁷ or Z groups, wherein when two Z groups are on same atom the two Z groups together with the atom to which they are attached optionally form a (C₃-C₇)carbocycle or 4, 5 or 6-membered heterocycle;

or any of R¹ and R^s, R¹ and R² or R¹ and R¹³ together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or the 4,5,6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1,2 or 3) Z⁷ or Z⁸

groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionaily form a jCrCikarbocycle or 4,5 or 6membered heterocycle;

X is independently selected from O, -C(O)-, -C(0)0-, -S-, -S(O)-, -SO₂., -(Cp C₆)alkylO-, -(C_rC₆)alkylC(O)-, -(Ci-C₆)alkylC(O)O-,-(Ci-C_s)alkylS-, -(O C₆)alkylS(O)- and -(C_rC₅)alkylSO2-;

each Z¹ is independently selected from halo, -NO2, -OH, =NORa, -SH, -CN, (Ci-C₆)alkyi, (C₂-C₀)alkenyl, (C2-C₆)alkynyl, (C_t-C6)haloalkyl, (C₃-C7)carbocycle, (C₃C7)halocarbocycle, aryl, heteroaryl, heterocycle, -0(Ci-C6)alkyl, -O(C₂-C₆)alkenyl, -O(C2-C(j)alkynyl, -O(Ci-C6)haloalkyl, -O(C₃-C₇)carbocycle, -0(C₃-C₇)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(C|-C₆)a[ky|, -S(C2-Cs)alkenyl, -S(C?Cfi)alkynyl, -S(Ci-C6)haloalkyl, -S(C₃-C₇)carbocyc]e, -S(C₃-C₇)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocyçle, -S(O)(Ci-Ci)alkyl, -S(O)(C2-C6)alkenyl, -S(O)(C₂C_é)alkynyl, -S(O)(C|-C6)haIoalkyl, -S(O) (C₃-C7)cartx)cycle, -S(O)(C₃C?)halocarbocycle, -SO2(C₁-C6)alkyl, -S(O)aryl, -S(O)carbocycle, -S(O)heteroaryl, -S(O)heterocycle, -SCh^-CsJalkenyl, -SO2(C_z-C₆)alkynyl, -S02(C_rC6)haloalkyl, -SO₂(C₃-C₇)carbo€ycle, -S0₂(C₃-C7)halocarbocycle, -SCharyl, -SO2heteroaryl, -SOiheterocycle, -SO₁NR_cR_<i, -NR^, -NR.CtOJR., -NR_aC(0)OR_a. -NR,C(O)NR_<R_d-NR_BSO₂Rb, -NRiSOiNRçRd, -NRaSOO/Cj-Cjjcarbocycle, -NR_aSO₂0aryl. -OS(0)₂Ka, -C(O)Ra, -C(O)ORh, -C.(0)NRJG, and -OCÎOjNRtRj, wherein any (Ci-Céjalkyl, -(CjC₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (C₃-C₇)halocarbocycle, (C₃C₇)carbocycle, (C₃-C₇)halocafbocycle, aryl, heteroaryl and heterocycle of Z, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) halogen, -OH, -ORb, -CN, -NRaC(O)_zRb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle or -S/O^NR^;

each Z² is independently selected from -NO2, -CN, spiro-heterocycle, bridgedheterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NRaSO-fCjC₇)carbocycle, -NR_aSO₂aryI, -NRaSO2heteroaryl, -NR^ChNRcRd, -NRaS020(C₃C₇)carbocycle and -NRaSO₂Oaryl;

each Z³ is independently selected from -NO2, -CN, -OH, oxo, =N0R_a, thïoxo, -aryl, -heterocycle, -heteroaryl, (C₃-C₇)caibocycle, (C₃-C?)halocarbocycle, -0(Cr C₆)alkyl, -O(C₃-C₇)carbocycle, -Ohalo(C₃-C₇)carbocycle, -Oaryl, -Oheterocycle,

-Oheteroaryl, -S(Ci-C₆)alkyl, -S(C₃-C₇)carbocycle, -S(Cj-C7)halocarbocycle, -Saryl, Sheterocycle, -Sheteroaryl, -S(O)(C|-C₆)alkyl, -S(0)(C₃-C7)carbocycle, -S(O)(C₃C₇)halocarbocycle, -S(O)aryl, -S(O)heterocycle, -S(0)heteroatyl, -S0₂(C]-C6)alkyl, -SO₂(C₃-C₇)carbocycle, -SO₂(C₃-C7)haiocarbocycle, SO₂aryl, -SOjheterocycle,

-SO^eteroaryl, -NR_aR_b, -NR_aC(O)Rt„ -C(O)NR_<R₁, -SOiNR^Rj, -NR_aSO₂NR_<R_<i_i-NRaSO₂O(C₃-C₇)carbocycle and -NR_aSO₂Oaryl;

each Z⁴ is independently selected from halogen, -(Ci-Cejalkyl, (C₃C7)carbocycle, -halo(Ci-C6)alkyI, -NO₂, -CN, -OH, oxo, =NORa, thîoxo, -aryl, -heterocycle, -heteroaryl, -(C₃-C7)halocarbccycle, -O(C]-C6)alkyl, -O(C₃10 C₇)carbocycle, -0(C3'C₇)halocarbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(Cp Cs)alkyl, -S(C₃-C₇)carbocycle, -S(C₃-C₇)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(O)(CrC6)alkyl, -S(O)(C₃-C₇)carbocycle, -S(0)(C₃-C₇)haIocarbocycle, -S(O)aryl, -S(O)heterocycle, -S(O)heteroaryl, -SO2(C|-C6)alkyI, -S0₂(C₃C₇)carbocycle, -SO₂(C₃-C₇)halocarbocycte, SO₂aryl, -SO₇heterocycle, -SO2heteroaryl,

-NR_aRb, -NR_aC(O)Ra, -C(O)NR_cR_<I, -SOiNRRj, -NR₁S0₂NR_cR_d, -NRaS0₂0(C₃C₇)carbocycle and -NRaSO₂0ajyI;

each Z^s is independently selected from -NO₂, -CN, -NRaSO^RJR), -NRaSO₂0(C₃-C₇)carbocycle, -NR_aSO₂Oaiyl, -NRaSOjiCi-QOalkyl, -NRaSO₂(C₂Côlalkenyl, -NR_eS0₂(C₂-C6)alkynyl, -NRaS02(C3-C₇)carbocycle, -NR_aSO₂(C₃20 C₇)halocarbocycle, -NRaSO₂aiyl, -NR_aSO₂heteraryl, -NRSOjheteroaryl, -NR₄SO₂heterocycle, -NR^CCOJalkyl, -NR₉C(O)alkenyl, -NRXÇOJalkynyl, -NR*C(0) (C₃-C₇)carbocycle, -NR_aC(O)(C₃-C₇)halocarbocycIe, -NRaC(O)aryl, -NRaC(O)heteroaryl, -NR„C(O)heterocycle, NR_aC(O)NR₍R₍| and NR,C(O)ORb;

each Z⁶ is independently selected from -NO₂, -CN, -NR_aR_a, NR_aC(O)R(„

-C(O)NRcR<j, -(C3-C₇)halocarbocycle, -aryl, -heteroaryl, -heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C3-C₇)halocarbocycle, -O(Ci-C₆)alkyl, -O(C₁-C_fi)alkyI-O-(Ci-C6)alkyl, -O(C₃-C₇)carbocycle, -Ohalo(Ci-C₆)alkyl, -Saiyl, -Sheteroaryl, -Sheterocycle, -S(C₃-C₇)haIocarbocycle, -S(Cj-C6)alkyl, -S(C₃C₇)carbocycle, -S(CrC6)haloalkyl, -S(O)aryl, -S(0)heteroaryl, -S(O)heterocycle, 30 S(0)(C₃-C₇)halocarbocycle, -S(O)(Ci-C6)alkyi, -S(O)(Cj-C₇)caTbocycle, -S(O)halo(CiC₆)alkyl, -SO₂aryl, -SO₂hcteroaryl, -SO₂heterocycle, -SO₂(C[-C6)alkyl, -SO₂halo(Cr Ce)alkyl, -S0₂(C₃-C₇)carbocycle, -S0₂(C₃-C₇)halocarbocycle, -SO₂NR<;R<j,

-NR_aSO₂(C₃-C₇)halocarbocycle, -NR_aSO_;aryl, -NR_aSOiheteroaryI, -NR_aSO₂heteroary!. -NR_aSO₂NR_tR<j, -NRjSOîO/Cî-C-lcaîbocycle and -NR_aSO₂Oaryl;

each Z⁷ is independently selected from -NO2, =NOR>, -CN, -(Cj-C6)alky]-Z¹², -(C2-C₆)alkenyl-Z¹², -(C2-C6)alkenylOH, -(CrC6)alkynyl-Z¹², -(CrC₆)alkynyl-OH,

-(Ci-Ci)haloalkyl-Z¹² -(Ci-CéJhaloalkyiOH, -(C3-C7)carbocycie-Z¹², -(C3C₇)carbocycleOH, -(C₃-C₇)haJocarbocycle, -(Ci-C^alkylNRcRa, -(CiC6)alkylNRaC(0)Ra, -(C|-C6)alkylNR_aSO₂R_a, -aryl, -heteroaryl, -heterocycle, -O(C |C₆)alkyl-Z¹², -O(C2-C6)alkenyl, -O(C2-C6)alkynyi. -O(Ci-C6)haloalkyl, -O(C3C7)carbocycle, -0(C3-C7)ha[ocarbocycle, OaryI, -O/Cj-CiJalkylNRcR^, -O(Cj10 C^alkylNRaCfOJRj, -O(C[-C6)alkylNRaSO2Ra, -Oheteroaryl, -Oheterocycle, -S(CiC6)alkyl-Z¹², -S(C2-C₆)alkenyl, -S(C₂-C₆)alkynyl, -S(Ci-C₆)haloalkyl, -S(C₃C₇)carbocycle, -S(C₃-C₇)halocarbocycle, -SfCrCfiJalkylNReRj, -S(CiCôJalkylNRaCtOJRa, -S(Ci-C6)alkyINRaS0₂Ra, -Saiyl, -Sheteroaryl, -Sheterocycle, -S(OXC)-C6)alkyl, -S(O)(C₂-C₆)aikenyl, -S(O)(C₂-C₆)allcynyl, -SfOXC^haloalkyl,

-S(O)(C₃ -C₇)carbocycle, -S(0)(C₃~C₇)halocarbocycle_J -SO₂(Ci -C₆)alkyl, -S(O)(Ci C₆)alkylNR_cRd, -S/OXCi-C^alkylNRaCRR,, -S(O)(C₁-C₆)alkylNR_aSO₂R_e, S(O)aryl, -S(O)heteroaryl, -S(O)heterocycle, -SOXCrCj^kyl, -SO₂(C₂-C₆)alkenyl, -SOîfCî-Cfilalkynyl, -SO₂(Ci-C6)haloalkyl, -SCh(C₃-C?kaibocycle, -SO₂(C₃C₇)halocarbocycle, -SO₂aryl, -S0₂hcteroaryl, -SChheterocycle, -SO₂(C_r

CôJalkylNRcRd, -SO₂(Ci-C6)alkylNR_aC(O)R_a, -SO₂(C₁-C₆)alkylNR_aSO₂R_a, -SOzNRcR* -NR_aC(O)OR_b. -NR.qOJNR^ -NR^QA, -NR_aSO₂NR_cR_dt-NR_iS0₂0(C₃-C7)carbocycIe, -NRaSO₂Oaiyl, -OSfO)^, -C(O)NR;Rd, and -OC(O)NRcRd, wherein any (Ci-Cfi)alkyl, (Ci-C₄)haloalkyl, (Cj-CJalkcnyl. (C₂C₆)alkynyl, (C₃-C₇)carbocycle, (C₃-C7)halocarbocycle, aryl, heteroaryl and heterocycle of Z⁷, either alone or as part of a group, is optionally substituted with one or more (e.g.

1,2, 3,4 or 5) halogen, -OH, -ORb, -CN, -NR_aC(O)₂R_bl -heteroaryl, -heterocycle, Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(O)₂NR_CR₍| each Z⁸ is independently selected from -NO₂ and -CN;

each Z⁹ is independently selected from -(Cj-Ce^alkyl and -O(C|-C₆)aIkyl;

each Z¹⁰ is independently selected from:

i) halo, oxo, thioxo, (C₂-C6)alkenyl, (Cj-C6)haloalkyl, (C₃C₇)cycloalkyl, (Ca-C^cycloalkylXCi-C^alkyl-, -OH, -O(C|-

θ'?

L· L·

Cé)alkyl_t -O(C;-C₆)haÎoalkyl, -SH, -S<Ci-C₆)aikyl, -SO(Cr

C₆)alkyl, -SO₂(C_rC₆)alkyl, -NH₂, -NH(C_rC₆)alkyl and -N((C_t-C₆)alkyI)₂;

ii) (C j -C$)alkyl optional ly substituted with -OH, -O-(C i-

Cô)haloalkyl, or -O-(CrCfi)alkyl; and iii) aryl, heterocycle and heteroary], which aryl, heterocycle and heteroaryl is optionally substituted with halo, (Ci-Cgjalkyl or COOH;

each Z¹¹ is independently selected from Zⁱ⁰, -C(=O)-NH_2j -C(=O)-NH(Cr C4)alkyl, -C(=O)-N((Ci-C4)aIkyl)2, -C(=O)-aryl, -C(-0)-hcterocycle and

-C(=O)-heteroaryl;

each Z¹² is independently selected from -NO2, ^_NOR2, thioxo, -aryl, -heterocycle, -heteroaryl, -(C3-C₇)halocarbocycle, -(C;-C₇)carbocyc!e, -O(C3-C7)carbocycle, -OhaloiCi-CjJcarbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(Cj-C6)alkyl, -S(C3-C7)carbocycle, -Shalo(C3-C₇)carbocycle, -Saryl, -Sheterocycle,

-Sheteroaryl, -S(O)(C i -C₆)alkyl, -S(O)(C3-C₇)carbocycIe, -S(0)halo(C3-C₇)carbocycle,

-S(O)aryl, -S(O)heterocycle, -S(0)heteroaryl, -SO₂(Ci-C6)alkyl, -SO₂(C3-C₇)carbocycle, -S02(C3-C₇)halocarbocycle, SO₂aryl, -SO₂heterocycle, -SO₂hetcroaryl, -NR^R», -NR_aC(O)R_b, -C(O)NR_ÎR_J> -SOiNR^, -NR_aSO₇NRcR_d, -NR_aS0₂0(C₃-C₇)carbocycle and -NRjSOîOaiyl;

each Z^B is independently selected from -NO₂, -OH, =NOR_a, -SH, -CN, -(C₃C₇)halocarbocycle, -O(C_rC6)alkyl, -O(C₂-C6)alkenyl, -O(C₂-C₆)alkynyl, -O(C|Ce)haloalkyl, -O(C₃-C₇)carbocycle, -O(C3-C₇)haIocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(Ci-C6)alkyl, -S(C₂-Cs)alkenyl, -S(C₂-C6)alkynyl, -S(Ci-C6)haloalkyl, -S(C3-C₇)carbocycle, -S(C3-C₇)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle,

-SCOXCj-QQalkyl, -S(O)(C₂-C_É)alkcnyl, -S(O)(C₂-C₆)alkynyl, -S(O)(Ci-C₆)haloalkyl, -S(0)(C3-C₇)carbocycle, -S(0)(C3-C₇)halocarbocycle, -S(O)ary), -S(0)heteroaryl, -S(O)heterocycle, -SOXCi-CsJalkyl, -SO₂(C₂-Cs)alkenyl, -SO2(C₂-C6)alkynyI, -SO₂(Ci-Cfi)haloalkyl, -SO2(C3-C₇)carbccycle, -S0₂(C3-C₇)halocarbocycle,-Sü₂aryi, -SO₂heteroaryl, -SO₂heterocycle, -SO₂NRtR<i, -NRcRj, -NR_aC(0)Ra, -NRaC(0)0Rb,

-NR_aC(O)NRçR<f -NR_aSO₂Rb, -NR.SOjNR.Rd, -NR,SO₂O(C₃-C₇)carbocycle, -NR_aSO₂Oaryl, -OS(O)₂Ra, -C(0)R_a, -C(O)ORb, -C(O)NR_cR_d, and -0C(0)NRJ> wherein any (Cj-C^alkyl, -(C]-C₆)haloalkyl, (C₂-C6)alkenyl, (C₂-Cé)alkynyl, -(C₃-

*16294

C - 23

C7)halocarbocycle, (C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl and heterocycle of Z¹³, either alone or as part of a group, is optionally substituted with one or more (e.g. I, 2, 3, 4 or 5) halogen, -OH, -OR₆. -CN, -N’R_aC(OhR«, heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or

-S(O)_:NR_cR_d;

each Z¹⁴ is independently selected from -NO-, =NOR₁₍ -CN, -(C₃C₇)halocarbocycle, -0(C₃-C₇)halocarbocycle, -S(C₃-C₇)halocarbocycle, -S(O)(C₃C₇)halocarbocycle, -SO2(C₃-C₇)halocarbocycle, -NRSO-NRR, -NR_aSO2O(C₃C₇)halocarbocycle, -NRaSO₂Oaiyl and -OSfO^Ra, wherein any -(C₃-C7)halocarbocycle 10 of Z¹⁴, either alone or as part of a group, îs optionally substituted with one or more (e.g.

1,2, 3,4 or 5) halogen, -OH, -OR, -CN, -NR_aC(O)₂Rb. heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(O)₂NR.Ri;

each R# is independently H, (Cj-Cs)alkyl, -(C₂-C&)alkeny|, -(C_rC6)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryl(Ci-C6)alkyl-, heteroaryl or heteroaryl(C]15 C₆)alkyl-, wherein any (C_rC₆)alkyl, (C₂-C6)alkenyl, (CrC^alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl or heteroaryl of R», either alone or as part of a group, is optionally substituted by one or more (e.g. 1,2,3,4 or 5) halogen, OH and cyano;

each R, is independently -(Ci-C₆)aikyl, -(C2-C₆)alkenyl, -(C₂-C6)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryl(Cj-C6)alkyl-, heteroaryl or hcteroaryl(CiC₆)alkyl-, wherein any (Ci-C₆)alkyl, -(C₂-Cs)alkenyl, -(Cî-Csjalkynyl, (C₃-C₇)carbocycle, heterocycle, aryl or heteroaryl of Rb, either alone or as part of a group, is optionally substituted by one or more (e.g. 1,2, 3, 4 or 5) halogen, OH and cyano;

Rc and R are each independently selected from H, (C]-C₆)alky], (C₂-C6)alkenyl, (C2-C6)alkynyl, (C₃-C7)carbocycle, aryl, aryl(C]-C₆)alkyl-, heterocycle, heteroaryl and heteroaryl(Ci-C6)alkyl-, wherein any (Ci-C^alkyl, -(C₂-C6)alkenyl, -(C₂-Ci)alkynyl, (C₃-C7)carbocycle, heterocycle, aryl and heteroaryl of Rc or Rj, either alone or as part of a group, is optionally substituted by one or more (e.g. 1,2,3,4 or 5) halogen, OH and cyano; or Rc and Ri together with the nitrogen to which they are attached form a heterocycle, wherein any heterocycle of Rand Rj together with the nitrogen to which

they are attached is optionally substituted by one or more (e.g. 1,2,3,4 or 5) halogen, OH or cyano;

each R< is independently selected from -OR., (Ci-C₆)aikyl and (C₃-C₇)carbocycle, wherein (C_rC₆)alkyl and (C₃-C₇)carbocycle îs substituted by one or 5 more (e.g. 1,2,3,4 or 5) Z⁶ and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z^!, -(Cî-CsJhaloalkyl, -(Cj-C^aikenyl and -(C₂-C6)alkynyl, wherein any -(Cî-C^haloalkyl, -(C₇-C6)alkcnyl and -(C₂-C6)alkynyl is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹, and aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl is substituted by one or more (e.g. 1,2,3,4 or 5) Z⁵;

each Rf is independently selected from -R_& -ORa, -(Ci-C₆)alkyl-Z⁶, -SC+R», C(O)R_g, C(O)OR_g and -C(O)NR<R_g; and each Rg is independently selected from H, -ORa, (CrCelalkyl, (C₃-C7)carbocycle, (Cj-Qjhaloaikyl, (C₂-CÊ)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, wherein any (C_rC6)alkyl,(C3-C7)carbûcycle, (Ci-Ci)haloalkyl, (C₂-C₆)alkenyl, (C2-C₆)alkynyl, aryl, heterocycle and heteroaryl of Rg is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

or a sait thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable sait thereof, in combination 20 with a pharmaceutically acceptable carrier.

The invention also provides method for treating (e.g. preventing, mediating or inhibiting) the prolifération of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human), comprising administering a compound of formula I, or a pharmaceutically acceptable sait thereof, to the mammal.

The invention also provides a compound of formula I, or a pharmaceutically acceptable sait thereof for use in medical therapy (e.g. for use in treating (e.g. preventing, mediating or inhibiting) the prolifération of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human)).

The invention also provides a compound of foimula I, or a pharmaceutically acceptable sait thereof for use in the manufacture of a médicament for treating (e.g. preventing, mediating or inhibiting) the prolifération ofthe HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human).

C

The invention also provides a compound of formula I, or a pharmaceutically acceptable sait thereof, for use in the prophylactic or therapeutic treatment (e.g. prévention, médiation or inhibiting) of the prolifération of the HIV virus or AIDS or for use în the therapeutic treatment of delaying the onset of AIDS or ARC symptoms.

The invention also provides processes and intermediates disclosed herein that are useful for preparîng compounds of formula l or salts thereof.

Detailed Description of the Invention

Définitions

Unless stated otherwise, the following terms and phrases as used herein are intended to hâve the following meanings:

When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradcname product.

Alkyl” is hydiocarbon containing normal, secondary or tertiary atoms. For example, an alkyl group can hâve l to 20 carbon atoms (i.e, (Cj-C₂o)alkyl), l to 10 carbon atoms (i.e., (C|-Cw)alkyl), l to 8 carbon atoms(Le., (Ci-Cj)alkyl)or l to 6 carbon atoms (i.e., (C\-C& alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH₃), ethyl (Et, -CH₂CH₃), 1-propyl (n-Pr, n-propyl, CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, -CH(CH₃)2), 1-butyl (n-Bu, n-butyl, CH₂CH₂CH₂CH₃), 2-methyl- 1-propyl (i-Bu, i-butyl, -CH₂CH(CH₃)₂), 2-butyi (s-Bu, sbutyl, -CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH₃)₃), 1-pentyl (npentyl, -CH2CH₂CH₂CH₂CH₃), 2-pentyl (-CH(CH₃)CH₂CH₂CH₃), 3-pentyl (-CH(CH₂CH₃)2), 2-methyl-2-butyl (-C(CH₃)2CH₂CH₃), 3-methyl-2-butyI (-CH(CH₃)CH(CH₃)₂), 3-methyl-l-butyl (-CH₂CH₂CH(CH₃h), 2-methyl-l-butyl (-CH₂CH(CH₃)CH₂CH₃), 1-hexyl (-CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (-CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2pentyl (-C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4methyl-2-pentyl (-CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (-C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (-CH(CH₂CH₃)CH(CH3)₂), 2,3-dimethyl-2-butyl (-C(CH₃)2CH(CH₃)₂), 3,3-dimethyl-2-butyl (-CH(CH₃)C(CH₃)3, and octyl (-(CH₂)7CH₃). “Alkyl” also refers to a saturated, branched or straight chain hydrocarbon

radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkyl groupcan hâve l to 10carbon atoms(ie., (Ci-Cio)alkyl), or l te 6carbonatoms(i.e., (CrC6)alkyl) or 1-3 carbon atoms(i.e., (Cj-C₃)alkyj). Typical alkyl radicals include,but are not limited to, methylene (-CH₂-), 1,1-ethyl (-CHfCIb)-), 122-ethyl (-CH₂C1I;-), 1,1propyl (-CH(CH₂CH₃>), U-propyl (-CH₂CH(CH₃)-), 1,3-propyl (-CH₂CH₂CH₂-), 1,4butyl (-CH₂CH₂CH₂CH₂-), and the like.

“Alkenyl” is a straight or branched hydrocarbon containing normal, secondary or tertiary carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp²10 double bond. For example, an alkenyl group can hâve 2 to 20 carbon atoms (i. e., C₂C₂o alkenyl), 2 to 8 carbon atoms (Le., C₂-Cj alkenyl), or 2 to 6 carbon atoms (i.e., C₂C₆ alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH₂), alïyl (-CH₂CH=CH₂), cyclopentenyl (-C5H7), and 5hexenyl (-CH₂CH₂CH₂CH₂CH=CH₂).

“Alkynyl” is a straight or branched hydrocarbon containing normal, secondary or tertiary carbon atoms with at least one site of unsaturation, Le. a carbon-carbon, sp triple bond. For example, an alkynyl group can hâve 2 to 20 carbon atoms (i.e., C₂-C₂q alkynyl), 2 to 8 carbon atoms (Le., C₂-C* alkyne,), or 2 to 6 carbon atoms (i.e._t C₂-C$ alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-OCH), propargyl (-CH₂C=CH), and the like.

The term “halo” or “halogen” as used herein refers to fiuoro, chloro, bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent. For example, a 25 (Ci-C₆)haloa)kyl is a (Ci-Côjalkyl wherein one or more of the hydrogen atoms hâve been replaced by a halo substituent. Such a range includes one halo substituent on the alkyl group up to complété halogénation of the alkyl group.

The term “aryl” as used herein refers to a single aromatic ring or a bicyclic or multicyclic ring. For example, an aryl group can hâve 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical or an ortho-fused bicyclic or multicyclic radical having about 9 to 14 atoms in which at least one ring is aromatic (e.g. an aryl fused to onc or more aryl or carbocycle). Such bicyclic or •Λ'

C 27 multicyclic rings may be optionally substituted with one or more (e.g. 1,2 or 3) oxo groups on any carbocycle portion of the bicyclic or multicyclic ring. It is to be understood that the point of attachment of a bicyclic or multicyclic radical, as defined above, can be at any position of the ring including an aryl or a carbocycle portion of the 5 ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,

4-tetrahydronaphthyl, anthracenyl, and the like.

‘'Arylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl radical as described herein (i.e., an aryl-alkyl- moiety). The alkyl group of the “arylalkyl” is typically 1 to 6 10 carbon atoms (i.e. aryl(C(-Cf,)aJkyl). Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 1-phenylpropan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl and the like.

The term “heteroaryl” as used herein refers to a single aromatic ring or a multiple condensed ring. The term includes single aromatic rings of from about 1 to 6 15 carbon atoms and about 1 -4 heteroatoms selected from ûe group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be présent in an oxidîzed form provided the ring is aromatic. Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. The term also includes multiple condensed ring Systems (e.g, ring Systems comprising 2 or 3 rings) wherein a heteroaryl group, as 20 defined above, can be fused with one or more hcteroaryls (e.g. naphthyridinyl), carbocycles (e.g. 5,6,7,8-tetrahydroquinolyl) or aryls (e.g. indazolyl) to form a multiple condensed ring. Such multiple condensed rings may be optionally substituted with one or more (e.g. 1,2 or 3) oxo groups on the carbocycle portions of the condensed ring. It is to be understood that the point of attachment of a heteroaryl multiple condensed ring, 25 as defined above, can be at any position of the ring including a heteroaryl, aryl or a carbocycle portion of the ring. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadïazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quïnazolyl, 5,6,7,830 tetrahydroisoquinolinyl benzofuranyl, benzimîdazolyl and thianaphthenyl.

The term “heterocyclyl” or “heterocycle” as used herein refera to a single saturated or partially unsaturated ring or a multiple condensed ring system. The term

C includes single saturated or partiaîly unsaturated ring (e.g. 3, 4, 5, 6 or 7-membered ring) from about î to 6 carbon atoms and from about l to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be substituted with one or more (e.g. 1,2 or 3) oxo groups and the sulfur and nitrogen atoms may also be présent in their oxidized forms. Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl. The term also includes multiple condensed ring Systems (e.g. ring Systems comprising 2 or 3 rings) wherein a heterocycle group (as defined above) can be connected to two adjacent atoms (fused heterocycle) with one or more heterocycles (e.g. decahydronapthyridinyl ), heteroaryls 10 (e.g. 1,2,3,4-tetrahydronaphthyridinyl), carbocycles (e.g. decahydroquinolyl) or aryls.

It is to be understood that the point of attachment of a heterocycle multiple condensed ring, as defined above, can be at any position of the ring including a heterocycle, heteroaryl, aryl or a carbocycle portion of the ring. Exemplary heterocycles include, but are not limited to azîrtdinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, 15 morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dîhydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dîhydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3benzodioxolyl and 1,4-benzodioxanyl.

The term “bridged-heterocycle” as used herein refera to a 4, 5,6,7 or 820 membered heterocycle as defined herein connected at two non-adjacent atoms of the 4,

5,6,7 or 8-membered heterocycle with one or more (e.g. 1 or 2) 3,4,5 or 6-membered heterocycles or a (C₃-C7)carbocycles as defined herein. Such bridged-heterocycles include bicyclic and tricyclîc ring Systems (e.g. 2-azabicyclo[2.2.1]heplanc and 4azatricyclo[4.3.1.1³’⁸] undecane).

The term “spiro-heterocycle” as used herein refers to a 3,4, 5,6, 7 or 8membered heterocycle as defined herein connected to one or more (e.g. 1 or 2) single atoms of the 3,4, 5,6,7 or 8-membered heterocycle wilh one or more (e.g. 1 or 2) 3,4,

5,6-membered heterocycles or a (C₃-C7)carbocycles as defined herein. Such spiroheterocycles include bicyclic and tricyclîc ring Systems (e.g. l,4-dioxaspiro[4.5]dec-7- enyl).

The term “macroheterocycle” as used herein refers to a saturated or partiaîly unsaturated8,9,10, Il or 12-memberedringcomprisingabout 5to 11 carbonatoms

Ύ'

C

ΙΟ and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring which may be optionally fused at two adjacent atoms of the macroheterocycle to one or more (e.g. 1,2 or 3) aryls, carbocycles, heteroaryls or heterocycles. The macroheterocycle may be substituted with one or more (e.g. 1,2 or 3) oxo groups and the sulfur and nitrogen atoms may also be présent in their oxidized forms.

“Heteroarylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl radical as described herein (i.e., a heteroaryl-alkyl- moiety). The alkyl group of the “heteroarylalkyl” is typically 1 to 6 carbon atoms (i.e. heteroaryl(Ci-C_s)aIkyl). Heteroarylalkyl groups include, but are not limited to heteroaiykCHj-, heteroaiylCH(CH₃>, heteroaryl-CHîCHî-, 2-(heteroaryl)ethan-l-yl, and the like, wherein the “heteroaryl” portion includes any of the heteroaryl groups described above. One skilled in the art will also understand that the heteroaryl group can be attached to the alkyl portion of the heteroarylalkyl by means of a carbon-carbon bond or a carbonheteroatom bond, with the proviso that the resulting group is chemically stable. Examples of heteroarylalkyls include by way of example and not limitation 5membered sulfur, oxygen, and/or nitrogen contaîning heteroaryls such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen contaîning heteroaryls such pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

“Heterocyclylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl radical as described herein (i.e., a heterocyclyl-alkyl- moiety). The alkyl group of the “heterocyclylalkyl” is typically 1 to 6 carbon atoms (Le. heterocyclyl(Ci-C6)alkyl). Typical heterocyclylalkyl groups include, but are not limited to heterocyclyl-Cfy-, heterocyclyl-CHiCHj)-, heterocyclyl-CHjCHr, 2-(heterocyclyl)cthan-l-y[, and the like, wherein the “heterocyclyl” portion includes any ofthe heterocyclyl groups described above. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carboncarbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is

C

ΙΟ chemicaily stable. Examples of hetèrocyclylalkyls include by way of example and not limitation 5-membercd sulfur, oxygen, and/or nitrogen containing heterocycles such tetrahydrofuranylmethyl and pynoldinylmethyl, etc., and 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, etc.

The tenu “carbocycle” or “carbocyclyl” refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g. cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a monocycle or a multicyclic ring system. In one embodiment the carbocycle îs a monocycle comprising 3-6 ring carbons (i.e. (Ci-C*)carbocycle). Carbocycle includes multicyclic carbocycles hâve 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle provided that the largest single ring of a multicyclic carbocycle is 7 carbon atoms. The term “spiro-bicyclic carbocycle” refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to a single carbon atom (e.g. spiropentane, spiro[4,5]decane, spiro[4.5]decane, etc), The term “fused-bicyclic carbocycle” refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to two adjacent carbon atoms such as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system (e.g. decahydronaphthalene, norsabinane, norcarane). The term “bridged-bicyclic carbocycle” refers to a carbocycle bicyclic ring System wherein the rings of the bicyclic ring system are connected to two non-adjacent carbon atoms (e.g. norbomane, bîcyclo[2.2.2]octane, etc). The “carbocycle or “carbocyclyl may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopcntyl, 1-cyclopcnt-l-enyl, l-cydopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl and 1-cyclohex3-enyl.

The term “halocarbocycle” as used herein refers to a carbocycle as defîned herein, wherein one or more hydrogen atoms are each replaced by a halo substituent. For example, (C₃-C₇)halocarbocycle is a (C3-C₇)carbocycle wherein one or more of the hydrogen atoms hâve been replaced by a halo substituent. Such a range includes one halo substituent on the carbocycle group to complété halogénation of the carbocycle group.

The term “macrocarbocycle” as used herein refers to a saturated or partially unsaturated 8, 9,10, 11 or 12-membered ring comprising 8 to 12 carbon atoms which may be optionally fused at two adjacent atoms of the macrocarbocycle to one or more (e.g. 1,2 or 3) aryls, carbocycles, heteroaryls or heterocycles. The macrocarbocycle may be substituted with one or more (e.g. 1,2 or 3) oxo groups.

“Carbocyclylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein (i.e., a carbocyclyl-alkyl- moiety). The alkyl group ofthe “carbocyclylalkyl” is typically 1 to 6 carbon atoms (i.e. wrbocyclyl(Ci-Cs)alkyl).

Typical carbocyclyl alkyl groups include, but are not limited to carbocyclyl-CHj-, carbocyclyl-CH(CH₃)-, carbocyclyl-CH2CH2-, 2-(carbocyclvl)ethan-l-yl, and the like, wherein the “carbocyclyl” portion includes any of the carbocyclyl groups described above.

It is to be understood that when a variable is substituted, for example, as described by the phrase “(Ci-CJaikyl, either alone or as part of a group, is optionally substituted ”, the phrase means that the variable (C 1 -CeJalkyl can be substituted when it is alone and that it can also be substituted when the variable “(Ci-Cgjalky]” is part of a larger group such as for example an aryKCi-Cjjalkyl or a -( Ci-Cejalkyl-SOi-fCiC₆)alkyl-(C₃-C'7)carbocycle group. Similariy, when stated, other variables (e.g. (C_;20 Ccjalkenyl, (CrCgjalkynyl, aryl, heteroaryl, heterocycle, etc... ) can also be substituted “either alone or as part of a group.”

It is to be understood that certain variables of formula 1 that connect two chemical groups may be oriented in either direction. Thus, for the X group of formula I (e.g. O, -C(O)-, -C(O)O-, -S-, -S(O>, -SCh-, -(C_rC₆)alkylO-, -(Ci-C₆)alkylC(O)-, 25 -(C_rC₆)alkylC(O)O-, -(Ci-C₆)alkylS-, -(C)-C₆)alkylS(O)- and -(C_rC₆)alkyISO2-) certain values of X that are not symmetric can be oriented tn either direction. For example, the -C(O)O-, can be oriented as either -C(O)O* or -OC(O)-, relative to the groups it connects.

It is to be understood that the nitrogen that is încluded in the core of the compound of formula I can be présent in an oxidized form. For example, the quinoline nitrogen of either G¹ or G² of formula I can be an N-oxidc. Accordingly, the invention

includes a compourid of formula I (as defined in the summary of the invention) or a sait or N-oxide thereof.

One skilled in the art will recognize that substituents and other moieties of the compounds of formula l should be selected in order to provide a cornpound which is 5 sufficiently stable to provide a pharmaceutically useful cornpound which can be formulated into an acceptably stable pharmaceutical composition. Compounds of formula I which have such stability are contemplated as falling within the scope of the présent invention.

The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity).

The term “chiral” refers to molécules which have the property of nonsuperimposability of the mirror image partner, while the term “achiral” refers to molécules which are superimposable on their minor image partner.

The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers or axes of chîrality and whose molécules are not minor images of one another. Diastereomers typically have different physical properties, e.g., melting points, boilîng points, spectral 20 properties, and reactivities. Mixtures of diastereomers may separate under high résolution analytical procedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a cornpound which are nonsuperimposable mirror images of one another.

Certain compounds of the invention can exist as atropisomers. For example, it 25 has been discovered that atropisomers exist for certain substituents at the R⁴ position of formula I as marked by an asterisk in the formula below.

C

The chirality that résulte from the atropisomers at the asterisk position îs a feature of certain compounds of the invention. Accordingly, the invention includes ail atropisomers of compounds of the invention including mixtures of atropisomers and well as mixtures that are enriched in an atropisomer as well as single atropisomers, 5 which mixtures or compounds possess the useful properties described herein.

In one embodiment, the compounds of the invention of formula I are at least 60% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the compounds of the invention of formula l are at least 70% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the 10 compounds of the invention of formula 1 are at least 80% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 90% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodimen( the compounds of the invention of formula I are at least 95% a single atropisomer for the R⁴ substituent at the asterisk position. In 15 one embodiment the stereochentistry for the R⁴ substituent at the carbon marked with an asterisk as shown above for Formula I is the (R) stereochemîstry. In another embodiment the stereochemîstry for the R⁴ substituent at the carbon marked with an asterisk as shown above for Formula 1 is the (S) stereochemîstry.

The term “treatment” or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.

Stereochemicai définitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book 25 Company, New York; and Eliel, E. and Wilen, S., Stereochemîstry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i. e., they hâve the ability to rotate the plane of planepolarized light. In describing an optically active compound, the préfixés (D and L) or (R and S) are used to dénoté the absolute configuration of the molécule about its chiral 30 center(s). The préfixés d and 1 or (+) and (-) are employed to desîgnate the sîgn of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefîxed with(+) or d is dextrorotatory. For a

A

C

The chirality that results from the atropîsomers at the asterisk position is a feature of certain compounds of the invention. Accordingly, the invention includes ail atropîsomers of compounds of the invention including mixtures of atropîsomers and well as mixtures that are enriched in an atropisomer as well as single atropîsomers, 5 which mixtures or compounds possess the useful properties described herein.

In one embodiment, the compounds of the invention of formula I are at least 60% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 70% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the 10 compounds of the invention of formula I are at least 80% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 90% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 95% a single atropisomer for the R⁴ substituent at the asterisk position. In 15 one embodiment the stereochemistry for the R⁴ substituent at the carbon markcd with an asterisk as shown above for Formula I is the (R) stereochemistry. In another embodiment the stereochemistry for the R⁴ substituent at the carbon marked with an asterisk as shown above for Formula I is the (S) stereochemistry.

The term “treatment” or treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibîting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.

Stereochemical définitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms ( 1984) McGraw-Hill Book

Company, New York; and Elîel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they hâve the ability to rotate the plane of planepolarized light. In describing an optically active compound, the préfixés (D and L) or (R and S) are used to dénoté the absolute configuration of the molécule about its chiral center(s). The préfixés d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is ievorotatory. Acompoundprefixed with(+) ord is dextrorotatory. Fora

C given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A spécifie stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoîd of optical activity.

Protecting Groups

In the context of the présent invention, protecting groups include prodrug moîeties and chemical protecting groups.

“Protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry. Théodore W. Greene, 15 John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivîty of certain functional groups, to assist in the efficiency of desired chemical réactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivîty of the protected functional group, such as the polarity, 20 lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be bîologically active or inactive.

Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and 25 résistance to enzymatic dégradation or séquestration. In this rôle, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater 30 potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after

C deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more désirable if the products are pharmacologically innocuous.

Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, le.

routes or methods to préparé the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will be dépendent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. PGs do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwîse facilitate the synthetic efficiency. The order of deprotection to yield free deprotected groups is dépendait upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.

Various functional groups of the compounds of the invention may be protected. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonïc acid, or other fonctions) include “ether- or ester-forming groups”. Ether- or ester-forming groups are capable of fonctioning as chemical protecting groups in the 20 synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.

A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in 25 Organic Synthesis. Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301 -6) (“Greene”). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting 30 Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter

5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic

C acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of ali stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or ail asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictîons are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are ail within the scope of the invention. The racemic mixtures can be separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the séparation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.

The compounds of the invention can also exist as tautomeric îsomers in certain cases. Although only one delocalized résonance structure may be depîcted, ail such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, îmidazole, guanidine, amidinc, and tetrazole Systems and ail their possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

Examples of pharmaceutically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali métal (for example, sodium), an alkaline earth métal (for example, magnésium), ammonium and NX/ (wherein X is C]-C₄ alkyl). Pharmaceutically acceptable salts of a hydrogen atom or an amino group include for example salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartane, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic,

benzenesulfomc and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids. Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na* and NX/ (wherein X is independently selected from H oraC|-C4 alkyl group).

For therapeutic use, salts of active ingrédients of the compounds of the invention will typîcally be pharmaceutically acceptable, le. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the préparation or purification of a compound of formula I or another compound of the invention. Ail salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the présent invention.

Métal salis typîcally are prepared by reacting the métal hydroxide with a compound of this invention. Examples of métal salts which are prepared in this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble meta! sait can be precipitated from the solution of a more soluble sait by addition of the suitable métal compound.

In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H2SO4, H3PO4 or organic sulfonic acids, to basic centers, typîcally amines, or to acidic groups. Finally, it îs to be understood that the compositions herein comprise compounds of the invention in their un-îonized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the naturel or unnatural amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typîcally is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isolcucinc, or leucine.

Spécifie values listed below for radicals, substituents, and ranges in the embodiments of the invention are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. Isotopes

It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or ail atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (²H or

D). As a non~limiting example, a -CH₃ group may be substituted with -CD3.

S

Compounds of formula I.

A spécifie group of compounds of formula 1 are compounds of formula la

la

Another spécifie group of compounds of formula I are compounds of formula

Ib.

Another spécifie group of compounds of formula I are compounds of formula le.

Id.

Another spécifie group of compounds of formula I are compounds of formula

Another spécifie group of compounds of formula I are compounds of formula le.

le [X

Another spécifie group of compounds of formula I are compounds of formula

If.

Another spécifie group of compounds of formula I are compounds of formula

Ih.

Ih

Another spécifie group of compounds of formula I are compounds of formula Ii.

Ii

Another spécifie group of compounds of formula I are compounds of formula Ij.

ii

Another spécifie group of compounds of formula I are compounds of formula

Ik.

Ik

Another spécifie group of compounds of formula l are compounds of formula 'S

Im.

Im

Another spécifie group of compounds of formula I are compounds of formula

In.

wherein the ring W is heteroaryl optionally substituted with one or more (e.g, l, 10 2,3,4 or 5) Z¹ groups.

Another spécifie group of compounds of formulai are compounds of formula lo.

wherein the ring W is heteroaryl optionally substituted with one or more (e.g. I,

2,3,4 or 5) Z¹ groups.

Another spécifie group of compounds of formula I are compounds of formula

Ip.

wherein the ring W is heteroaryl optionally substituted with one or more (e.g. 1,

2, 3,4 or 5) Z¹ groups,

Another spécifie group of compounds of formula I are compounds of formula

Iq.

wherein the ring W is heteroaryl optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups.

Another spécifie group of compounds of formula I are compounds of formula

Ir.

Ir

Another spécifie group of compounds of formula I are compounds of formula

Is.

Is

Another spécifie group of compounds of formula I are compounds of formula It.

lu.

f

It

Another spécifie group of compounds of formula I are compounds of formula

2,3,4 or 5) Z¹ groups.

Spécifie values listed below are values for compounds of formula I as well as the compounds of formula la, Ib, le, Id, le, If, Ig, Ih, Ii, Ij, Ik, Im, In, Io, Ip, Iq, Ir, Is, It and lu.

A spécifie group of compounds of formula I are compounds wherein at least one of R¹, R², R³, R³’, R⁴, R⁵, R⁶, R⁷, R⁸ or R¹³ is selected from R^,b, R*. R^3b, R^3b’, R^4b, 10 R^Sb, R^6b, R⁷⁶, R^8b and R^13b.

Another spécifie group of compounds of formula I are compounds wherein at least two of R¹, R², R³, R³’, R⁴, R³, R⁶, R⁷, R⁸ or R¹³ is selected fiom R^lb, R^lb, R^3b, R³’, _R4b _RSb, _R6b, _R7b, _R8b _{Qr R}iJb

Another spécifie group of compounds of formula I are compounds wherein at least three of R¹, R², R³, R³, R⁴, R⁵, R⁶, R⁷, R⁸ or R¹³ is selected from R^lb, R²”, R^3b, R^3b’, R^4b, R^Sb, R^6b, R⁷⁶, R^8b and R^I3b.

Another spécifie group of compounds of formula I are compounds wherein at least four of R¹, R², R³, R³’, R⁴, R^s, R⁶, R⁷, R⁸ or R¹³ is selected from R^lb, R^2b, R^3b, R^3b\ R^4b, R^5b, R^6b, R^7b, R^sb and R^I]b.

Another spécifie group of compounds of formulai are compounds wherein at least five of R¹, R², R³, R³’, R⁴, R⁵, R⁶, R⁷, R⁸ or R¹³ is selected from R^lb, R^2b, R^3b, R^3b’, R^4b, R³”, R^6b, R^Tb, R^8b and R^13b.

Another spécifie group of compounds of formulai are compounds wherein at least six of R¹, R², R³, R³', R⁴, R³, R⁶, R⁷, R⁸ or R¹³ is selected from R^lb, R^ïb, R^3b, R^3b', 25 R^4b, R^3b, R^6b, R^7b, R^8b and R^13b.

Another spécifie group of compounds of formula I are compounds wherein at least seven of R¹, R², R³, R³', R⁴, R⁵, R⁶, R⁷, R^s or R¹³ is selected from R^lb, R^2b, R^3b, R^3b, R^4b, R^Sb, K^6h, R⁷⁵, R^8b and R^I3b.

Another spécifie group of compounds of formula I are compounds wherein at 5 least eight of R¹, R², R³, R³’, R⁴, R⁵, R⁶, R⁷, R⁸ or R¹³ is selected from R^lb, R^2b, R^3b, R^3b, R^4b, R^5b, R^6b, R⁷*, R^8b and R^13b.

Another spécifie group of compounds of formula I are compounds wherein at least nine of R¹, R², R³, R³, R⁴, R⁵, R⁶, R⁷, R⁸ or R¹³ is selected from R^lb, R^2b, R³\ R^3b’, R^4b, R^Sb, R⁶**, R^7b, R^8b and R^,3b.

Another spécifie group of compounds of formula I are compounds wherein R¹,

R², R³, R³’, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹³ is selected from R^lb, R^2b, R^3b, R^3b\ R^4b, R^ib, R^6b, R⁷*¹, R^8h and R^l3b.

A spécifie value for R³ is R^3b.

A spécifie value for R^3b is -OCtCHj^CHzOH, -OC(CH₃)2CH₂OH,

O(C_rC₆)alkyl-0-C(O)-NH_2ï -O(Ci-C₆)alkyl-0-C(ü)-N(CH3)20T -O(Ci-C₆)alkyl-O-C(O)-NH(phenyl).

Another spécifie value for R^3b is -(Ci-C^alkylOH or

-O(CrC()alkyl-O-C(O)-NRcRd.

Another spécifie value for R³ is R³.

A spécifie value for R³* is (Ci-C₆)alkyl, (C₂-Cô)alkenyl or -O(Ci-Cé)alkyl, wherein any (Ci-Cs)alkyl or (C₂-C₆)alkenyl of R^3a is optionally substituted with one or more groups selected from -O(Ci-C6)alkyl, halo, oxo and -CN.

Another spécifie value for R³‘ is -OC(CH₃).

A spécifie value for R³ is R^îb .

A spécifie value for R^3b is (Ci-C^jalkyl or -0(Cj-C6)alkyl.

A spécifie value for R³ is R³¹.

A spécifie value for R^îa îs H.

A spécifie group of compounds of formula I are compounds wherein R^3b and R^3b together with the carbon to which they are attached form a (C₃-C7)carbocycle or heterocycle, wherein the (CrCEJcarbocycIe or heterocycle is optionally substituted with one or more Z¹ groups.

ΙΟ

Another spécifie group of compounds of formula I are compounds wherein R^3band R^3b together with the carbon to which they are attached form a (C3-C₇)carbocycle or a 4,5 or 6-membered heterocycle, wherein the (C3-C6)carbocycle or the 4, 5 or 6membered heterocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^3hand R together with the carbon to which they are attached form a (C4-C₆)carbocycle or a 5 or 6-membered heterocycle, wherein the (OCeJcarbocycle or the 5 or 6membered heterocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^3band R^3b together with the carbon to which they are attached form a 5 or 6-membered heterocycle, wherein the 5 or 6-membered heterocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^3band R^3b together with the carbon to which they are attached form a tetrahydropyran or telrahydrofuran optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^îbJL* and R together with the carbon to which they are attached form:

each of which is optionally substituted with one or more Z¹ groups, and wherein dénotés the point of attachaient to the carbon of the compound of formula I.

A spécifie value for R⁴ is R^4b.

A spécifie value for R^4b is (CrC₆)alkyi, (C₂-C₆)alkenyl or (CrCeialkyuyl, wherein (Ci-C6)alkyl, (CrCeJalkenyl or (C^-Cgjalkyny: are each optionally substituted with one or more Z¹ groups.

Another spécifie value for R^4b is:

optionally substituted with one or more Z¹ groups.

Another spécifie value for R^4& is (CrCyjcarbocycle, wherein (C3-C7)carbocycle is optionally substituted with one or more Z¹ groups, or wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C(,)carbocycle 5 or 5-6-membered heterocycle.

Another spécifie value for R^4b is:

WVW each of which is optionally substituted with one or more Z¹ groups.

Another spécifie value for R^4b is aryl, heterocycle or heteroaryl, wherein aryl, 10 heterocycle or heteroaryl are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another spécifie value for R^4b is:

Another spécifie value for R⁴ is R⁴’.

A spécifie value for R^4a is:

A spécifie group of compounds of formula I are compounds wherein R⁴ and R³together with the atoms to which they are attached form a macroheterocycle or a 5 macrocarbocycle, wherein any macroheterocycle or macrocarbocycle of R⁴ and R³together with the atoms to which they are attached may be optionally substituted with one or more Z¹ groups; and R³ is H, (C i -C^alkyl or -O(Cj-Cs)alkyl.

Another spécifie group of compounds of formula I are compounds wherein R⁴and R³ together with the atoms to which they are attached form a macroheterocycle or a 10 macrocarbocycle, wherein any macroheterocycle or macrocarbocycle of R⁴ and R³together with the atoms to which they are attached may be optionally substituted with one or more Z¹ groups; and R³ is H.

Another spécifie group of compounds of formula I are compounds wherein R⁴and R³ together with the atoms to which they are attached form the macroheterocycle or a macrocarbocycle which is further fused to a Z group;

wherein:

Z is aryl, heteroaryl or (CVC^carbocycle;

n3 is 2, 3 or 4;

W¹ and W²are each independently O, NH or CH₂; and wherein “•dénotés the R⁴ point of attachment of the macroheterocycle or macrocarbocycle to the compound of formula I and “·♦” dénotés the R³ point of attachment of the macroheterocycle or macrocarbocycle to the compound of formula I, and wherein the macroheterocycle or a macrocarbocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein, R⁴and R³ together with the atoms to which they are attached form the macroheterocycle:

wherein:

ni is 3 or 4; n2 is 2,3 or 4; n3 is 2,3 or 4; W is 0, NH orN(Ci-C₄)alkyl; and wherein “· dénotés the R⁴ point of attachment of the macroheterocycle to the compound of formula I and dénotés the R³ point of attachment of the macroheterocycle to the compound of formula I; and wherein the macroheterocycle or a macrocarbocycle is optionally substituted with one or more Z¹ groups.

A spécifie value for R is R^lb.

W -b _^· Λ

Another spécifie value R¹ is R^k.

A spécifie value for R^Ia is H or halo.

A spécifie value for R² is R^2b.

Another spécifie value R² is R^2a.

A spécifie value for R²* is H, halo or -CH₃.

Another spécifie value for R^2a is -Cl.

A spécifie value for R⁵ is R^ib.

Another spécifie value for R⁵ is R^ia.

A spécifie value for R^Sa is H.

A spécifie value for R⁶ is R⁶**.

Another spécifie value for R⁶ is R^6a.

A spécifie value for R⁶* is H.

A spécifie value for R⁷ is R⁷⁰.

Another spécifie value for R⁷ is R⁷’.

A spécifie value for R⁷¹ is H, -CH₃, CF₃ or halogen.

A spécifie value for R⁸ is R^8b.

Another spécifie value for R⁸ is R⁸*.

Another spécifie value for R⁸* is H.

A spécifie group of compounds of formula 1 are compounds wherein R^4b is selected from:

a) (C[-Ci)alkyl, (C₂-C6)alkenyl and (C₂-C₆)alkynyl, wherein (C]-C₆)alkyl, (C_rC₆)alkenyl and (C₂-C₆)alkynyl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

h) (C3-Ci4)carbocycle, wherein (C₃-C_I4)carbocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

c) Spiro-heterocycle and bridged-heterocycle, wherein spiro-heterocycle and bridged-heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

d) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1,2,3,4 or5) Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴® is selected from:

a) (Cï-C₆)alkyl, (C-2-C_é)alkenyI and (C₂-C6)alkynyl, wherein (Ci-Cj)alkyl, (Ci-Cgjalkenyl and (C₂-C(>)alkynyl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) (C₃-Ci₄)carbocycle, wherein (Cj-C|₄)carbocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃C₇)carbocycle or heterocycle; and

c) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups.

Another spécifie group of compounds of formula 1 are compounds wherein R^4bis selected from:

a) (C i -C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C6)alkynyl, wherein (C _rC₆)alkyl, (C₂-Ci)alkenyl and (C₂-Cô)alkynyl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) (C₃-C|₄)carbocyclc, wherein (C₃-Ci4)carbocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

Another spécifie group of compounds of formula I are compounds wherein R³ is (Ci-Cs)alkyl, (C2-Cf,)alkenyl or -O(Ci-C6)alkyl, wherein any (Ci-C6)alkyl or (C2-C(î)alkenyl of R³ is optionally substituted with one or more groups selected from -O(C1-Ce)alkyl, halo, oxo and -CN, and wherein R³ is H.

Another spécifie value for R³ is -O(Ci-C6)alkyl.

Another spécifie value for R³ is -OtBu.

Another spécifie value for R³ is H.

Another spécifie value for R² is halo, H or -CH₃.

Another spécifie value for R² is chloro or -CH₃.

Another spécifie value for R² is -CH₃.

C

Another spécifie value for R¹ is H.

Another spécifie value for R⁶ is H.

Another spécifie value for R^s is H or (Ci-Ce)alkyl.

Another spécifie value for R⁵ is H or -CH3.

Another spécifie value for R⁵ is H.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from:

a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected ftom halo, (C i-C$)alkyl, (Ci-Célalkcnyl, (Cj-Qhaloalkyl, (C₃-C₇)cycloalkyl, OH, -OfCi-QUlkyl, -SH, -S(C|-C6)alkyl, -NH₇₎ -NH(C_rC₆)alkyI and -NffCrC^alkylJz, wherein (C i-CéJalkyl is optionally substituted with hydroxy, -O(Ci-Cs)alkyi, cyano or oxo;and

b) (C3-Ci4)carbocycle, wherein (C₃-Ci₄)carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z^! groups together vrith the atom or atoms to which they are attached optionally form a (C3-C₇)carbocycle or heterocycle; and

c) aryl, heteroaryl, spiro-hcterocycle, fused-heterocycle and bridgedheterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle are each independently substituted with one or more Z⁷ groups and — optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula 1 are compounds wherein R⁴ is selected from:

a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (Ci-Ce)alkyl, (C2-C6)alkenyl, (C]-Ci)haloalkyl, (C₃-C₇)cycloalkyl, OH, -O(Ci-C6)alkyl, -SH, -SÎC_rCs)alkyl, -NHj, -NH(C_rC₆)alkyl and -N((Ci-C₆)alkyl)ï, wherein (C i-Cefalkyl is optionally substituted with hydroxy, -OfCj-Ceialkyl, cyano or oxo;

b) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle, wherein spiro-heterocycle, fused-heterocycle and bridged-hetcrocycle are

each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (Cj-Csjalkyl, (C₂-C6)alkenyl, (Cj-Côjhaloalkyl, (Cj-CYjcycloalkyl, OH, -OtCi-C₆)alkyl, -SH, -S(Ci-C_s)aikyl, -NH₂, -NH(C_L-C₆)alkyl and -NftCj-CôJalkylh, wherein (Ci-C^alkyl is optionally substituted with hydroxy, -O(Ci-Cs)alkyl, cyano or oxo;and

b) aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

a) heterocycle, wherein heterocycle is optionally substituted with one or more groups each independently selected from halo, (C)-Cejalkyl, (C₂-Ci)alkenyl, (CjC₆)baloalkyl, (C₃-C₇)cycloalkyl, -OH, -OfC^jalkyl, -SH, -SfCi-CeW. -NH₂, -NH(C_rCs)alkyl and -N((C|-C6)alkyl)2, wherein (Ci-Cé)alkyl is optionally substituted with hydroxy, -O(Ci-C<j)alkyI, cyano or oxo; and

b) fused-heterocycle, wherein fused-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

a) bicyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl, wherein bicyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (CrC₆)alkyl, (C₂-C₆)alkenyl, (C_rC_É)haloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(Ci-C₆)alkyl SH, -S(C_rC₆)alkyI,-NH₂, -NH(C,-C₆)alkyl and -N((Ci-C₆)alkyl)₂, wherein (C_rC₆)aIkyl îs optionally substituted with hydroxy, -OfCi-Cejalkyl, cyano or oxo; and

C

b) bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle, and tricyclic fused-heterocycle, wherein bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle and tricyclic fused-heterocycle are each independently substituted with one or more Z⁷5 groups and optionally substituted with one or more Z¹ groups.

a) bicyclic heterocycle and tricyclic heterocycle, wherein bicyclic heterocycle and tricyclic heterocycle arc each optionally substituted with one or more groups each independently selected from halo, (Ci-Ci)alkyl, (Cï-Cs)alkenyl, (C[C₆)haloalkyl, (Cj-C₇)cycloalkyl, -OH, -O(Ci-C₆)alkyl, -SH, -S(C_rQ)alkyl, -NH₂, -NH(CiCfi)alkyl and -N((Ci-C6)alkyl)2, wherein (Ci-C6)alkyl is optionally substituted with hydroxy, -O(Ci-C6)alkyl, cyano or oxo; and

b) bicyclic fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle arc each substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹groups.

a) bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl wherein bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (Cj-CôJalkyl, (C₂-C6)alkenyl, (CiC₆)haloalkyl, (C₃-C₇)cycloalkyl, -OH, -OfCi-CeJalkyl, -SH, -S(Ci-Cg)alkyI, -NH₂, -NH(Cr

C₆)alkyl and -N((C[-C₆)alkyl)₂₎ wherein (Ci-C₆)alkyl is optionally substituted with hydroxy, O(C|-C₆)alkyl, cyano or oxo; and

b) bicyclic fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle are each substituted with one or more Z⁷ groups and optionally substituted with one or more Z^! groups.

a) tricyclîc heterocycle, wherein tricyclîc heterocycle is optionally substituted with one or more groups each independently selected from halo, (CiCsJalkyl, (C₂-C6)alkenyl, (Ci-C6)haioalkyl, (C₃-C7)cycloalkyl, -OH, -O(C]-C6)alkyI, -SH, SfCi-CûJalkyl, -NH₂, -NH(C_rC₀)alkyl and -NftCj-CeJalkylh, wherein (C₍-C₆)alkyl is optionally substituted with hydroxy, -OfCi-Cejalkyl, cyano or oxo; and

b) tricyclîc fused-heterocycle wherein tricyclîc fused-heterocycle is

1 substituted with one or more Z groups and optionally substituted with one or more Z groups.

a) (C₃-Cu)carbocycle, wherein (C₃-C]₄)carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-Cj)carbocycle or heterocycle; and

b) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle, wherein aryl, heteroaryl or spiro-heterocycle, fused-heterocycle and bridged-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle, wherein spiro-heterocycle, fused-heterocycle and bridged-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is fused-heterocycle, wherein fused-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z^! groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from bicyclic aryl, tricyclîc aryl, bicyclic heteroaryl, tricyclîc heteroaryl

ΙΟ bicyclic fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclic aryl, ·%

- » tricyclic aryl, bicyclic heteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle and tricyclic fused-heterocycle are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from bicyclic fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle are each substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹groups.

Another spécifie group of compounds of formula 1 are compounds wherein R⁴ is tricyclic fused-heterocycle, wherein tricyclic fused-heterocycle fused-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹groups.

A spécifie value for Z^lftis:

i) halo, (Ci-C$)haloalkyl; or ii) (Ct-C&)alkyl optionally substituted with -OH, -0(Ci-Cfijhaloalkyl.

Another spécifie value for Z¹’ is halo.

Another spécifie value for R⁴ is:

^wv

Another spécifie value for R⁴ îs:

Another spécifie value for R⁴ is:

Cl

AW

Another spécifie value for R⁴ is:

C

«ΛΑ/W

Another spécifie value for R⁴ is:

ΛΛΛ/

Another spécifie value for R⁴ is:

Cl

Another spécifie group of compounds of formula I are compounds wherein the stereochemistry of the R⁴ substituent relative to the carbon of formula I to which it is attached is the (R) stereochemistry.

t 64

Another spécifie group of compounds of formula I are compounds wherein the steréochemistry of the R⁴ substituent relative to the carbon of formula I to which it is attached is the (S) stereochemistry.

Another spécifie group of compounds of formula I are compounds wherein R⁷ is 5 selected from:

a) H, halo, (C[-C₆)alkyl and (C_rC₆)haloalkyl;

b) (Ci-Côjalkenyl, (Cj-C^alkynyl, (C;-C₇Xycloa!kyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) ₇C(=O)-R^h, -C(=O)-O-Rⁿ, -O-Rⁿ.-S.R¹¹,-S(O>R^,1,-SO2-R^,, _>

-(C_rC₆)alkyl-R¹¹, -(Ct-C6)alkyl-C(=O)-Rⁿ, -(Ci-C6)alkyl-C(=O)-0-Rⁿ, -(Cj-COalkylO-R¹¹, -(C rCsÎalkyl-S-R¹¹, -(CrC^alkyl-SiO^R¹¹ and -(CrC^alkyl-SOî-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Céjalkyl, (Cj-C₆)all<enyl, (C2Céjalkynyl, (Ci-CsJhaloalkyl, (C₃-C7)cycioaikyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more

Z groups;

d) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R³⁰, -O-C(=O>N(R^?)R¹⁰, -S02-N(R’)R^!0, -(Ci-C6)alkyl-N(R⁹)R^I°,-(C|-C6)alkyl-C(=O)-N(R⁹)R^I0,-(CI-C₆)alkyl-O-C(=O)N(R⁹)R¹⁰ and -(Ci-C^alkyl-SCh-NfR^R¹⁰, wherein each R⁹ is independently selected from H, (C]-C₆)alkyl and (C₃-C7)cycloalkyl, and each R^1Dis independently selected fromR^u,-(Ci-Cs)alky)-R¹³, -SCb-R¹¹, -C(=O)-R³¹, -C(=O)OR¹¹ and -C(=O)N(R⁹)R^l!, wherein each R¹¹ is independently selected from H, (CpCcjalkyl, (C₂-C6)alkenyl, (C₂C₆)alkynyl, (Cj-Cyhaloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more

Z¹⁰ groups;

e) -<C₁-C₆)alkyl-SO₂-(C₁-C₆)alkyi-Z¹³, -C(0)<4<\)alkyl-Z’³. -O-(Cr C₆)alkyl-Z¹³, -S-(Ci-C6)alkyl-Z^î3, -S(O)-(Ci-C6)alkyl-Z¹³, -SO2-(C1-C6)alkyl-Z¹’, -(Ci-Csjalkyl-Z¹⁴, -(CrCéJalkyl-CiOXCi-CÈjalkyl-Z^-tCi-CeJalkyl-CfOJ-OtC]C6)alkyl-Z¹³, -(CrGjalkyl-O^CrCéialkyl-Z¹¹, -(Ci-C()alkyl-S-(Ci-C6)alkyl-Z^,3t -(Ci-

C₆)alkyl-O-(Ci-C₆)alkyl-(C3-C7)carbocycle,-(Ci-C₆)alkyl-S-(C]C6)alkyl-(C₃-C7)carbocyc]e, -(Ci-Cs)alkyl-S(O)-(C|-C6)alkyl-(C3-C7)carbocycle, -(CjC₆)alkyl-SO2-(C_l-C₆)alkyl-(C3-C₇)carbocycle,-(C2-C₆)alkenyl-(C_I-C₆)haloalkyl_î -(C₂A

C

C6)alkynyl-(Ci-C6)ha(oalkyl, -(Cî-C₇)halocarbocycle, -NRSOARR. -NR_aSO_?.O(C;C₇)carbocycle, -\R_aS0₂0aryl, -(Ci-CôJalkenyRCs-C.Ocarbocyclc, -(C2-C₆)alkenylaryl, -(Cî-CéJalkenyl-heteroaryl, -(C₂-C6)aikenyl-heterocycle, -(C2-C6)alkynyl-(C₃-C₇)carbocyclc, -(C₂-C6)alkynyl-aryl, -(CrCeJaH^nyl’heteroaryl, -(C₂-C6)alkynyl-heterocycle, -(Cj-CjJcarbocycle-Z¹ and -halo(Ci-Ci)alkyl-Z³ _} wherein any (CpCJalkyl, (Ci-Cô)haloalkyl, (Ca-CjJcarbocycle, (C₂-C(,)alkenyl, (C₂-Cs)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

f) -X(Ci-C₆)alkyl, -X(Ci-C₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-C6)alkynyl and -X(Cj-C₇)carbocycle, wherein any -X(CrC_É)alkyl and -X(CiCe)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any -X(C2-C6)alkenyl, -X(C₂-C6)alkynyl and -X(C₃-C7)carbocycIe is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups;

g) (C] -C«)alkyl, wherein (C i-CeJalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

h) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹groups;

i) (C i -C₆)haloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl, wherein (Ci-Cfi)haloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-Ci)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

j) -NRR_f, -C(O)NRR_f, -OC(O)NR.R_f, -SO₂NR.Rf, -(Ci-C^alkyi-NRRf, -(Ci-C₆)alkylC(O)-NRR_f, -(C₁-C₆)alkyl-O-C(O)-NR_ïR_f and -(CrQJalkyl-SOîNRRf, wherein each (Ci-Cfi)alkyl is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁷ is selected from:

a) H, (C i -C₆)alkyl and (Ci-C₆)haloalkyl;

C

b) (Cî-CiJalkenyl, (C₂-C_É)alkynyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z^t0 groups;

c) -C(=O)-0-Rⁿ, -O-R“, <CrC6)alkyl-R^H and -(C^C^alkyl-O-R*¹, wherein each R¹¹ is independently selected from H, (CrCôJalkyl, (Cî-CeJalkenyl, (Cr C6)alkynyl, (Ci-C_e)haloalkyl, (C3-C₇)cycloaikyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z groups;

d) -N(R⁹)Rⁱ⁰, -C(-O)-N(R⁹)R^1Ij, -(Ci-C6)alkyl-N(R⁹)R^Î0, whereineach R⁹is independentlyselected from H, (Cj-Cejalkyl and (C',-Ci)cycloalkyl, and each R¹⁰is independently selected from R¹¹,-(C|-C6)alkyl-R¹¹, -SO2-R¹¹, -C^OJ-R¹¹, -CGOJOR¹¹and -CÎ’OJNiR.’jR¹¹, wherein each R¹¹ is independently selected from H, (Ci-C^alkvl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cj-C₆)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) -(C2-Cfi)alkynyl-(C3-C7)carbocycle and -(C2-C6)alkynyl-aryl, wherein -(C2-C₆)alkynyl-(C3-C₇)carbocycle and -(C2-C6)alkynyl-ary] are each optionally substituted with one or more Z¹ groups;

f) -X(Ci-C6)alkyl, wherein -X(Ci-C6)alkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein X is O;

g) (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

h) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are each substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups;

i) (Ci-C₆)haloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkenyl and (CrCe)alkynyl, wherein (Ci-C6)haloalkyl, (C3-C₇)carbocycle, (C₃-C6)alkenyl and (C₂-C6)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

j) -NR«Rf, -C(O)NReRf and -(G-Célalkyl-NR^Rf. wherein each (Ci-Ce)alkyl is optionally substituted with one or more Z¹ groups.

C

a) H, (C_t-Cs)alkyl and (Ci-Csjhaloalkyl;

b) (Cj-Côjalkenyl, (C₂-C₆)aikynyL (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -C(=O)-R‘ -C(-0)-0-R^li, -O-R¹ -(Ci-CiJalkyl-R¹¹ and -(Cr Cfijalkyl-O-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-C6)alkyl, (C₂CéJalkenyl, (C₂-C6)alkynyl, (CpCyhaloalkyl, (Cj-Cîjcycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R^w, -(Q-C^alkyl-NCR^R¹⁰, wherein each R⁹is independently selected from H, (Ci-C₆)alkyl and (C3-C₇)cycloalkyl, and each R^l0is independently selected from R'^-tCi-Cfijalkyl-R¹¹, -SOrR¹¹, -C(=O)-Rⁿ, -C(=Û)OR^tl and -C(=O)N(R⁹)R¹ \ wherein each R¹¹ is independently selected from H, (C _rC₆)alkyl, (Cj-C₆)alkenyl, (Ci-Côjalkynyl, (Ci-C₆)haloalkyl, (Cj-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) -(C₂-C6)alkynyl-(C₃-C7)carbocycle and -(C₂-C6)alkynyl-aryl, wherein 20 -(Cz-CôjalkynylXCj-CîJcarbocycIe and -(C₂-C$)alkynyl-aryl are each optionally substituted with one or more Z¹ groups;

f) -XfCi-Csjalkyl, wherein -X(C_rC6)alkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein X is O;

g) (Ci-Ci)alkyl, wherein (C j -C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups;

h) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are each substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups;

i) (Ci-Csjhaloalkyl, (CrC₇)carbocycle, (C₂-Cs)alkenyl and (C₂-C6)alkynyl, 30 wherein (Ci-Cgjhaloalkyl, (Cj-C₇)caTbocycle, (C₂-C6)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

j) -NRçRf, -CCOJNRcRf and -(Ci-C₆)alkyi-NR_<:Rf, wherein each (Ci-Cfi)alkyl is optionally substituted with one or more Z¹ groups.

a) H, (Ci-Cé)alkyl and (Ci-Cfijhaloalkyl;

b) (C₂-C6)alkenyl, (C₂-C6)alkynyl, (C.rCjkydoalkyt, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -C(=O)-R^tl, -C(-O)-O-Rⁿ, -0-R¹¹, -(CrûOalkyl-R” and -(Ci-

Cijalkyl-O-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Cijalkyl, (C₂Csialkenyl, (C₂-C6)alkynyl, (Ci-C^Jhaloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R^w, -(CrC₆)aUcyl-N(R⁹)R¹⁰, whereineach R⁹ îs independently selected from H, (C_rC₆)a]kyl and (Cj-C₇)cycloalkyl, and each R¹⁰is independently selected from R”,-(CrC6)alkyl-Rⁿ, -SO2-R¹¹, -C(=O>Rⁿ, -C(=O)ORⁿand -C(=O)N(R⁹)R¹¹, wherein each R¹¹ is independently selected from H, (Ci-C^alkyl, (CrC^alkenyl, (C2-Cj)alkynyl, (Ci-Cs)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) -(C₂-C6)alkynyl-(C3-C₇)carbocycle and -(C₂-C₆)alkynyl-aryl, wherein -(C₂-C()alkynyI-(C₃-C7)carbocycie and -(C₂-C6)alkynyl-aryl are each optionally substituted with one or more Z¹ groups;

f) -X(C 1 -C₆)alkyl, wherein -X(C 1 -Ctlalkyl is substituted with one or more

Z³ groups and optionally substituted with one or more Z¹ groups, and wherein X is O; and

g) -NRJRf.

a) (Ci-C6)haloalkyl; and

b) (Ci-Cijhaioalky 1, wherein (C i-C₆)haloalkyl is substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups.

Of

C - 69

Another spécifie group of compounds of formula l are compounds wherein R⁷ is selected from:

a) (C i -C^Jalkyl and (C ! -C_g)haloalkyl;

b) (C2-C₆)alkynyl, (C₃-C₇)cycloalkyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Ci-Cejalkyl-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Cs)alkyl, (CrC_g)alkenyl, (C₂-Cfe)alkynyl, (Ci-Ctlhaloalkyl, (CrCXcycIoalkyl and aryl, wherein aryl is optionally substituted with one or more Z¹⁰ groups;

d) -(Cï-C(i)alkynyl-{CrC7)carbocycle andXCj-CsJalkynyl-aryl, wherein

-(C2-C6)alkynyI-(C₃-C₇)carbocyde and-(C₂-C6)alkyny]-aryl are each optionally substituted with one or more Z¹ groups;

e) (Ci-C₆)alkyl, wherein (Cj-C^lkyl is substituted with one or more Z²groups and optionally substituted with one or more Z^J groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and

g) (Ci-C$)ha!oalkyl, (C₃-C₇)carbocycle and (C₂-Ci)alkynyl, wherein (Ci-C^haloalkyl, (C₃-C₇)carbocycle and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z’ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁷ is 20 selected from:

a) (Ct-CôJalkyl and (Cj-C6)haloalkyl;

b) (C₂-C₆)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Ci-Cyalkyl-R¹¹, wherein each R¹¹ is independently selected from (C3-C₇)cycloalkyl and aryl, wherein any aryl is optionally substituted with one or more Z groups;

d) -(C₂-C6)alkynyl-(C3-C₇)carbocycle and-(C₂-C6)alkynyl-aryl, wherein -(C2-C₆)alkynyI-(C3-C₇)carbocycle and-(C₂-C<;)alkynyl-aryl are each optionally substituted with one or more Z¹ groups;

e) (C_rC₆)a!kyl, wherein (C]-C_É)alkylis substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups;

C

g) (C[-Cs)haloalltyl and (Cï-Csjalkynyl, wherein (C|-C₆)haloalkyl and (Cî-CeJalkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁷ is selected from;

a) (Ci-Côjalkyl and(C|-C6)haloalkyl;

b) (Cî-Csialkynyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) (Ci-C^Jalkyl, wherein (Ci-Cè)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

d) aryl, wherein aryl is substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups.

a) (Ci-C6)alkyl and (Ci-Ce)haloalkyl; and

b) (C₂-Cj)alkynyl and aryl, wherein any aryl is optionally substituted with one or more (Cj-CsJalkyl groups.

Another spécifie group of compounds of formula I are compounds wherein R⁷ is selected from (Ci-C₆)alkyl, CrQJhaloalkyl and (Cî-Qalkynyl.

Another spécifie group of compounds of formula I are compounds wherein R^Tis selected from:

a) -(Ci-Ciialkyl-SOrtCrQalkyl-Z¹³, -C(O)-(CÎ-C6)alkyl-Z^u, -0-(0,Csialkyl-Z¹³, -S-(Ci-C6)alkyl-Z¹³, -S(O)-(Ci-C.6)alkyl-Z¹³, -SO2-(C_rC₆)alkyl-Z¹³, (C1-C6)alkyl-Z¹⁴, -(Ci-CeJalkyl-CiOHCi-CeJalkyl-Z^.XCrCeJalkyl-CtOi-OfCiCé)alkyl-Z^!-(CrCiJaikyl-O-ÎCi-^alkyl-Z'³, -(Ci-Qalkyl-SXCi-CÊÎalkyl-Z¹³, -(C_rC6)alkyl-0-(Ci-C6)alkyI-(Cî-C7)carbocycle, -(Ci-C6)alkyl-S-(CiCé)alkyl-(C3-C₇)carbocycle, -(Ci-Côlalkyl-SlOXCVCValkyRCrCvlcarbocycle, -(CiC6)alkyl-SO2-(Cî-C6)alkyl-(C3-C7)carbocycle, -(C₂-C₆)alkenyl-(CrC6)haloalkyl, -(C₂C₆)alkynyl-(Cj-C6)haloaikyl, -(Cî-C7)halocarbocycle, -NRSGbNRRd, -NR»SO₂O(C₃C7)carbocycle, -NR₅SO₂Oaryl, -(C₂-Cô)alkenyl-(Cj-C7)carbocycle, -(C₂-C6)alkenyl16294

C - 7l aryl, -(C₂-C6)alkeny[-heteroaryl, -(CrGjaïkenyi-heterocydc, -(C2-C6)alkynyl-(C₃-C₇)carbocycle, -(Cj-Côjalkynyl-ar- ·, -(C2-C₆)alkynyl-heteroaiyi, -(Ci-CeJalkynyl-heterocycle, -(C₃-C₇)carbocycle-Z’ and -halo(C_t-C6)alkyl-Z³, wherein any (Cj-Cejalkyl, (C i -C^haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C.>-C<,jalkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, are each optionally substituted with one or more Z¹ groups;

b) -X(C|-C₆)alkyl, -X(C_rC₆)haloalkyl, -X(C₃-C₆)a]kenyl, -X(C₂-Cfi)alkynyl and -X(C₃-C₇)carbccycle, wherein -X(Ci-Cé)alkyl and -X(CiCôJhaloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein -X(C₂-C6)alkenyl, -X(C₂'C6)alkynyl and.

-X(C₃-C₇)carbocyclc are each substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups;

c) (Ci -C(>)alkyl. wherein (C i -Côjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaiyl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹groups;

e) (CrCéJhaloalkyl, (C₃-C₇)carbocycle, (C2-C₆)a.ikenyl and (C₂'C₆)alkynyl, wherein (Cj-C6)haloalkyl, (C₃-C₇)carbocycle, (C^-C^jalkcnyi and (C₃-Ce)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

f) -NRcRf, -C(O)NReR_f, -OC(O)NR<R_f, -S0₂NR_eR_f, -(Ci-CsJalkyl-NReRf, -(C_rC6)alkylC(O)-NR.R_t, -(CrCfilalkyl-O-CCO-NReRf and -(C_i-C₆)alkyl-SO₂NR_<R_f, wherein each (Ci-C₆)alkyl is optionally substituted with one or more Z¹ groups. Another spécifie group of compounds of formula I are compounds wherein R⁷ is selected from:

a) -(C2-Ce)alkynyl-(C₃-C₇)carbocycle and -(C₂-Cs)alkynyl-aryl, wherein -(C₂'C6)alkynyl-(C₃-C₇)carbocycle and -(C₂-C6)alkynyl-aryl are each optionally substituted with one or more Z¹ groups;

b) -X(C[-C6)alkyl, wherein -X(C)-C6)alkyl is substituted with one or more

Z³ groups and optionally substituted with one or more Z¹ groups, and wherein X is O;

L

c) (Ci-C6)alkyl, wherein (C i-C6)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are each substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups;

e) (Cj-C ^haloalkyl, (CrC₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C6)alkynyl, wherein (Cj-CiJhaloalkyl, (Cj^Jcarbocycle, (CrC^alkenyl and (C₂-Cfi)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z^! groups; and

f) -NRtRf, -€(O)NR_cR_f and -(Ci-CfiJalkyl-NReRj, wherein (Ci'Cfi)alkyl is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁷ is (Ci-Côihaloatkyl, wherein (Ci-Cé)haloalkyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) -(C₂-C6)alkynyl-(Cj-C₇)carbocÿcIe and-(C₂-C$)alkynyl-aryl, wherein -(C₂-C6)alkynyl-(Cj-C7)carbocycle and-(C₂-C6)alkynyl-aryl are each optionally substituted with one or more Z¹ groups;

b) (Ct -Cejalkyl, wherein (C i-Ce)alkyl is substituted with onc or more Z²groups and optionally substituted with one or more Z¹ groups;

c) aryl, wherein aryl is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and

d) (Ci-Csihaloalkyl, (Ci-C₇)carbocycle and (C₂-Cs)alkynyl, wherein (Ci-C6)haloalkyl, (C₃-C₇)carbocycle and (C₂-Ci)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) -(C₂-C6)alkynyl-(C3-C₇)carbocycle and-(C₂-C6)alkynyl-aryl, wherein -(C₂-C6)alkynyl-(C3-C₇)carbocycle and-(C2'C₆)alkyny]-aryl are each optionally substituted with one or more Z¹ groups;

C

b) (C i -Cé)alkyl, wherein (C i -C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z^! groups;

d) (Ci-Cejhaloalkyl and (C₂-C_&)alkynyl, wherein (C-C^haloalkyl and (C2-Ci)aikynyl are each substituted with one or more Z^É groups and optionally substituted with one or more Z¹ groups.

a) (Ci-CôJalkyl, wherein (Ci-C<,)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; and

b) aryl, wherein aryl is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^7a is selected from:

' a) H, halo, (Ci-C₆)alkyl and (Ci-C₆)haloalkyl;

b) (C2-C6)alkenyl, (C₂-Cè)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-Rⁿ, -C(=O)O-R, -O-R¹¹, -S-Rⁿ, -S(O)-Rⁿ, -SO2-R¹¹,

-(Ci-C₆)alkyl-R’¹, -(C1-C6)alky4-C(=O)-R^{l 1}, <CrC6)alkyl-C(=O)-O-R'¹, -(Ci-QJalkylO-R¹¹, -(Ci-C6)alkyl-S-R¹¹, -(CrC₆)alkyl-S(O)-R^1! and -(Ci-C6)alkyl-SOrR^1!, wherein each Rⁿ is independently selected from H, (CpC^alkyl, (CX-C^alkenyl, (C2C₆)alkynyl, (Ci-C₆)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R'°, -O-C.(-O)-N(R⁹X°, -SO2-N(R⁹)R¹⁰,

-(Ci-C₆)alkyl-N(R⁹)R'⁰, -(Ci-C6)alkyl-C(=O)-N(R⁹)R^lû, -(C]-C6)alkyl-0-C(=0)N(R⁹)R¹⁰ and -(CI-C6)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (CrCfi)aIkyI and (C3-C7)cycloalkyl, and each R¹⁰ is independently selected from R'^Ci-Célalkyl-R¹’, -SO2-Rⁿ, -C(=O)-Rⁿ, -C(=0)OR and -0(=0)14^⁹)^ wherein each R¹¹ is independently selected from H, (Ci-Cejalkyl, (C2-C6)alkenyl, (C₂30 Ck)alkynyl, (C]-C₆)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl of R^7ais optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups, and wherein R^7a is not OH.

Another spécifie group of compounds of formula I are compounds wherein R⁷ has any of the above recited values for R⁷ provided R⁷ is not OH.

Another spécifie value for R⁷ is:

À	. 1		Ph
àf	A/	.	. œ.
Cf	<Y^Xn-nh	V	liV	(f N
<V^K Wn 1	</ HN^	a.	Cf	Cf.
<^ZJ /	rr^xM .	W .	ff.	àf N ’
	O^A S7	or OH
Another spécifie value for R⁷ is:
y x H '		Ph X ‘	A·	M.

ΰχ ,^p^ Ύ·c/· cA A· cA 'f* ' f₃c^a .

^Η°χΑ ,

Another spécifie value for R⁷ is:

F

Another spécifie group of compounds of formula In, lo, Ip and Iq are compounds wherein W is a five-membered heteroaryl optionally substituted with one or more (e.g. I, 2, 3,4 or 5) Z¹ groups.

Another spécifie group of compounds of formula In, Io, Ip and Iq are compounds wherein W is imidazolyl, triazolyl, or tetrazolyl each optionally substituted with one or more (e.g. 1 ,.2, 3,4 or 5) Z¹ groups.

A spécifie value for Z* is -(C i -C₆)alkyl or -aryl, wherein any (C ; -Cô)alky 1, or aryl of Z¹ is optionally substituted with one or more (e.g. 1,2,3,4 or 5) halogen, -OH, 10 -ORb, -CN, -NRaCtOhRb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, NHheteroaryl, -NHheterocycle, or -SiO^NRcRd.

Another spécifie group of compounds of formula I are compounds wherein R^l3a is selected from:

a) R¹¹, -C(=O>R¹¹, -C(=0)-0-Rⁿ, -O-R^-S-R¹¹, -S(O>Rⁿ, -SO_rR, - (Cj-C^alkyl-R¹¹, -(Cj-CfiJalkyl-Cf^OJ-R¹¹, -(C1-C6)alkyl-C(=0)-0-R¹¹, -(CpCiJalkylO-R¹¹, -(Ci-CeÎalkyl-S-R¹¹, -(Ci-C6)alkyl-S(O)-Rⁿ and -(CrC6)alkyl-SO2-Rⁿ, wherein each R¹¹ is independently selected from H, (Ci-C<s)alky 1, (C2-C₆)alkenyl, (C₂Ce)alkynyl, (Ci-Cs)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups; and

b) -C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R’°, -(CrC₆)alkyl-N(R⁹)R¹⁰, -(C r C6)alkyl-C(=O)-N(R⁹)R¹⁰, -(C|-C6)alkyl-O-C(=O)-N(R⁹)R¹⁰ and -(Ci-C6)alkyl-SO2N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Cs)alkyl and (C3C₇)cycloalkyl, and each R^l0is independently selected from R¹¹, -(Ci-CeJalkyl-R¹¹, -

SÛ2-R¹¹, -C(=O)-R^{l l}, -C(=O)OR¹¹ and -C^NiR^R¹¹, wherein each R¹¹ is independently selected from H, (CpC^alkyl, (C₂-C6)alkenyl, (C₂-C6)alkynyl, (C_rCf.)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or

3) Z¹¹ groups; provided R^13a is not H.

Another spécifie group of compounds of formula I are compounds wherein

C

R^13a îs selected from:

a) R^u, -C(=O)-Rⁿ, -C( O)-O-R”, -O-R^-S-R¹¹, -S(O)-R^ll,-SO2-R¹¹, (Ci-CfiJalkyl-R'^XCrCeialkyl-C^OJ-R¹¹, -(C]-C6)alkyI-C(=O)-O-Rⁿ, -(C l-C6)alkyb O-R'¹, (CrC₆)alkyl-S-R^ll? -((^^)^1-5(0)^¹¹ and -(CrC₆)alkyl-SOrR, wherein each Rⁿ is independently selected from (CrCsjalkyl, (Cî-C^alkenyl, (CE-CôJalkynyk (Ci-CeJhaloalkyi, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Zⁿ groups; and

b) -C(=O)-N(R⁹)R^I(1, -SO₂-N(R⁹)R'^u, -(Ci-C6)alkyl-N(R⁹)R^l°, -(Ct-

C₆)alkyl-C(--O)-N(R⁹)R’°, -(Ci-C6)alkyl-O-C(=O)-N(R⁹)R¹⁰ and -ÎCrC₆)alkyl-SO₂N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-C&)alkyl and (C3C7)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,-(Ci*C6)alkyl-R¹\ SO2-R¹¹, -C(=O>R¹¹, -C(=O)ORⁿ and -C(=O)N(R⁹)R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Ci)alkyl, (C2-Cs)a]lcenyl, (C₂-C6)alkynyi, (Ci15 Cô)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R¹³is selected from:

a) R¹¹ and -(Ci-Côjalkyl-R¹¹, wherein each R^1J is independently selected from (Ci-Cé)alkyl, (Cj-Cèjalkenyl, (Cj-CeJaikynyl, (C)-C₆)haloalkyl, (C₃C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

b) -(Ci-C6)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from

H, (Ci-Ce)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰is independently selected from R^-tCi-C^alkyl-R¹¹, -SOi-R¹¹, -C(O)-R¹¹, -C(-OjOR^,; and -C(=O)N(R⁹)Rⁿ, wherein each R¹¹ ïs independently selected from H, (CpC^alkyl, (Cî-C^alkenyl, (C₂Cejalkynyl, (Ci-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more(e.g. l,2or3)Zⁿ groups;

c) (C [-C/ialkyl, wherein (Ci-Cs)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) . aryl, heteroaryl, heterocycle, wherein aryl heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

e) (Ci-CeJhaloalkyl, (C₃-C₇)carbocycle, (Cj-CiJalkenyl and (CACéjalkynyl, wherein (Ci-Céjhaloalkyl, (C3-C₇)carbocycle, (C^-C^alkcnyl and (Ci-Cs)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

f) -(C i-CeJalkyl-NRiRf, wherein -(Cj-C^alkyl-NReRf is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups.

a) R¹¹ and -(Cj-Csjalkyl-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-C₆)alkyl, (C2-Cô)alkenyl, (C₂-C6)alkynyl, (Ci-Cejhaloalkyl, (C3C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

b) -(Ci-Ci)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Cô)alkyl and (C3-C7)cycloalkyl, and each R¹⁰ is independently selected from R^ll,-(Ci-C6)aIkyl-R¹¹, -SO2-R¹¹, -C(=O)-R^]1, -C(O)0Rⁿ and -C^OJNfR^R¹¹, wherein each Rⁿ is independently selected from H, (CrC₆)alkyl, (C^-C^alkenyl, (C2Ce)alkynyl, (Ci-Cejhaloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

c) (Ci-CeJalkyl, wherein (C j-C^alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

d) aryl, heteroaryl, heterocycle, wherein aryl heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z^s groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

e) (Ci-Cé)haloalkyl, (C₃-C7)carbocycle, (C₂-C₅)alkenyl and (C2-C₆)alkynyl, wherein (Ci-Cejhaloalkyl, (Cî-C₇)carbocycle, (Cî-Csialkenyl and (Cz-Csjalkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z^s groups and optionally substituted with one ormore(e.g. 1,2,3,4 or 5) Z¹ groups; and

f) -(Ci-Câ)alkyl-NReRf, wherein each (Ci-C₆)alkyl is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups.

Another spécifie group of compounds of formula 1 are compounds wherein R¹³is selected from:

a) R¹¹ and -(CrCsialkyl-R¹¹, wherein each Rⁿis independently selected from (Ci-Cf,)alkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups; and

b) -(Ci-C6)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H and (Cj-Céjalkyl, and each R^tois independently selected from R¹¹, wherein each R¹¹is independently selected from H, (C|-Cé)alkyl and aryl, wherein aryl, is optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups.

Another spécifie value for R¹³ is H.

Another spécifie value for R¹³ is:

Cl or

A spécifie group of compounds of formula 1 are compounds wherein R_g îs independently selected from -OR^ (C i -C^Jalkyl, (C₃-Cj)carbocycle (C]-C₆)ha!oalkyl, (C₂-C₆)alkenyl, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, wherein any (C|-C₆)alkyl, (C₃-C₇)carbocycle -(C_t-C6)haloalkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl of R_g is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups.

In one embodiment, the invention provides a compound of the invention which is a compound of formula I:

wherein:

G¹ is N; G² is CR⁸; and the dashed bond is a double bond; or

G¹ is CR⁵; G² is N; and the dashed bond is a double bond; or

G¹ is CR⁵; G² is NR¹³; the dashed bond is a single bond; and R⁷ is an oxo (=0) group;

R² is R ·ογ R^2b;

R³isR^3aor R^3b;' '

R³’ is R^3a or R^3b’;

R⁴ is R^4a or R^4b;

R⁵ isR^5aor R^Sb;

R⁶ is R⁶² or R⁶⁵;

R⁷ is R^7a or R⁷⁵;

R⁸ is R⁸³ or R^8b;

R^!3isR^13aorR^l3b;

R^lais selected from:

a) H, halo, (Ci-Cé)alkyl and (Ci-CeihaloaDcyl;

b) (C2-C6)alkenyl, (C2-C₆)aikynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-Rⁿ, -C(=O)-O-Rⁿ, -O-R¹¹, -S-R*¹, -S(O)-R^ll> -SO2-R¹¹, -(Cp^alkyl-R”, -(CrC^alkyl-C^CO-R¹¹, -(C]-C6)alkyl-C(=O)-O-Rⁿ, -(Ci-C6)alkylO-R¹¹, -(CrC^alkyl-S-R¹¹, -(CrC6)alkyl-S(O)-R¹¹ and -(CrQalkyl-SCh-R¹¹; wherein each R¹¹ is independently selected from H, (Ci-CeJalkyl, (Cz-Ceialkenyl, (C2Cé)alkynyl, (CrCs)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)Rⁱ⁰, -C(=O)-N(R⁹)R¹⁰, -O-C(=O)-N(R⁹)R^l(ï, -SO2-N(R⁹)R¹⁰, -(Ci-Céialkyl-NCR’JR¹⁰, -fCrCsJalkyl-C^OJ-NfR^R¹⁰, -(Ci-C6)alkyl-O-C(=O)N(R⁹)R¹⁰ and -(Ci-C6)alkyl-SO2-N(R⁹)R¹⁰; wherein each R⁹ is independently selected from H, (Ci-Ce)alkyl and (C3-C7)cycloalkyl; and each R¹⁰ is independently selected from R¹¹,-(Cj-Ce^kyl-R¹ *, -SO2-R'^l, -C(=O)-Rⁿt C( ^_O)OR^fl and -C(=O)N(R⁹)Rⁿ; wherein each R¹¹ is independently selected from H, (Ci-Cs)alkyl, (C2-C₆)alkenyl, (C^-Ckjaikynyl, (Ci-C6)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle or heteroaryl of R^lais optionally substituted with one or more (e.g. 1, 2 or 3) Z¹⁰ groups;

R^lb is selected from:

a) -(C i-C₆)aikyl-O-(C 1 -C₆)alkyl-(C3-C₇)carbocycle, -(C i-Cô)alkyl-S-(C 1C6)alkyl-(C₃-C₇) carbocycle, -(CrC_fi)alkyl-S(O)-(Cj-C6)alkyl-(C3-C6) carbocycle, -(C|C₆)alkyl-SO2-(Ci-C_s)alkyl-(C3-C₇)caibocycle, -(Ci-Cjalkyl-SO^^Ci-Ceialkyl-Z¹³, -

C

C(O)-(Ci-C₆)alkyI-Z^l3, -O-(CrC6)alkyl-Z^{l !}, -S-(Ci-QJalkyl-Z¹³, -S(O)-.(CrC₆)alkylZ¹³, -SCMC,-C6)alkyl-Z¹³, -(C,-C6)aikyi-Z'\ -(CpCtJalkyî-CtOXCj-C^alkYi-Z'·³, (Ci-C6)alkyl-C(())-O(CrC6)alkyl-Z^!', -(Ci^alkyl-O^i-Cfijalkyl-Z¹³, -(CrC₆)alkylS~(C_;-C₀)alkyl-Z¹³, -(Ci-C6)alkenyt-(C]-C₆)haloalkyl, -(C₂5 Ci)alkynyl-(Ci-Cô)haloalkyl, - (Cj-C7)halocarbocycle,-NR_aS02NR_cRd, -NR_aSO₂O(GC7)carbocycle_i -N'RiSO₂Oaryl, -(C₂-C₆)alkenyl-(C3-C₇'>caibocyclc, -(CE-C^alkenylaryl, -(Cî-CfiJalkenyl-heteroaryl, -(C2-Cé)aikenyl-heterocycle, -(C₂-C6)alkynyl-(C₃C₇)carbocycle, -(Cz-CsJalkynyl-aryl, -(Cj-CsJalkynyl-heteroaryl -(C₂-C6)alkynylheterocycle, -iC3-C₇)carbocycle-Z¹ or -halo(Ci-C6)alkyl-Z³; wherein (Cj-CiJalkyl, (C_t-C₆)haloalkyl, (C₃-C₇)carbocycle, (C2-C₆)alkenyl, (C₂-C^)alkynyl₁ aryl or heteroaryl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

c) (Ci-Ce)alkyl; wherein (C|-C6)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g 1,2,3,4 or 5) Z¹ groups;

d) -X(C|-C₆)alkyl, -X(Ci-C₆)haloalkyl_t -X(C2-C₆)alkenyl,

-X(C₂-C_é)alkynyl and -X(C3-C₇)carbocycle; wherein (C j-C₆)alkyl and (Ci-Cejhaloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups; and wherein (C₂-C₆)alkenyl, (Ci-Cglalkynyl and (C3-C₇)carbocycle are each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and-Xheterocycle; wherein aryl heteroaryl and heterocycle are each substituted with one or more (e.g. 1,2, 3, 4 or 5) Z³ groups and optionally substituted with oneor more Z¹ groups;

f) (Ci-C6)haloalkyl, (C₃-C₇)carbocycle, (C₃-C6)alkenyl, and (C₂-C₆)alkyny); wherein (C |-C₆)haloalkyl, (C3-C₇)carbocycle₎ (C₂-Cf.)a’kenyl and (C₂-C₆)alkynyl are each substituted with one or more (e.g. 1,2, 3,4 or 5) Z⁶ groups and optionally substituted with one or more Z¹ groups; and fi

g) -NR_cR_f, -C(O)XRA -OCtOJNR.Rf, -SO₂NR<Rf, -(Cj-CsJalkyl-NReRf, XC-QalkylCtOXNRcRi, -(Ci-Ceialkyl-O-CtOJ-NI^Rf and -(C_;-C₀)alkyl-SO_:NR_cR:·; wherein each (Ci-Cs)alkyl is substituted with one or more (e.g, l,2,3,4or5) Z⁶groups and optionally substituted with one or more Z^J groups;

R^2a is selected from:

a) H, (C_rC₆)alkyl and -OCCi-C₆)alkyl;

b) (C2-Ce)alkenyl, (C₂-C₆)alkynyl, (Cj-Cslhaloalkyl, (Cj-CrJcycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) C(=O)-R“, -C(=O)-O-R^li, -S-Rⁿ, -S(O)-Rⁿ, -SO2-R^U, XCi-C6)alkyl-R^1], <CrC6)aÎkyl-C(=O)-Rⁿ, -(CrC₆)alkyI-C(=O)-O-R¹¹, -(CrC6)alkylO-R¹¹, -(Ci-Csialkyl-S-R¹¹, -(CrC^alkyl-SfOXR’¹ and -(CrCsJalkyl-SOrR¹¹; wherein each R¹¹ is independently selected from H, (CpC^alkyl, (C2-C6)alkenyl, (C₂Cbjalkynyl, (Ci-C₆)haloalkyl, (C₃-C₇)cycioalkyl, aryl and heterocycle and heteroaryl; wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

d) -OH, -O(C₂-C6)alkenyJ, -O(C₂-C6)alkynyl, -O(C]-Cs)haloalkyl, -O(C₃C₇)cycloalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl; and

e) -N(R’)R¹⁰, -C(=O)-N(R⁹)R^W, -0-0(=0)-^⁹^¹ °, -SCh-NiR^R¹⁰, -(Cr C6)alkyl-N(R⁹)R¹⁰, -(Ci-C6)alkyl-C(=O)-N(R⁹)R¹⁰, -(CrC6)alky'l-O-C(=O)-N(R⁹)R¹⁰, and -(Ci-C6)alky4-SO2-N(R⁹)R¹⁰; wherein each R⁹ is independently selected from H, (Ci-Cs)alkyl and (C3-C7)cycloalkyl; and each R^,ois independently selected from R^li,(CrCslalkyl-R, -SO2-R^tl, -C(=O)-R'^l, -C(=O)0Rⁿ and -0(=0)14^¹’; wherein each R¹¹ îs independently selected from H, (C₁-C₆)a]kyl, (C₂-C6)alkenyl, (C₂C6)alkynyl, (C]-C6)haloalkyl, (C₃-C₇)cydoalkyl, aryl, heterocycle and heteroaryl;

R^2b is selected from:

a) -(Ci -Cs)alkyl-O-(Ci-C6)alkyl-(C3-C7)carbocycle, -(C j-Ci)alkyl-S-(C i C₆)alkyl-(C₃-C₇)carbocyclc, -(Ci-C6)alkyl-S(0)-(Ci-C6)alkyl-(C3-C₇)carbocycle, -(CiC<j)alkyl-SO₂-(C | -C₆)alkyl-(C₃-C₇)carbocycle, -(C₂-Ci)alkenyl-(Ci-C6)haloalkyl, -(C₂C₆)alkynyl-(CrC6)haloalkyl, -(Ci-CftJalkyl-SOz-tCj-CéJalkyl-Z¹³, -C(O)-(Ci-C6)alkylZ¹³, -O-(Ci-C6)alkyl-Z¹³, -S-(Ci-C6)alkyl-Z¹³, -S(O)-(C]-C6)alkyl-Z¹³, -SO2-(C,C6)alkyl-Z¹³, -(CrC6)alkyl-Z¹⁴, -(Ci-C6)alkyl-C(O)-(C1-C6)alkyl-Z^!3, -(Ct-C6)alkylC(O)-O(Ci-C6)alkyl-Z¹³, -(C_rC₆)alkyl-O-(Ci-C₆)alltyl-Z¹³, -(CrCeJalkyl-S-ÎCr

C₆)alkyl-Z , -(C₃-C7)halocarbocycÎe,-NR_aS0₂NR_<R_<l, -NR_JSO2O(C3-C₇)carbocycle, NRaSOiOaryl, -(C2-C6)alkenyl-(C₃-C₇)carbocycle, -(Cî-CôJalkenyl-aryl, -(C2-C₆)alkenyl-heteroaryl, -(C2-C_é)aîkeny|-heterocycle, -(C₂-C6)alkynyl(C3-C₇)carbocycle_I -(C₂-C₆)alkynyl-aryl. -(C₂-C₆)alkynyl-heteroaryl, -(C2-C₆)alkynylheterocyclej-XCs-CjJcarbocycle-Z¹ or -halo(C|-C6)alkyl-Z³; wherein (Cj-Cs)alkyl, -(Ci-Csihaloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl, (C₂-C6)alkynyl, aryl or heteroaryl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups;

b) spîro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C3-C₇)carbocycle or heterocycle wherein the (C3-C6)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (C t -Ce)alkyl; wherein (C ) -C$)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(Ci-C₆)alkyl, X(C₁-C₆)haloalkyl, X(C2-C₆)alkenyl, -X(C2-C₆)alkynyl and -X(C3-C₇)carbocycIe; wherein (Cj-C^alkyl and (Ci-Ceïhaloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and wherein (C2-C₆)alkenyl, (C₂-C6)alkynyl and (C3-C₇)carbocycle are each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xhetcroaryl and -Xheterocycle; wherein aryl heteroaryl and heterocycle are each substituted with one or more (e.g. 1,2,

3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups;

f) (C j-CeJhaloalkyl, (C₃-C₇)carbocycle, (Ci-C^alkenyl, and (C2-Cfi)alkynyl; wherein (Ci-Cé)haloalkyl, (Cî-C₇)carbocycle, (C₂-C$)alkenyl and (C2-Ce)alkynyl are each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 ot5) Z¹ groups; and

C

g) -NR^Rf, -ClCnN^Rf, -OC(0)NR_cR₁, -SChNR^Rf, -(Cj-Cs^lkyl-NRcRf, -(Ci-C₆)alkylC(0)-NR_eR_t/-(C_l-C6)alkyl-0-C(0>NR_<Rfand-(C_Î-C₆)alkyl-S02NR_cRf, wherein each (Ci-C₆)alkyl is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (c.g. 1,2,3,4 or 5) Z¹ groups;

R³* is (Ci-Csjalkyl, (C|-C6)haloalkyL (C2-C6)alkenyl, (C2-C6)al kynyl· -(Ci-C6)alkyl-(C3-C7)cydoalkyli ~(C] -CéJalkyl-aryl, -(Ci-CbJalkyl-heterocycle, -(Ci-Cô)dkyl-heteroaryl, -O(Ci-Cs)alkyl, -O(C[-C6)haloalkyl, -O^-C^alkenyl· -O(C2-Cfi)alkynyl, -O(C3-C7)cycloalkyI, -Oaryl, -O(CrCi)alkyl-(C3-C7)cycloalkyl, -O(CrC6)alkyl-aryI, -0(Ci-C6)alkyl-heterocycle and -OfCpCelalkyl-heteroaryl; wherein any (CrC6)alkyl, (Ci-C6)haloalkyl, (C2-C6)alkenyl or (C2-Ci)alkynyl of R^3a is optionally substituted with one or more (e.g. 1,2 or 3) groups selected from -0(CiC6)alkyl, halo, oxo and -CN; and wherein any (C3-C₇)cycloalkyl, aryl, heterocycle, or heteroaryl of R^3a is optionally substituted with one or more (e.g. 1,2 or 3) groups selected from (Ci-C₆)alkyl, -O(Ci-C6)alkyl, halo, oxo and -CN; and R³* is H;

R^3b is -(C3-C7)carbocycle, aryl, heteroaryl, heterocycle, -(Cj-CôjalkylOH, -(CiCeialkyl-OXCrCéïalkyl-Z¹², -(CrC6)alkyl-O-(C₂-C₆)alkenyl-Z¹², -(C2-C6)alkyl-O-(C2C6)alkynyl-Z^î2, -(CpC^alkyl-S-lCr^alkyl-Z'², -(Ci-C6)alkyl-S-(C₂-C₆)alkenyl-Z¹², (C2-C6)alkyl-S-(C2-C6)alkynyl-Z^l2,-(C)-C_<Î)alkyI-S(O)-(Ci-C₆)a]kyl-Z¹², -(Ci-C6)alkylS(O)-(C2-C6)alkenyl-Z¹², -(C2-C₆)alkyl-S(O)-(C₂-C₆)alkynyl-Z¹², -(Ci-C6)alkyl-SO2(Ci-CsJalkyl-Z¹², -(€Ι-€6)η1ΚγΙ-50₂-(0₂-θ6>υίεηγ1-Ζ^η,-(02-06)&11ίγ1-302-(€2C6)alkynyl-Z¹², -(C2-C₆)alkyl-NR_aR_b, -(C₂-C₆)alkylOC(O)-NR_iR_dl -(C₂-C₆)alkyl-NRr C(O)-OR_b, -(C₂-C₆)alkyl-NR₃-C(())-NR₁R_h, -(CrC₆)a]kyl-SO₂(C]-C₆)adkyl, (CiC₆)alkyl-SO₂NR_cR_<I, -(C₁-C₆)alkyl-NR_aSO₂NR_<R_d) -(Ci-C₆)alkyl-NR₄S0₂0(C₃C₇)carbocycle, -(C rC^alkyl-NRjSO^aryk -(Cj-C6)alkyl-NRa-SO₂-(Cj -Cs)alkyl, -(Ci-C₆)alkyl-NR_e-S0₂-halo(C₁-C₆)alkyl, -(C,-C₆)alky].NR.-SOr(C2-C«)alkeny], -(Ci-C₆)alkyI-NR_a-SO₂-(C₂-C₆)alkynyl, -(C_rC₆)alkyl-NR₁-SO₂-(C3-C₇)carbocycle₁-(C i-C6)alkyl-NRa-SO₂-halo(C3-C₇)carbocyclc, -(C _rC6)alkyl-NR_a-SO₂-aryl, -(C i -C6)alkyl-NRa-SO₂-heteroaryl, -(C i-Ce)alky I -NRa-SO₂-heterocycle, -O(C j C₆)alkyl-NR_aRb, -OÎCi-CejalkylOCfOj-NR.Ra, -OfCrCjjalkyl-NRa-CtOj-ORb, -O(Ci-C₆)alkyl-NR_a-C(O)-NR_iR_b,-O(C₁-C₆)alkyl-NR_a-SO₂-(Ci-C₆)alkyl, -0(Ci-C₆)alkyl-NR_î-S0₂-halo(Cj-Cfi)alkyl, -O(C₁-C_É)alkyl-NR_a-SO₂-(C₂-C₆)alkenyl, -O(C_rC₆)alkyi-NR_a-SO₂-(C₂-C₆)alkynyl, -0(Ci-C₆)alkyl-NR_a-S0₂-(C₃-C₇)carbocycIe,

-0(Ct-C6)alkyl-NR_a-S0₂-halo(C₃-C7)carbocycle, -0(C|-C6)alkyl-NR_a-S0₂-aryl, -0(C_l-Ci)alkyl-NR_a-S0₂-heteroaryl, -OiCi-C^alkyl-NRa-SCb-heterocycle, -OfCrC^alkyl-NRa-SCh-NRaRb. - O(C i -C^al ky l-NR»- SO₂-(C 3-C?) carbocycle, -0(Ci-C_s)alkyI-NRa-S0₂-haIo(C3-C7)carbocycle, -OiCrCjJalkyl-NRa-SC^-aryl, -O(Cj5 CfOalkyl-NRaSCENRcRj, -O(C|-C6)alkyl-NR_aSO2O(C3-C0carbocycle, -O(C[-C6)alkylNRaSO₂0aryl, -Oheteroaryl, -Oheterocycle, -Sheteroaryl, -Sheterocycle, -S(O)heteroaryl, -S(O)heterocycle, -SOjheteroaryl or -SO₂heterocycle, wherein any (C[-C₆)a]kyk aryl, (C3-C₇)carbocycle, heteroaryl or heterocycle of R^3b is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; andR^3b is H, (C]-Cs)alkyl 10 or -O(Ci-Cfi)alkyl; or R^3b and R^3b together with the carbon to which they are attached form a heterocycle or (C₃-C7)carbocycle which heterocycle or (Cj-C;)carbocycle of R^3band R together with the carbon to which they are attached is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z’ groups;

R⁴* is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁴¹ is optionally substituted with one or more (e.g. 1,2,

3.4 or 5) groups each independently selected from halo, (Ci-C₆)a!kyl, (C₂-C6)alkenyl, (Cf-Céjhaloalkyl, (C₃-C₇)cyclcalkyl, -OH, -O(Ci-C₆)alkyl, -SH, -SfCi-C^alkyl, -NHi, NHfCi-Csialkyl and -N((Ci-Cs)alkyl)2; wherein (C)-Cs)alkyl is optionally substituted with hydroxy, -O(Ci-C6)alkyl, cyano or oxo;

R^4b is selected from:

a) (Ci-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl; wherein (Ci-C₆)alkyl, (C₂-Cé)alkenyl or (C₂-C6)alkynyl are each optionally substituted with one or more (e.g.

1.2.3.4 or 5) Z¹ groups;

b) (C₃-Cj4)carbocycle; wherein (C₃-Ci4)carbocycle is optionally substituted with one or more (e.g, 1,2,3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃C7)carbocycle or heterocycle;

c) Spiro-heterocycle or bridged-heterocycle; wherein spiro-heterocycle or bridged-heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; or wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C7)carbocycle or heterocycle; and

C

d) aryl, heteroaryl, spiro-, fused-, or bridged-heterocycle; wherein aryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle are each independently substituted with one or more Z groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; or

R⁴ and R³ together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R⁴ and R³ together with the atoms to which they are attached may be optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; andR^3b isH or (C|~Cf;)alkyl, -O(Ci-C6)alkyl.

R⁵* is selected from:

a) halo, nitro and cyano;

b) R¹¹, -C(-O)-R, -C(=O)-O-Rⁿ, -O-R¹¹, -S-R¹¹, -S(O)-Rⁿ, -SOi-R¹¹, (Q-Côjalkyl-R¹¹, -(CI-C6)alkyl-C(=O)-R¹¹, -(C1-C₆)alkyl-C(=O)-O-R^:i, -(CrCeialkylO-R¹¹, -(Cj-COaikyl-S-R¹¹, -(C|-C₆)alkyl-S(O)-R^H and -(Ci-C^alkyl-SOrR¹'; wherein each R¹¹ is independently selected from H, (Ci-C₆)alkyl, (C2-Cs)alkenyl, (C₂Csjalkynyl, (Cj-Cyhaloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

c) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R^!0, -O-C(=O)-N(R’)R^1c, -SO2-N(R⁹)R¹⁰, -(Ci20 C6)alkyi-N(R⁹)R^!0, <C|-C6)alkyl-C(=O)-N(R⁹)R¹⁰, -(Ci-COalkyl-O-Ct^-NtR’X¹⁰.

and -(C]-C6)alkyl-SO2-N(R⁹)R¹⁰; whereineach R⁹ is independently selected from H, (Ci-C₆)alkyl and (C₃-C₇)cycloalkyl; and each R¹⁰is independently selected from Rⁿ,-(C]-COalkyl-R¹¹, -SO2-R¹¹, -C(=O)-R^U, C(=O)OR^If and -C(=O)N(R⁹)R^{] l}; wherein each Rⁿ is independently selected from H, 25 (Ci-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C0alkynyl, (Ci-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^Sb is selected from:

a) -ÎCj-C6)alkyl-O-(C|-C6)alkyl-(C₃-C₇)carbocycle,

-(C,-Cfi)alkyI-S-(C i-Ce)alky 1-(C₃-C₇)carbocycle,

-(Ci-C₆)alkylS(0)-(C]-C₆)alkyl-(C3-C₆)carbocycle,

-(C 1 -C0alkylSO₂(C ₁ -C^alkyl-(Cî-C₇)carbocycle, -(C2-C_f.)alkcnyl-(C, -C6)haloalkyl, (C₂-C6)alkynyl-(Ci-C6)haloaIkyl, - (C3-C₇)halocarbocycle, -NRaSO^NR^,

-NRaSO₂O(C3-C7)carbocycle, -NR_âS0₂0aryl. -(C₂-C₀)a]kenyl-(C₃-(Xkarbocyc]e, -(Cî-Cfilalkenyl-aryl, -(C₂-Ci)alkenyI-heteroaryl, -(CrC^alkenyl-heterocycle, -ÎC2-C6)alkynyl-(C₃-C₇)carbocycle, -(Ci-C^alkynyl-aryl, -(C₂-Ci)alkynyl-heteroaryl, -(Ci-CfiJalkynyl-heterocyclc, -(Cs-CvXarbocycle-Z¹ or-halo(C|-C6)alkyl-Z³; wherein (Ci-Cslaikyl. (Ci-Cijhaloalkyl, (C₃-C₇)carbo€ycic, (C₂-C₆)alkenyl, (C₂-Ce)alkynyl, aryl or heteroaryl are each optionally substituted with one or more(e.g. 1,2,3,4 or 5) Z¹groups;

b) spiro-bicyclic carbocycle, fiised-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fiised-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

c) (Ci -C6)alkyl ; wherein (C i-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g 1,2,3,4 or 5) Z¹ groups;

d) -X(Ci-C₆)alkyl,-X(C_rC₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C2-C_s)alkynyl and -X(C₃-C7)carbocycle; wherein (Ci-Cejalkyl or (Ci-Cs)haloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more Z¹groups; and wherein (C₂-C6)alkenyl, (CrCsJalkynyl and (C₃-C₇)carbocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle; wherein aryl heteroaryl are heterocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z^s groups and optionally substituted with one or more (e.g. 1,

2,3,4 or 5) Z* groups;

f) (Ct-Cgjhaloalkyl, (C₃-C₇)carbocycle, (C₂-C_fi)alkenyl, and (C₂-C₆)alkynyl; where (C|-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₇-Ct,)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z^! groups; and

g) -NReRf, -CfOjNRçRf, -OC(O)NR_eR_f, -SO₂NR_£R_fl -(C_l-C_â)alkyi-NR_tR_f)-(C_I-C₆)aIkylC(O)-NR_eR_f, -(CrCbjalkyl-O-QOj-NReRf and -(Ci-C.ialkyl-SO^N^R,-; wherein each (Ci-Cs)alkyl is independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z^! groups;

R⁶¹ is selected from:

a) H, halo, (Ci-Ci)alkyl, and (Cj-Cô)haloalkyl

b) (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (C3-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle or heteroaryl;

c) -C(=O)-Rⁿ, -C(=O>O-R¹¹, -O-R¹¹, -S-R¹¹, -S(O)-Rⁿ, -Sü₂-R¹¹,

-(Ci-C₆)alkyl-R“, -(CrCftlalkyl-C^OJ-R¹¹, -(CrC6)alkyl-C(-O)-O-R^u, -(Cj-C6)alkylO-Rⁿ, -(Ci-Csjalkyl-S-R¹¹, -(CrCéJalkyl-StOJ-R¹¹ and -(Ci-C6)alkyl-SO2-R; wherein each R¹¹ is independently selected from H, (C]-C6)alkyl, (C2-Ci)alkenyl, (C₂Cfi)alkynyl, (Ci-CsJhaloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R^w, -C^-NtR^R¹⁰, -O-C(=O)-N(R⁹)R¹⁰, -SOrNiR^R¹⁰,

-(Cl-C₆)alkyl·^^,(R⁹)R¹⁰,-(Cl-C6)alkyl-C(-O)-N(R⁹)R^;f),-(Cl-C6)aikyl-O-C(-O)N(R⁹)R¹⁰ and -(Ci-Côlalkyl-SCh-NiR^R¹⁰; wherein each R⁹ is independently selected from H, (Ci-C6)alkyl and (C3-C₇)cycloalkyl; and each R¹⁰is independently selected from Rⁿ,-(Ci-C6)alkyl-R^H, -SO2-Rⁿ, -C(=O)-Rⁿ, 20 C(=O)OR’¹ and -C(=O)N(R⁹)R‘ *; wherein each R¹¹ is independently selected from H, (Cj-Cc)alkyl, (C2-C₆)alkenyl, (C₂-C₆)alkynyi, (C_rC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle or heteroaryl of R^,a is optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups;

R⁶¹ is selected from:

a) -(C]-C§)alkyl-0-(CrC6)alkyl-(C3-C₇)carbocycle, -(Ci-C_e)alkyl-S-(CjC6)alkyL(C3-C₇)carbocycle, -(Ci-Ci,)a]k71-S(0)-(Ci-C_i)alkyl-(C₃-C₇)carbocycle, -(CjC6)aIkyl-SO2-(Ci-C6)alkyI-(C3-C₇)carbocycle, -(C2-C₆)alkenyl-(CrC$)haloalkyl, -(C₂C6)alkynyl-(Ci-C6)haloalkyl, -halo(C3-C₇)caib()cycle,-NR_JS02NR_<Rd,-NR_aSO₂O(C330 C₇)carbocycle, -NR^SOjOaryl, -(C₂-C6)alkenyl-(C3-C₇)carbocycle, -(Cb-Csjalkenylaryl, -(C₂-C6)alkenyl-heteroaryl, -(C₂-C6)alkenyl-heterocycle, '(C₂-C6)alkynyl-(C3-C₇)carbocycle,-(C₂-C6)alkynyl-aiyl,-(Cî-Côlalkynyl-heteroaryl,

-(C₂-C6)alkynyl-heterocycle, -(C3-C₇)carbocycle-Zⁱ or -halo(Ci-C6)alkyl-Z³; wherein (Cj-C₆)alkyl, (Ci-C6)haloalkyl, (Cj-C₇)carbc>CYclc, (Cz-Côialkenyl, (CrCs)alkyny], aryl or heteroaryl are optionally substituted with one or more (e.g. i, 2,3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

c) (Ci-Cs)alkyl; wherein (C |-Ce)alkyl is substituted with one or more (e.g.

1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z^[ groups;

d) -X(C]-C₆)alkyl, -X(C]-C_É)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C7)carbocyc)e; wherein (CrC^alkyl or (Ci-C^haloalkyf are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more Z¹ groups; and wherein (C₂-C6)alkenyl, (C₂-Ce)alkynyl and (C₃-C₇)carbocycle are each independently substituted with one or more Z⁴ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaryi, -Xheteroaryl and -Xheterocycle wherein aiyl heteroaryl and heterocycle are each independently substituted with one or more Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups;

f) (Ci-CsJhaloalkyl, (C₃-C₇)carbocycle, (Cj-C^alkenyl, and (C2-C6)alkynyl; wherein (C[-C₆)haloalkyl, (C₃-C₇)carbocycie, (C₂-C6)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z^e groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NIkRf, -C(O)NReRf, -OC(O)NKRf, -SO₂NReR_r, -(Cj-QJalkyl-NReRf, -(Ci-C₆)alkylC(O)-NReRf, -(CVC₆)alkyl-O-C(O)-NR_cR_f and (Ci-C_É)alkyi-SO₂NR_<R_f; wherein each (Ci-Cô)alkyl is independently substituted with one or more (e.g. 1,2,3,4

or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z^lgroups;

R^Ta is selected from:

a) H, halo, (C_rC₆)alkyl and (C_rC₆)haloalkyl;

b) (Cj-Céjalkenyl, (CrCsjalkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(O)-R, -C(=O)-O-R^!I, -O-R“, -S-R¹¹, -StOl-R¹', -SO2-R¹¹, -(C1-Cft)alkyl-R¹¹, -fC,-Q)alkyl-C(=O)-Rⁿ, -(CrC₆)alkyl-C(=O)-O-R¹¹, -(CrCfi)alkylO-R, -(Ci-C6)alkyl-S-R^[i, -(C!-C5)alkyi-S(O)-R and -(Cj-C^alkyl-SOi-R, wherein each R¹¹ is independently selected from H, (Ci-C₆)alkyl, (C₂-Ci)alkenyl, (C₂C₆)alkynyl, (Ci-CeJhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R^!0, -O-C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(Ci-C6)alkyl-N(R⁹)R¹⁰, -(Ci-CeJalkyl-C^OJ-NÎR^R¹⁰, -(CrC6)alkyl-O-C(=O)N(R^q)R¹⁰ and -(Ci-C6)alkyl-SO2-N(R⁹)R¹⁰; wherein each R⁹ is independently selected from H, (Ci-Côjalkyl and (C₃-C₇)cycloalkyl; and each R^I0is independently selected fromRⁿ,-(C)-C6)alkyl-R”, -SOyR”, -C(“O)-R”, C(-O)()Rⁿ and “C(=O)N(R⁹)Rⁿ; wherein each R¹¹ is independently selected from H, (CrCs)alkyl, (Ci-C^alkenyl, (Cî-Csjalkynyl, (Ci-Côjhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle or heteroaryl of R¹¹ is optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups;

R⁷⁶ is selected from:

a) -(C_rC₆)alkyi-SOHC_rC₆)aikyl-Z¹³, -QOXCrCsJalkybZ¹³, -0-(Cr C6)alkyl-Z¹³, -S-(C1-C₆)alkyl-Z¹³. -S(O)-(Cj-C6)alkyl-Z¹³, -SO2-(C_rC₆)alkyl-Z¹³,

-(Ci-Cejalkyl-Z’^-KCj-CeJalkyl-CiOXCj-Cejalkyl-Z’^-ÎCj-CiJalkyi-qOXXCiC₆)alkyl-Z¹³, -(Ci-CeJalkyl-O-tCrCsjalkyl-Z¹³, -(C1-C6)alkyl-S-(C1-C6)alkyl-Z'³, -(CjC6)alkyl-0-(Ci-C6)aIkyI-CC_î-C₇)carbocycle,-(C₁-C₆)alky]-S-(CiC₆)alkyl-(C₃-C7)carbocycle, -(C 1 -C₆)alkyi-S(O)-(C i-C₆)alky 1-(C₃-C₇)carbocyclc, -(C jC6)alkyl-S0₂-(Ci-C6)alkyl-(C₃-C₇)carbocycle, -(C₂-C£)alkenyl-(Ci’C6)haloalkyl, -(C₂30 CsJalkynyl-fCi-Côjhaloalkyl, -(C₃-C₇)halocarbocycle, -NR_aSO₂NRcR<i, -NRaSO₂O(C₃ C₇)carbocycle, -NRaSO₂Oaryl, -(C₂-C6)alkenyl-(C₃-C₇)carbocycle, -(C₂-Cs)alkenyiaryl, -(C₂-C6)aIkenyI-heteroaryI, -(C^Csjalkenyi-heterocycle, y

C

-(C2-C6)alkynyl-(Cj-C_T)carbocycle, -(Cz-C^alkynyl-aryl, -(C₂-C6)alkynyl-heteroaiyl, -(C₂-C6)alkynyl-heterocycle_} -(C₃-C₇)carbocycle-Z^! or -halo(C]-C6)alkyl-Z³ ; wherein (C_rC₆)alkyl, (Cj-C₆)haloalkyl, (C₃-C7)carbocycle, (C₂-C_fi)alkenyl, (C2-C₆)alkynyl, aryl or heteroaryl are each optionally substituted with one or morefe.g. 1,2,3,4 or 5) Z¹ groups;

b) spîro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C7)carbocycle or heterocycle wherein the (C₃-C6)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (C i-C₆)alkyl; wherein (C i -C₆)aikyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(C_I-C₆)alkyl,X(C₁-C₆)haloalkyl_J X(C2-C₆)alkenyl,-X(C₂-C₆)alkynyi and -X(C₃-C₇)carbocycle; wherein (Ci-CeJalkyl and (Ci-CsJhaloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more Z¹groups; and wherein (C^-Côjalkcnyl, (CrC^alkynyl and (C₃-C7)carbocycle are each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. l,2,3,4or5)Z’ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle; wherein aryl, heteroaryl and heterocycle are each substituted with one or more Z^sgroups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

f) (Cj-C* (haloalkyl, (C₃-C7)carbocycle, (Cî-C^alkenyl and (C₂-C6)alkynyl;

wherein (C i-Cfi)haloalkyl, (C₃-C7)carbocycle, (C₂-C₆)alkenyl and (C₂-C6)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NR«R& -C(O)NR_cR_f, -OC(0)NRcRf, -SO₂NR_eR_f, -(Cj-CfiJalkyl-NRA, -(CrCfilalkylCfO^NReRi, -(C₁-C₆)alkyl-0-C(0)-NR₄R_f and -(Ci-C6)alkyl-SO₂NReRf, wherein each (Ci-C₆)alkyl is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z^! groups;

R^8a is selected from:

C

a) halo, nitro and cyano;

b) R, -C(=O)-Rⁿ, -C(=O)-O-Rⁿ, -O-R^-S-R¹¹, -S(O>R, -SO2-R^!1, (ει<6)3ΐΐίγΐ-κ^[1ί-(ει-ε6)3ΐΐίγΐ-α=θ)-κ^1,Ι-(ε₁<₆)3ΐΐί7Κ(=ο)-ο-Ε^1ι,-(ε)-ε6)3^ιO-R, -(Ci-GJalkyl-S-R¹¹, -(C|-C6)alkyl-S(O)-R’ ¹ and -(CYC^alkyl-SO.-R¹¹, wherein each R¹¹ is independently selected from H, (Cj-Céfalkyl, (Ci-C^alkenyl, (C₂C₆)alkynyl, (Ci-Ce)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

c) -N(R⁹)R¹⁰, -C(-O)-N(R⁹)R'°, -O-C(=O)-N(R⁹)R¹⁰, -SO₂-N(R⁹)R^iû, -(Ci-

C₆)alkyl-N(R⁹)R¹⁰, -(Ci-^alkyl-CtOl-NiR^R¹⁰, -(CrC6)alkylO-C(=O)-N(R⁹)R^11Jand -(Ci-C6)alkyl-SO2’N(R⁹)R¹⁰; wherein each R⁹ is independently selected from H, (C_:-C₆)alkyl and (C₃-C₇)cycloalkyl; and each R¹⁰is independently selected from R¹¹, -(Ci-Csïalkyl-R¹¹, -SOrR¹¹, -C(=O)-Rⁿ, C(=O)OR¹¹ and -C^OJNtR^R¹¹; wherein each R¹¹ is independently selected from H, (Ci-Cijalkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (C_rC₆) haloalkyl, (C₃-C7)cycloalkyl, aryl, heterocycle and heteroaryl;

R⁸⁸ is selected from:

a) -(Ci-Cfilalkyl-SOî-ÎCrCÉÏalkyl-Z¹³, -C(O)-(Ci-C6)alkyl-Z¹³, -O-(Cr C^alkyl-Z¹³, -S-(CrC6)alkyl-Z¹³, -S(O)-(C,-C6)alkyl-Zⁿ, -SO₂-(Cj-C₆)alkyl-Z¹³,

-(Ci-C₆)alkyl-Z¹⁴, -(CrC^alkyl-CXOl-iCrQalkyl-Z¹³, -(CrC6)alkyl-C(O)-O(Cr C6)alkyl-Zⁿ, -(Ci-C6)alkyl-OXCi-CÉ)alkyl-Z¹³, -(CrQalkyl-S-tCt-CôJalkyl-Z¹³, -(C_rC₆)alkyl-O-(C_rC₆)aIkyl-(C₃-C₇)carbocycle, -<Ci-C«)alkyl-S-(CiC6)alkyl-(C₃-C₇)carbocyc!e, -(Ci-C₆)alky)-S(O)-(C|-C₀;ia!kyÎ-(C3-C₇)carbocycle, -(CjC₆)alkyl-SO₂-(Ci-C₆)alkyl-(C₃-C7)carbocycle, -(C2-C₆)alkenyl-(C_rC6)haloalkyl, -(C_r

C6)alkynyl-(Ci-C6)haloalkyl, -halo(C₃-C7)carbocycle_J-NR_aSO₂NR_cR_<i, NRaS020(C3-C₇)carbocycle, -NR_aSO₂Oaryl, -(C2-C6)alkenyl-(C₃-C₇)carbocycle, -(C₂-C6)alkenyl-aryl, -(CrCfiJalkenyl-heteroaryl, -(C₂-C6)alkenyl-heterocycle, -(C2-C6)alkynyl-(C₃-C₇)carbocycle, -(C₂-C₆)alkynyl-aryl, -(C₂-C6)alkynyl-heteroaryl, -(CrC^alkynyl-heterocycIe, -(C₃-C₇)carbocycle-Z¹ or-halo(Ci-C6)alkyl-Z³; wherein (C]-C₆)alkyl, (C_rC6)haloalkyl, (C₃-C₇)carbocycle, (C₂-C_fi)alkenyl, (C₂-C₆)alkynyl, aryl or heteroaryl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z^!gtoups:

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Ci-CeJalkyl; wherein (CpCiJalkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(C_l-Cé)aikyl, -X(Ci-C₆)haloalkyl, -X(C₂-C₆)alkenyl,

-X(C₂-C(i)alkynyl and -X(C3-C7)carbocycle; wherein (Ci-C₆)alkyl and (Cj-C^haloalkyl are each independently substituted with one or more Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and wherein any (CrCôJalkcnyl, (C₂-Ci)alkynyl and (C₃-C₇)carbocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more(e.g. 1,2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein any aryl heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z^s groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

f) (C[-C₆)haloalkyl, (C₃-C₇)carbocycie, (C₂-C₆)alkcnyl and (C₂-Cé)alkynyl; wherein (Ci-Cô)haloalkyl, (C₃-C₇)carbocycle, (C₂-C_É)alkcnyl and (C₂-C6)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z^s groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NRRf, -C(O)NRR_f, -OC(O)NR.R_f, -SChNRRf, -(Cj-Ceialkyl-NRRf,

-(Ci-C₆)alkylC(O)-NR_cR_f,-(C₁-C₆)alkyl-O-C(O)-NR_<:Rfand-(Ci-C₆)alkyl-SO2NR_cRf; wherein each (C[-Cs)alkyl is independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g, l, 2,3,4 or 5) Z¹groups;

R^lîa is selected from:

a) Rⁿ, -C(=O)-Rⁿ, -C(-O)-O-R, -O-R¹¹, -S-Rⁿ, -S(O)-R^h, -SO2-R^h, (CI-C₆)alkyl-R¹¹, -(C,-C6)alkyl-C(=O)-R¹¹, -(Cj-CeJalkyl-C^OÎ-O-R¹¹, -(Ci-C₆)alkyl16294

O-R^l-(C^C^jalkyLS-R¹¹, -(Ci-Cfijalkyl-SfOj-R¹ ’ and •(CrQalkyl-SOj-R; wherein each R¹¹ is independently selected from H, (Ci-C6)aikyl,(C₂-C6)alkenyl, (C₂Cfi)alkynyl, (Ci-Céjhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more(e.g. l,2or3)Zⁿ groups;and

b) -C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R^ic, -(Cl-Câ)alkyl-N(R⁹)R^1Q, -(CiC6)alkyl-C(=O)-N(R’)R¹⁽⁾, -(C)-C6)alky]-0-C(=0)-N(R⁹)R^l° and -(C^alkyl-SOr N(R⁹)R¹⁰; wherein each R⁹ is independently selected from H, (C(-C6)alkyl and (CjC?)cycloalkyl; and each R¹⁰is independently selected from R¹¹, -(CrC^alkyl-R¹¹, SO2-R^h, -C(=O)-Rⁿ, -C(=O)OR and -C(=O)N(R⁹)R^U; wherein each R¹¹ is independently selected from H, (C i-C^alkyl, (Cj-C^alkenyl. (CrCejalkynyi, (CiCejhaloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^13b is selected from:

a) -(CrCiJalkyl-SOî-tCi-CeW-Z¹³, -C(O)-(Cj-C6)alkyl-Z¹³, -O-(Cr C₆)alkyl-Z¹³, -S-(C)-C6)alkyl-Z¹³, -S(O)-(C[-C6)alkyl-Z¹³, -SO2-(CrCi)alkyl-Z¹³, -iCi-C6)alkyl-Z¹⁴,-(Ci-C6)alkyi-C(O)-(Ci-C6)alkyl-Z¹³,-(Ci-C6)alkyl-C(O)-O(C]C6)alkyl-Z‘³, -(CrC6)aIkyl-O-(CrC6)aIkyl-Z³³, -(CrC₆)aM-S^CrC₆)aIkyl-Z³³, -(CiC6)alkyl-O-(C]-C6)alkyl-(C3-C7)carbocycle, -(CrC6)alkyl-S-(C]~ C6)alkyl-(C3-C7)carbocycle, -(C|-C6)alkyl-S(O)-(C1-C6)alkyl-(C3-C7)carbocycle, -(CjC6)alkyl-SO2-(Ci-C6)alkyl-(C3-C7)carbocycle, -(C2-CÉ)alkenyl-(Ci-C6)haloalkyl, -(C2Cé)alkynyl-(Ci-C6)haloalkyl, -halo(C3-C7)carbocycle, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C;-Cé)alkcnyl-aryl, -(Ci-Cfjalkenyl-heteroaryl, -(Cï-Cejalkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)cajbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(CrC^arbocycle-Z¹ or halo/Cj-Cfijalkyl-Z³, -NR#SO₂NR_cR_d, -NR_aS0₂0(C₃-C₇)carbocycle, -NR_aSO₂Oarvl; wherein (CrCejalkyl, (Ci-C₆)haloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl, (C₂Cfi)alkynyl, aryl or heteroaryl are each optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups:

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they

C are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C7)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Ci-Ce)alkyl; wherein (C|-Cf.)aiky! is substituted with one or more Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(C_rCi)alkyl, -XfCrCeJhaloalkyl, -X(€_rC₆)alkenyl, -XtCî-Céjalkynyl and -X(C3-C7)carbocycle; wherein (Cj-Cs/alkyl and (Ci-Cejhaloalkyl are each independently substituted with one or more Z³ groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and wherein any (CyC₆)alkenyl, (CN-CsJalkynyl and (C3-C_T)carbocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein any aryl heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z* groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

f) (C i -Cgjhaloalkyi, (C₃-C?)carbocycle, (C2-C₆)alkenyl and (CrC₆)alkynyi; wherein (Cj-Cftjhaloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-Cf,)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted wth one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -C(O)NReR_ft -SChNRcRf, -(Ci-Cftjalkyl-NRJlf, -(C₁-C₆)alkylC(O)NR^Rf, -(C rC^alkyl-O-QOj-NRjRf and -(Cj-C^alkyl-SOîNRcRf; wherein each (Ci-C_fc)alkyl is independently substituted with one or more (e.g. 1,2, 3,4 or 5) Z^sgroups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

or any of R^Sa and R⁶*, R^6a and R^7a, R^7a and R^8s, R¹ and R⁸, R¹ and R² or R¹ and

R¹³ together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5,6 or 7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a 4, 5,6 or 7-membered heterocycle îs optionally substituted with one or more (e.g. 1, 2 or 3) substituents each independently selected from halo, (Ci -Csjalkyl, (C₂-C₆)alkenyl, (Ci-C₆)haloalkyl, (C₃-C7)cycloalkyl, -OH, -O(Ci-C₆)alkyl, -SH, -S(C_rC₆)alkyl, -NH₂, -NH(Ci-C₆)alkyl and -N((Ci-C₆)alkyl)₂;

or any of R⁵ and R⁶, R⁶ and R⁷ or R⁷ and R^s, together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5,6 or 7-memberetl heterocycle; wherein the 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1,2 or 3) Z⁷ or Z* groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C7)carbocycle or 4,5 or 6membered heterocycle;

or any of R¹ and R⁸, R¹ and R² or R¹ and R¹³ together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5, 6 or 7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle are each independentiy substituted with one or more (e.g. 1,2 or 3) Z⁷ or Z* groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C3*C₇)carbocycle or 4,5 or 6membered heterocycle;

X îs independently selected from O, -C(O)-, -C(O)O-, -S-, -S(0)-, -SO₂_. -(C_r

Cfi)alkylO-, -(Ci-C₆)alkylC(O)-, -(C_rC₆)alkylC(O)O-, -(Cj-CsJalkylS-, -(C_tC₆)alkylS(O)·, -(C₁-C₆)alkylSO₂-;

each Z¹ is independently selected &om halo, -NO₂, -OH, =NOR_a, -SH, -CN, -(Ci-Cô)alkyl, -(CrCéJalkenyl, -(C₂-Cé)alkynyl, -(C_;-C₆)haloalkyl, (C₃-C7)carbocycle, 20 (C3-C₇)halocarbocycle, -aryl, -heteroaryl, -heterocycle, -O(Cj-C&)alkyl, -O(C₂CôJalkenyl, -O(C₂-C6)alkynyl, -O(CrCi)haloalkyi, -0(C₃-C₇)carbocycle, -Ο(Ο₃C₇)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(Ci-C6)alkyI, -S(C₂C₆)alkenyl, -S(C₂-C6)alkynyl, -S(C|-C₆)haloalkyl, -S(C_rC₇karbocycle, -S(C₃C₇)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(O)(Ci-Ct,)a!kyl, -S(O)(C₂25 C₆)alkenyl, -S(O)(C₂-C₆)alkynyl, -S(0)(Ci-C6)haloalkyl, -S(O) (C₃-C₇)carbocycle, S(O)(C3-C₇)halocarbocycle, -SO₂(Ci-C6)a!kyl, -S(O)aryl, -S(O)carbocycle, S(O)heteroaryl, -S(O)heterocycle, -SO₂(C₂-C6)aJkenyl, -SOXCrCeJalkynyl, -SO₂(C|C₆)haloalkyl, -SO₂(C3-C₇)carbocycle, -S0₂(C3-C₇)halocarbocycle, - SO₂aryl, SO₂heteroaryl, -SO₂heterocycle, -SO^NRcR. -NRcRj, -NRaC(0)R_a, -NRaC(O)OR_a,

-NRCiOjNRJL! -NR_aSO₂R_b, -NR_aSO₂NR_cR_d, -NR_aS0₂0(C₃-C₇)carbocyclc, NR_sSO₂Oaryl, -0S(O)₂Ra, -C(O)R_a, -C(O)ORb, -C(O)NR_cR_(t, and -OC^NRjÎd, wherein any (Ci-C₆)alkyl, (C₂-C6)alkenyl, (C₂-C₆)alkynyl, -(C₃-C₇)halocarbocycle, (C₃-

C . 99

C₇Xarbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z¹ is optionally substituted with one or more (e.g. 1,2, 3,4 or 5) halogen, -OH, -OR_n. -CN, -NRaCfO^Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, NHheterocycle, or -S(O)₂NR_<;R_<1;

each Z² is independently selected front -NO₂, -CN, spiro- heterocycle, bridgeheterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, N’R_aSO2(C₃C₇)carbocycle, -NRaSO₂aryl, -NR_aSO₂heteToaTyl, -NRj^OjNR^Rj, -NR^SO-OiCjC7)carbocycle and -NRaSOîOaryl;

each Z³ is independently selected from -NO_2> -CN, -OH, oxo, ~NOR_a, thioxo, 10 aryl, -heterocycle, -heteroaryl, -(C₃-C₇)halocarbocycle,-0(Ci-C6)alkyl, -O(C₃C₇)carbocycle, -Ohalo(C3-C7)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(Cj Ce)alkyl, -S(C₃-C7)carbocycle, -S(C3-C₇)h31ocarbocycle, -Saryl, -Sheterocycle, Sheteroaryl, -S(O)(Ci-C₆)alkyl, -S(O)(C₃-C₇)carbocycle, -S(O) (C₃-C₇)halocarbocycle, -S(O)aryl, -S(O)heterocycle, -S(O)heteroaryl, -SO₂(C;-C’6)alkyl,

-S02(C₃-C7)carbocycle, -S02(C₃-C₇)halocarbocycle, SO₂aryl, -SOjheterocyde. -SO2heteroaryl, -NRaRb, -NRaC(O)Rb, -C(O)NR_cRd, -SO^NRcRj, -NRjSChNRJL, -NRaSO2O(C₃-C7)carbocycle and -NRgSOjOaryl;

each Z⁴ is independently selected fiom halogen, -(Cj-CsJalkyl, (C₃C₇)carbocycle, -halo(Ci-C6)alkyl, -NO2, -CN, -OH, oxo, =NOR₁, thioxo, -aryl,

-heterocycle, -heteroaryl, -(C₃-C7)halocarbocycle, -O(Ci-C₆)alkyl, -O(C₃C₇)carbocycle, -0(C₃-C7)halocarbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C _rCe)alkyl, -S(C3-C₇)carbocycle, -S(C₃-C₇)halocarbocycle, -Saryl, -Sheterocycle, Sheteroaryl, -S(O)(Cj-C6)alkyl, -S(O)(C₃-C7)carbocycle, -S(0)(C₃-C7)halocarbocycle, S(O)aryI, -S(O)heterocycle, -S(O)heteroaryl, -SO2(Ci-C₆)alkyl, -S0₂(C_rC₇)carbocycle,

-SO2(C₃-C₇)halocarbocycle, SO-aryi, -SO2heterocycle,-SO₂heteroaryl, -NRiRt, -NRaC(O)R_a, -CONRJLj. -SOïNRcRo, -NRaSOzNR^Rj, -NR_aSO_IO(C₃-C₇)carbocycle and -NR_aS0₂Oaryl;

each Z^s is independently selected from -NO2, -CN, -NR.XXNR.Rj, NR_aS0₂0(C₃-C7)carbocycie, -NILSO-Oaryl, -NR_aSO₂(Ci-C₆)alkyl, -NRaSO₂(C₂30 Csjalkenyl, -NRaSO2(C2-Cô)alkynyl, -NR_aSO2(C₃-C₇)ciibocycle, -NR,SO2(C₃C₇)halocarbocycle, -NR_aSO₂aryl, -NRaSO₂heteraryl, -NR_aSO2hetcroaryl, -NRaSOjheterocycle, -NR_aC(O)alkyl, -NR,C(O)alkenyl, -NR£(O)alkynyl, -NR_aC(O) ιοο (Cs-C₇)carbocycle, ’NRaC(0)(Ci-C7)halocarbocycle, -NRaC(O)aryl, -NRaC/COheteroaryl, -NR_aC(0)heterocvcle, NR_dC(ü)NRcRd and NRaC(O)ORb;

each Z⁶ is independently selected from -NO₇, -CN, -NR_aR₄, NR^fOJRb,C(O)NR_cR{|, -(C3-C₇)halocarbocycle, -aryl, -heteroaryl, -heterocycle, -Oaryl, 5 Oheteroaryl, -Oheterocycle, -O(C₃-C₇)halocarbocycle, -O(Ci-Cs)alkyl, -0(0₃C₇)carbocycle, -Ohalo(Ci-Cû)alkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C₃C₇)halocarbocycle, -S(C|-C6)alkyl, -SfCs-C^arbocycle, -S(Ci-C6)haIoalkyl, -S(O)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S(O)(C3-C₇)halocarbocycle, -S(O)(C]-Cô)alkyl, -S(O)(C3-C₇)carbocycle, -S(O)halo(C]-C6)alkyl, -SO-aryl, -SOiheteroaryl,

-SO₂heterocycle, -SChfCi-CsJalkyl, -SO-halo/Cj-C^alkyl, -SO₂(C₃-C₇)carbocycle, -S0₂(C3-C₇)halocarbocycle, -SO₂NRcR<i, -NRaS0₂(C₃-C₇)halocarbocycle, -NR_aSO₂arvl, -NR_aSO₂heteraryI, -NR_aSO₂heteroaryL -NRjSO^NJLR^, -NRjSO^OfCjC₇)carbocycle and -NR_aSO₂Oaryl;

each Z⁷ is independently selected from -NO₂, =NOR_â, -CN, -(Cj-Qlalkyl-Z¹²,

-ÎC₂-C₆)alkenyl-Z¹², -(C2-C6)alkenylOH, -(C2-C6)alkynYl-Z'², -(C2-C₆)alkynyl-OH,

-(Ci-C₆)haloalkyl-Zⁿ, -(Ci-C6)haloalkylOH, -(C3-C7)carbocycle-Z¹², -(C3C₇)carbocycleOH, -(C₃-C₇)halocarbocycle, -(Ci-Cfi)alkylNRcRd, -(CiC6)alkylNR_aC(O)R., -(Ci-C6)aikylNR_aSO₂R_a, -aryl, -heteroaryl, -heterocycle, -O(C]C₆)alkyl-Z¹², -O(C2-C6)alkenyl, -O(C2-C6)alkynyl, -0(Ci-C6)haloaIkyl, -O(C320 C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -OfCi-C^alkylNRJL, -O(CiC6)alkylNRaC(O)R*, -O(C|-C6)aikylNRaSO2Ra, -Oheteroaryl, -Oheterocycle, -S(Cj C6)alkyl-Z¹², -S(C2-C₆)alkenyl, -StCrQalkynyl, -S(C)-C₆)haloalkyl, -S(C₃C₇)carbocycle, -S(C3-C₇)halocarbocycle, -StCj-CéJalkylNRiRj, -S(C]C6)alkyINRaC(O)Ra, -S(C]-C6)alkylNRaSO2R_a, -Saryl, -Sheteroaryl, -Sheterocycle,

-StOXCrCjJalkyl, -S(O)(C₂-C₆)alkenyl, -S(OXC₂-C₆)alkynyl, -S(OXCi-C₆)haloalkyl, S(0)(C₃-C₇)carbocycle, -S(OXC₃-C₇)ha]ocarbocycle, -SO₂(Ci-C6)alkyl, -S(O)(CiC₆)alkylNR«Rd, -S(C)XC₁-C₆)alkylNR₁C(O)R_J, -S(OXC₁-C₆)alkylNR_<SO₂R_a,S(O)aryl, -S(0)heteroaryl, -S(O)heterocycle, -SO₂(C_l-C₆)alkyl, -SO₂(C₂-C₆)alkenyl, -SO₂(C₂-C6)alkynyl, -SO₂(Ct-C6)haloalkyl, -S0₂(C₃-C₇)carbocycie, -SO₂(C₃30 C₇)halocarbocycle, -SO₂aryi, -SCbheteroaryl, -S0₂heterocycle, -SO₂(CiC6)alkylNRcRd, -SO₂(C_rCe)alkylNR_iC(O)R_i, -SO₂(C_t-C₆)alkylNR_aSO₂R_a, SO₂NRAi, -NR«C(O)OR_b, -NR_aC(O)NR_îR_d -NR_aSO₂R_t>, -NRjSOjN’R^Rj, 16294

ΙΟΙ

NRïSOîOCCrCy^arbocycle, -NRjSChOaryl, -OSfO^Ra, -C(O)NRiRa, and • -s

OCiOjNRJLj, wherein any (Cj-Cé)alkyl, (C2-C₆)a]kenyl, (C₂-Cô)alkynyl, (C₃C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z⁷ is optionally substituted with one or more (e.g. 1,2, 3,4 or 5) halogen, -OH, -ORb, -CN,

-NRaC(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, NHheterocycle, or -S(O)₂NR_<R_<j;

each Z⁸ is independently selected from -NO₂ or-CN;

each Z⁹ is independently selected from -(Ci-CsJalkyl, -O(Ci-C6)alkyl;

each Z¹⁰ is independently selected from

i) halo, oxo, thioxo, (C₂-Cs)alkenyl, (Ci-C₆)haloalkyl, (C₃C₇)cycloalkyl, (C₃-C₇)cycloalkyl-(C_rCt)alkyl-, -OH, -O(CiC₆)alkyl, -O(Ci-C₆)haloalkyl, -SH, -S(C!-C₆)alkyl, -SO(C_rC₆)alkyl, -SO₂(C,-C₆)alkyl, -NH₂, -NH(C_rC₆)alkyl and -NCÎCi-Csialkyl^;

ii) (Cj-Côjalkyl optionally substituted with -OH, -O-(Cr

Ce)haloalkyl, or -O-(Ci-CÉ)aIkyl; and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (C i-Cfi)alkyI or COOH;

each Z¹¹ is independently selected from Z¹⁰, -C(=O)-NH₂, -C(=0)-NH(Ci20 C₄)alkyl, -C(=O)-N((Ci-C₄)alkyl)₂, -C(=O)-aryl, -C(=0)-heterocycIe and -C(=O)-heteroaryl;

* ·>

each Z ts independently selected from -NO₂, -N0R_a, thioxo, -aryl, heterocycle, -heteroaryl, -(C₃-C7)halocarbocycle, -(C₃-C₇)carbocycle, -O(C₃-C₇)carbocycIe, -Ohalo(C₃-C₇)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl,

-S(Ci-C6)alkyl, -S(C₃-C7)carbocycle, -Shalo(C₃-C7)carbocycle, -Saryl, -Sheterocycle, Sheteroaryl, -S(O)(Ci-C6)alkyl, -S(O)(Cj-C₇)carbocycle, -S(O)halo(C₃-C7)carbocycle, -S(O)aryl, -S(O)heterocycle, -S(0)heteroaryl, -SO₂(Cj-C6)alkyl, -SO2(C₃-C7)carbocycle, -SO2(C₃-C₇)halocarbocycle, SO₂aryl, -SO₂heterocycle, SOjheteroaryl, -NRaRa, -NR_aC(O)R_b, -C(0)NKR<i. -SCbNRRj. -NR_dSO₂NR_<R_d, 30 NRaSO₂O(C₃-C₇)carbocycle and -NR_aSO₂Oaryl;

each Z¹³ is independently selected from -NO₂, -OH, - NOR,, -SH, -CN, -(C₃C₇)halocarbocycle, -O(Ci-C6)alkyl, -0(C2-C₆)a]kenyl,-0(C₂-Cfi)alkynyl, -O(Ci-

102

Q)haloalkv!, -O(C3-C₇)carbocycle, -0(C3-C₇)haiocarbocycle, -Oaryl, -Oheteroaryl, Oheterocycle, -S(Ci-Ce)alkyl, -S(C₂-C₆)alkenyl, -S(C₂-C₆)alkynyl, -S(C]-C₆)haloalkyl, -S(C3-C₇)carbocycle, -S(C3-C7)halocarbocycle, -Saryi, -Sheteroaryl, -Sheterocycle, -8(0)(^-C₆)alkyl, -S(O)(C₂-C₆)alkenyl, -S(O)(C₂-C₆)alkynyl, -S(O)(C_t-C₆)haloalkyl, 5 S(0)(C3-C₇)carbocycle, -S(0)(C3-C₇)halocarbocycle, -S(O)aryl, -S(O)heteroaryl, S(O)heterocycle, -SO₂(Ci-C6)alkyl, -SO₂(C₂-C6)alkenyl, -SC^fCrCéJalkynyi, -SOXCjCj)haloalkyl, -S0₂(C₃-C7)carbocycle, -SOj/CrCjhalocarbocycle, -SOjaryl, SO₂heteroaryl, -SCkheterocycle, -SO₂NR(Ri, -NRcRj, -NRaC(O)R_a, -NRaC(O)ORb, -NR_aC(O)NR_cR_d -NR^SOzRfc, -NR^C^NR^. -NR_aS(W(G-C₇)carbocycle, 10 NR_aSO₂Oaryl, -OS(O)₂R_a> -C(O)R_a, -C(O)OR_h; -C(O)NRcRd, and -OC(O)NKR_d;

wherein any (C|-C₆)alkyl, (C₂-C6)alkenyl, (C₂-C6)alkynyl, -(Cj-C₇)halocarbocycle, (C3C₇)carbocycle, (C₃-C7)halocarbocycle, aiyl, heteroaryl or heterocycle of Z¹³ is optionally substituted with one or more (e.g. 1,2,3,4 or 5) halogen, -OH, -ORb, -CN, -NR_aC(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, 15 NHheterocycIe, or -S(O)₂NR_CR_{J;

each Z¹⁴ is independently selected from -NO₂, =NOR_1> -CN, -(C3C₇)halocarbocycle, -0(C3-C7)halocarbocycle, -S(C3-C₇)halocarbocycle, -S(OXC₃C₇)halocarbocycle, -SO₂(C3-C₇)halocarbocycle, -NRaSO₂NR<Rd, -NR,S0₂O(C3C₇)carbocycle, -NRiSO2Oaryl, -OS(O)₂Rj; wherein any -(C3-C7)halocarbocycle of Z¹⁴ is optionally substituted with one or more (e.g. 1,2,3,4 or 5) halogen, -OH, -ORb, -CN, -NR_aC(O)₂Rt, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, NHheteroaryl, -NHheterocycIe, or -S(O)₂NR<R₄;

each Rj is independently H, (C|-C₆)alkyl, -(C₂-C₆)alkenyl, -(Cj-C^alkynyl, (C3-C₇)carbocycle, heterocycle, aryl, aryl(C]-C6)alkyl-, heteroaryl or heteroaryl(C]25 Cfi)alkyl-; wherein any (Ci -C₆)alkyl, (C₂-C6)alkenyl, (C₂-C₆)alkynyL (C3-C7)carbocycle, heterocycle, aryl, or heteroaryl of R_a is optionally substituted by halogen, OH and cyano;

each Rb is independently -(Ci-CeJalkyl, -(C₂-C6)alkenyl, -(C₂-C6)alkynyl, (C3-C₇)carbocycle, heterocycle, aryl, aryl(Ci-C6)alkyl-, heteroaryl orheteroaryl(Ci30 C₆)alkyl-; wherein any (Ci-Ce)alkyl, -(Cj-C^jalkcnyl, -(Cj-CbJalkynyl, (C3-C₇)carbocycle, heterocycle, aryl, or heteroaryl of Rb is optionally substituted by halogen, OH and cyano;

Rc and Rj are each independently selected from H, (Ci-C^jaikyl, (C₂-C6)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, aryl, aryl(Ci-C₆)alkyl-, heterocycle, heteroaryl or heteroaryl(Ci-C6)alkyl- wherein any (Ci-C₆)alkyl, -(C₂-C6)alkenyl, -(CrCéjalkynyï, (Cî-Cyjcarbocycle, heterocycle, aryl, or heteroaryl of R< or Rd is optionally substituted by halogen, OH and cyano; or R<· and R<j together with the nitrogen to which they are attached form a heterocycle; wherein any heterocycle of R^and Ra together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano;

each Rc is independently selected from -OR», (C]-C$)alkyl or (C3-C₇)carbocycie wherein (Cj-C$)alkyl or (C₃-C/)carbocycle is substituted by one or more Zd and optionally substituted with one or more Z₍; -(C₂-C6)haloalkyl, -(C₂-C$)alkenyl, or -(C₂-Ce)alkynyl wherein any haloalkyl, alkenyl or alkynyl is optionally substituted with one or more Zj; aryl, heterocycle or heteroaryl wherein aryl, heterocycle or heteroaryl is substituted by one or more Z_€;

each Rf is independently selected from -Rg, -ORa, -(Ci-Csjalkyl-Z⁶, -SO₂R_g, 15 C(O)R_g, C(O)OR_e, or -CfOjNRcRg; and each Rg is independently selected from -OR*, (Cj-C^jalkyl, (Cj-C₂)caibocycle (Cj-Csjhaloalkyl, (C^-Céjalkenyl, (C₂-Cs)alkynyl, aryl, heterocycle or heteroaryl wherein any (C|-C_é)alkyl, (C3-C7) carbocycle -(CpC^haloalkyl, (C₂-C6)alkenyl, (C₂-Ce)alkynyl, aryl, heterocycle or heteroaryl of Rg is optionally substituted with one 20 or more Zi groups;

or a sait thereof.

In one embodiment, the compounds of formula I include:

104

and salts thereof.

In another embodiment, the compounds of formula I include:

107

i 08

and salts thereof.

In one embodiment, the compounds of formula I include:

109

ΟΘ

10

î 1

OH

112

Cl

113

Ph

14

C

115

116

and salts thereof.

In one embodiment, the compounds of formula 1 include:

C

117

and salts thereof.

General Synthetic Procedures

Schemes 1,2 and 3 are provided as further embodiments of the invention and illustrate general methods which were used to préparé compounds of formula I and which can be used to préparé additional compounds of formula I. Schemes 4-11 outline methods that were used or can be used to préparé compounds of formula 1.

C

118

Scheme 1

o

Cyclocondensation of a substituted hydroxyaniline with a substituted, unsaturated aldéhyde leads to quinolinols. Brominatîon can be achieved using 5 electrophilic sources of bromine such as NBS. The pheno) can be activated by transforming to a leaving group such as trifluoromethanesulfonate by treatment with trifluoromethanesulfonic anhydride and an appropriate base such as 2,6-lutidme. Regioselective palladium catalysed cross-coupling reactions (e.g. Suzuki or Stille) can be used to alkyiate the quinoline with a vinyl group which can then be asymmetrically 10 di-hydroxylated using reagent mixtures such as AD-mix-α. Sélective protection of the primary hydroxyl can be achieved with bulky protectîng groups, such as pivaloyl *1 chloride. Formation of the R group can be achieved by alkylation of the secondary alcohol by various methods. Palladium catalysed cross coupling reactions (e.g. Suzuki or Stille) can be used to install the R⁴ group. Following hydrolysis of the protectîng 15 group, the primary alcohol may then be oxîdized to produce desired compounds.

119

Altematively, cyclocondensation of a halogenated aniline starting material that Îs substituted at R⁴ can undergo cyclocondensation with a substituted, unsaturated 5 aldéhyde can deliver R⁴ substituted, R³ halogenated quinolines directly. These can be further elaborated similarly to the methods described for Scheme 1 to produce desired compounds.

Génération of a quinoiinone intermediate is achieved by Λ-oxidation of the quinoline with a reagent such as mCPBA, followed by acylation, thermal rearrangement, and sélective removal of the acetate. Deprotonation of the quinoiinone followed by methods to favor O-alkylatîon when treated with an appropriate electrophile allow for substituents at R to be produced wherein the R group is an

C

120 ether. Subséquent hydrolysis and oxidation can provide compounds of formula 1 with R⁷ ether groups.

Deprotonation of the quinolinone followed by methods to favor N-alkylation when treated with an appropriate electrophile can yield desired alkylated quinolinone analogues with R¹³ modifications. Subséquent hydrolysis and oxidation produces desired compounds.

Scheme 5

The quinolinyl triflate can be made from the quinolinone. Cross coupling reactions with the triflate (e.g. Suzuki and Sonagashira reaction) can introduce different 15 R⁷ moieties. Hydrolysis and oxidation can yield the desired compounds.

121

Scheme 6

The quinolinone can be converted to 2-chloroquinoline by treatment with reagents such as phosphorous oxychloride. Nucleophilic aromatic substitution can 5 introduce different R⁷ groups wherein the R⁷ is linked through a heteroatom.

Hydrolysis and oxidation can produce the desired analogs.

122

Deprotonation of 2-chIoroquinoline, followed by reaction with trimethyl borate can generate the boronic acid. Zinc and acetic acid can be used to reduce the substituted chloroquinoline to the quinoline. Cross coupling and subséquent hydrolysis and oxidation can provide analogs with different R⁶ moieties.

Scheme 8

The methylquinoline can be oxidized with mCPBA to give the N-oxide, which can react with acetic anhydride and réarrangé to yield the hydroxymethylquinoline. Oxidation ofthe alcohol can provide the carboxylic acid. Coupling with different amines can provide R⁷ amide moieties. Subséquent hydrolysis can generate compounds of formula I with R⁷ amides.

123

Scheme 9

The quinoline carboxylic acid can be converted to a primaiy amine via a Curtius rearrangement which can be converted to additional R⁷ groups wherein the R⁷ group is an amine. Subséquent hydrolysis can provide compounds of formula 1 with R⁷ amine groups.

Scheme JO

The hydroxymethylquinoline can be converted to mesylate, which can be reacted with different nucleophîles to provide R⁷ groups wherein the R⁷ group is represented by the general formula “-CH₂XR” wherein X is 0, S or NR’. Subséquent hydrolysis can generate compounds of formula I.

Scheme 11

NaOH

MeOUTHF AO ‘C

The quinolînyl triflate can react with Grignard or alkyl-lithium reagents in the presence of a catalyst such as Fe(AcAc)₃ to give the corresponding quinoiine. Subséquent deprotection and oxidation can generate compounds of formula I.

Prodrugs

In one embodiment, the invention provides for a prodrug of a compound of the invention. The term “prodrug” as used herein refers to any compound that when administered to a biological System generales a compound of the invention that inhibits the réplication of HfV (“the active inhibitory compound”). The compound may be 5 formed from the prodrug as a resuit of: (i) spontaneous chemical reaction(s), (ii) enzyme catalyzed chemical reaction(s), (îiî) photolysis, and/or (iv) metabolic chemical reaction(s).

“Prodrug moiety” refers to a labile functional group which séparâtes from the active inhibitory compound during metabolîsm, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academie Publishers, pp. 113-191). Enzymes which are capable of an enzymatic activation mechanism with the prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbîal enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bîoavailability and efficacy. A prodrug moiety may include an active métabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters -CH₂OC(=O)R^W and acyloxymethyl carbonates -CH2OC(=O)OR where R⁹⁹ is Cj-R alkyl, CrQ substituted alkyl, C$-C₂o aryl or C6-C₂o substituted aryl. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570,4968788, 5663159 and 25 5792756. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bîoavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bîoavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM)

-CH₂OC(=O)C(CH3)3- An exemplary acyloxymethyl carbonate prodrug moiety is pïvaloyloxymethylcarbonate (POC) -CH₂OC(-0)OC(CH3)₃.

Aryl esters of phosphores groups, especially phenyl esters, are reported to

C

126 efthanceoral bioavailability (De Lombaert et al. (1994)./. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to a phosphate bave also been described (Khamnei and Torrence, ( 1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate parent phosphonic acids. In some cases, substituents at the ortho- or para- position may accelerate the hydrolysis. Benzyl analogs with an acylated phénol or an alkylated phénol may generate the phenolic compound through theaction of enzymes, e.g., esterases, oxidases, etc., which in tum undergoes cleavage at the benzylic C- O bond to generate phosphoric acid and a quinone methide intermediate., Examples of this class of prodrugs are described by Mitchell et al.

(1992) J. Chem. Soc. Perkin Trans. /72345; GlazierWO 91/19721. Still other benzylic prodrugs hâve been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate dnigs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. De-esterification or réduction of the disulfide generates the free thio intennediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996)7 Med. Chem. 39: 4958).

Pharmaceutical Formulations

The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in stérile form, and when intended for delivery by other than oral administration generally will be isotonie. Ait formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelatîng agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the lîke. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.

While it is possible for the active ingrédients to be administered alone it may be préférable to présent them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingrédient, <x

as above defined, together with one or more acceptable carriers and optionally other therapeutic ingrédients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingrédients of the formulation and physiological ly innocuous to the récipient thereof.

The formulations include those suitable for the foregoing administration routes.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bnnging into association the active ingrédient with the carrier which constitutes one or more accessory ingrédients. In general the formulations are prepared by umformly and intimately bringing into association the active ingrédient with liquid carriers or fînely divided solid carriers or both, and then, if necessaiy, shaping the product.

Formulations of the présent invention suitable for oral administration may be presented as discrète units such as capsules, cachets or tablets each containing a predetermincd amount of the active ingrédient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oîl-în-water liquid émulsion or a water-in-oil liquid émulsion. The active ingrédient may also be administered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or more accessory ingrédients. Compressed tablets may be prepared by compressîng in a suitable machine the active ingrédient in a frec-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingrédient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingrédient therefrom.

For administration to the eye or other extemal tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in incréments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10%

128 w/w, When formulated in an ointment, the active ingrédients may be employed with either a parafïïnic or a water-miscible ointment base. Alternatively, the active ingrédients may be formulated in a créant with an oil-in-water cream base.

„ If desired, the aqueous phase of the créant base may include, for example, at ieast 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or pénétration of the active ingrédient through the skin or other affected areas. Examples of such dermal pénétration enhancers include dîmethyl sulfoxide and related analogs.

The oily phase of the émulsions of this invention may be constituted from known ingrédients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an cmulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilie emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifîer(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and cmulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, nonstaining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stéarate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitale, butyl stéarate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft parafïin and/or liquid paraffin or other minerai oils are used.

C • 129

Pharmaceutical formulations according to the présent invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingrédient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powdcrs or granules, émulsions, hard or soft capsules, syrups or élixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable préparation. Tablets containing the active ingrédient in admîxture with non-toxic phaimaceutîcally acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscannellose sodium, povidouc, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystallinc cellulose, starch, gelatin or acacia; and lubricating agents, such as magnésium stéarate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingrédient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingrédient is mixed with water or an oil medium, such as peanut oil, liquîd parafïin or olive oil.

Aqueous suspensions of the invention contain the active materials in admixtuie with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occumng ¥

130 phosphatîde (e.g, lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stéarate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexîtol anhydride (e.g., polyoxyethylenesorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl orn-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingrédient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a minerai oil such as liquid parafïïn. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral préparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersîble powders and granules of the invention suitable for préparation of an aqueous suspension by the addition of water provide the active ingrédient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be présent.

The pharmaceutical compositions of the invention may also be în the form of oîl-in-water émulsions. The oîly phase may be a vegetable oil, such as olive oil or arachîs oil, a minerai oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occumng phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The émulsion may also contain sweetening and flavoring agents. Syrups and élixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demukenl, a preservative, a flavoring or a coloring agent.

- 131

The pharmaceutical compositions of the invention may be in the form of a stérile injectable préparation, such as a stérile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The stérile injectable préparation may also be a stérile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution în 1,3-butane-diol or prepared as a lyophilized powder. Amongthe acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonie sodium chloride solution. In addition, stérile fixed oils may conventionally be employed as a solvent or suspending medium. For this puipose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the préparation of injectables.

The amount of active ingrédient that may be combined with the carrier material to produce a single dosage form will vary dependîng upon the host treated and the 15 particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately l to 1000 mg of active material compounded with an appropriate and convenant amount of carrier material which may vary from about 5 to about 95% of the total compositions (weightiweight). The pharmaceutical composition can be prepared to provide easily measurable amounts 20 for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg of the active ingrédient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye drops wherein the active ingrédient is dissolved or suspended in a suitable carrier, especially an 25 aqueous solvent for the active ingrédient. The active ingrédient is preferably présent in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.

Formulations suitable for topîcal administration în the mouth include lozenges comprising the active ingrédient in a fiavored basis, usually sucrose and acacia or 30 tragacanth; pastilles comprising the active ingrédient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingrédient in a suitable liquid carrier.

132

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration hâve a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in incréments microns such as 0.5,1,30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingrédient. Formulations suitable for aérosol or dry powder administration may be prepared according to conventional methods and may be delîvered with other therapeutic agents.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingrédient such carriers as are known in the art to be appropriate.

Formulations suitable for parentéral administration include aqueous and nonaqueous stérile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutés which render the formulation isotonie with the blood of the intended récipient; and aqueous and non-aqueous stérile suspensions which may include suspending agents and thickening agents.

The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the stérile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from stérile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations arc those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingrédient.

It should be understood that in addition to the ingrédients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The invention further provides veterinary compositions comprising at least one active ingrédient as above defined together with a veterinary carrier.

133

Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingrédient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

Compounds of the invention can also be formulated to provide controlled release of the active ingrédient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingrédient Accordîngly, the invention also provides compositions comprising one or more compounds of the invention formulated for sustained or controlled release.

Effective dose of active ingrédient dépends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.

Routes of Administration

One or more compounds of the invention (herein referred to as the active ingrédients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parentéral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and épidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the récipient. An advantage of the compounds of this invention is that they are orally bioavaîlable and can be dosed orally.

The antiviral properties of a compound of îhe invention may be determined using Test A described below.

Test A: Antiviral Assays in MT4 Cells

For the antiviral assay utilizing MT-4 cells, 0.4 pL of 189X test concentration of 3-fold serially diluted compound in DMSO was added to 40 pL of cell growth medium (RPMI 1640, 10%FBS, 1% penicillin/Streptomycin, 1% L-Glutamine, 1% HEPES) in each well of 384-welt assay plates (10 concentrations) in quadruplicate.

134 l mL aliquQts of2xlOe6 MT-4 cells are pre-infected for l and 3 hrs respectively, @ 37°C with 25 μΕ (MT4) or of either cell growth medium (mockinfected) or a fresh 1:250 dilution of an HlV-IIlb concentrated ABI stock (0.004 m.o.i. for MT4 cells). Infected and uninfected cells are diluted in cell growth medium and 35 uL of 2000 (for MT4) cells is added to each well of the assay plates.

Assay plates were then incubated in a 37 °C incubator. After 5 days of incubation, 25 pl of 2X concentrated CellTiter-Glo™ Reagent (catalog # G7573, Promega Biosciences, Inc., Madison, WI) was added te each well of the assay plate. Cell lysis was carried out by incubating at room température for 2-3 min and then chemiluminescence was read using the Envisîon reader (PerkinElmer).

Compounds of the présent invention demonstraie antiviral activity in this assay (Test A) as depicted in the table below.

Compound Number	EC50(nM)
IL	170
2K	55
3L	1059
4J	543
5J	19
6D	20
7J	160
8L	559
9	173
10	897
11	479
12	210
13	150
14	983
15	334
16	220
17	359

135

	19	53000
1	20	1744
	21	231
	22	1075
	23	26385
	24	29783
	25	346
	26	45
	27	23
	28	43
	29	939
	30	153
	31	105
	32	108
	33	95
	34	266
	35	157
	36	20
	37A	36
	37B	46
	38	68
	39	11
	40	51
	41	26
	42	46
	43	27
	44	18
	45	29150
	46	20
	47	14
	48	26

L

136

49	27
50	24
51	30
52	25
53	360
54	87
55	41
56	40
57	20 ,
58	14
59	321
60	305
61	119
62	72
63	183
64	290
65A	85
65B	55
66	297
67	273
68	29150
69	82
70	206
71	118
72	194
73	247
74	92
75	38
76	267
77	135
78	163

Cr

137

79	86
80	52
81	69
82	171
83	42
84	330
85	131
86	78
87	175
88	514
89	42
90	67
91	73
92	300
93	94
94	149
95	54
96	37
97	898
98	251
99	12
100	75
101	367
IÔ2A	13
102B	110
103	25
104	720
105	105
106	25
107	n.d.
108	n.d.

138

109	n.d
110	n.d.
111	352
112	n.d.

n.d.(not determined)

In certain embodiments, the compounds demonstrate an EC5O of < 50 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 30 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 10 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 1 μΜ.

The spécifie pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are présent pharmaceutical carriers, as well as the type of formulation and mode of administration 10 employed, and such expected variations or différences in the results are contemplated in accordance with practice of the présent invention.

The invention has been described with reference to various spécifie and prefened embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope 15 of the invention.

The invention will now be illustrated by the following non-limiting Examples.

Example 1: Préparation of(S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2methylquinolin-6-yl)acetic acid (IL):

IJ

1K

IL

A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (l 1.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% ILO) to a volume of 114 mL. This stock solution (0.80 mL) was added to a solution of (S)-2-tert-butoxy-2-(7-chloro-5-(4chlorophenyl)-2-methylqumolin-6-yl)ethanol (1K) ( 11 mg, 0.027 mmol) in wet acetonitrile (3.0 mL), 0.75% H₂O) at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C and quenched with 1.5 Μ K2HPO4 solution. Ethyl acetate was added and the organic layer separated and washed with 1:1 brine/H₂O (2x) and saturated

NaHSOj /brine. The organic layer was dried (MgSO₄) and concentrated and purified

C - 140 by prep-HPLC to give IL as a TFA sait (8 mg, 57%). ^lH-NMR 300 MHz, (CDOD) S 8.19 (s, 1H), 8.17 (d,ÏH), 7.70-7.52 (m, 4H), 7.40-7.30 (m, 1H), 2.89 (s, 3H), 1.01 (s, 9H); LCMS-ESf (m/z): [M+H]* calcd for CjaH^hNOj: 419.3; Found: 418.1,420.1,

422.1.

Préparation of (S)-2-tert-butoxy-2-(7chloro-5-(4-chlorophenyl)-2methylquinolin-6-yl)ethanol (1K).

Step I.

Préparation of 7-chIoro-6-methoxy-2-methylquinoline (IB): To 3-chloro-410 methoxyanîline (IA) (5.0 g, 31.7 mmol) was added 6 M HCI (100 mL) and the reaction was heated to 100 °C with stirring. Toluene (30 mL) was added followed by the slow addition of crotonaidehyde (5.3 mL, 63.5 mmol) at 100 °C. The mixture was stirred at 100 °C for 2 hours and cooled to room température. The water layer was separated and neutralized with 2 M NaOH solution to pH ~ 8. The solid that formed was filtered and 15 collected. The crude product was purified by flash column chromatography to give IB as white solid (3.3 g, 50%). LCMS-ESI* (m/z): 208.2,210.2 (M+H)*.

Step 2.

Préparation of 7-chioro-2-methylquinolin-6-ol (IC); To a stirred solution of 7chloro-6-methoxy-2-methylquinoline (IB) (1.22 g, 5.9 mmol) in dichloromethane (15 20 mL) was added BBr₃ (23.6 mL 1 M DCM solution, 23.6 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours and quenched by the slow addition of a NaHCO₃solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography to give the pure product IC (0.91 g, 80%). LCMS-ESI* (m/z): 194.1, 25 196.1 (M+H)*.

Step 3.

Préparation of 5-bromo-7-chloro-2-methylquinolin-6-ol (ID): To a stirred solution of 7-chloro-2-methylquînolin-6-ol (IC) (450 mg, 2,3 mmol) in acetic acid (15 mL) was added Br₂ (0.13 mL, 2.4 mmol) at ambîent température. The mixture was 30 stirred at ambrent température for 2 hours. The solid that formed was filtered and collected to give ID as an off-white solid as the HBr sait (847 mg, 100%). LCMS-ESI* (m/z): 281.1,283.1 (M+H)*.

Step 4.

Préparation of 7-'chIoro-5-(4-chlorophenyl)-2-mcthyiquinolm-6-ol (1E): Pd(PPh₃)₄ (120 mg, 0.1 mmol) was added to a mixture of 5-bromo-7-chloro-2methylquinoIin-6-ol (ID) (345 mg, 1.04 mmol),4-chlorophenylboronic acid (326 mg,

2.09 mmol) and K₂CO₃ (2.3 mL 2 M în water, 4.7 mmol) in 1,2-dimethoxyethane (10 mL). The reaction mixture was flushed with nitrogen, heated at 80 °C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with a NaHCO₃ solution, water and brine, dried over Na₂SO₄, filtered and concentrated în vacuo. The obtained residue was purified by flash chromatography to provide 1E as a white solid (147 mg, 47%). LCMS-ESI* (m/z):

304.2,306.2 (M+H)*.

Step 5.

Préparation of 7-chloro-5-(4-chlorophenyl)-2-methylquinoIm-6-yl trifluoromethanesulfonate (IF): To a stirred solution of 7-chloro-5-(4-chloro-phenyl)-2“ 15 methylquînolin-6-ol (1 E) ( 13 8 mg, 0.46 mmol) in dichloromethane (4 mL) and pyridine (1.5 mL) was added Tf₂O (0.16 mL, 0.92 mmol) at 0 “C. The mixture was stirred at room température for 2 hours and quenched by the slow addition of a NaHCO₃ solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to get a brown solid (194 mg, 97%).

LCMS-ESI* (m/z): 436.0,437.9 (M+H)*. The crude product 1F was used on next step reaction without further purification.

Step 6.

Préparation of 7-chloro-5-(4-chlorophenyl)-2-methyl-6-vinylquinoline (1 G); Pd(PPh₃)i (52 mg, 0.045 mmol) and PdCl₂(PPh;)₂ (32 mg, 0.045 mmol) were added to 25 a mixture 7-chIoro-5-(4-chlorophenyl)-2-methyIquinolin-6-yl trifluoromethanesulfonate (IF) (194 mg, 0.45 mmol), tributyl(vinyl)stannane (0.17 mL, 0.58 mmol), lithium chloride (57 mg, 1.4 mmol) and 2,6-di-fôrt-butyl-4-methylphenol (cat. amount) in 1,4-dioxane (8 mL). The reaction mixture was flushed with nitrogen, heated at 80 °C for 16 hours, and then the volatile component was removed in vacuo.

The residue was dissolved în ethyl acetate (100 mL), washed with aNaHCO₃ solution, water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The obtained

A

residue was purified by flash chromatography to provide the desired product IG (50 mg, 35%). LCMS-ESI* fm/z): 314.2,316.2 (M+H)*.

Step 7.

Préparation of (S)-I -(7-chIoro-5-(4-chlorophenyl)-2-methylquinolin-65 yl)ethane-f,2-diol (IH): AD-mîx-α (1 g, excess) was added to a mixed solvent oflbutanol and water (4 mL /4 mL) and stirred at room température for 5 min and cooled to 0 °C. The mixture was transferred to another flask containing 7-chloro-5-(4chiorophenyl)-2-methyI-6-vinylquinoline (IG) (30 mg, 0.096 mmol) and stirred at 0 °C for 16 hours. The mixture was diluted with ethyl acetate, washed with NaHCO, solution, water and brine, dried over Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product IH (28 mg, 84%). LCMS-ESI* (m/z): 348.2, 350.2 (M+H)*.

Step 8.

Préparation of (8)-2-(7-chloro-5-(4-chlorophenyl)-2-methyIquinolin-6-yl)-215 hydroxyethyl pivalate (II): To a stirred solution of (S)-l -(7-chloro-5-(4-chlorophenyl)2-methylquinolîn-6-yl)ethane-l ,2-diol (IH) (28 mg, 0.081 mmol) in dichloromethane (2 mL) and pyridine (0.5 mL) was added trimethyl acetylchloride (0.020 mL, 0.16 mmol) at 0 °C. The mixture was stirred at room température for 2 hours and quenched by the slow addition of a NaHCOj solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product II (25 mg, 72%). LCMS-ESI* (m/z): 432.2, 434.2 (M+H)*.

Step 9.

Préparation of (S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-225 methylquinoItn-6-yl)eihyl pivalate (1 J): To a stirred solution of (S)-2-(7-chloro-5-(4chlorophenyI)-2-methylquinolin-6-yl)-2-hydroxyethyl pivalate (II) (25 mg, 0.058 mmol) in t-butylacetate (3 mL) was added 70% perchloric acid (0,02 mL, 0.23 mmol) at 0 °C. The mixture was stirred at room température for 2 hours and quenched by the slow addition of a NaHCCh solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product IJ (22 mg, 78%). LCMS-ESI* (m/z): 488.2, 490.2 (M+H)*.

- 143

Step 10.

Préparation of (S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2methylquinoIîn-6-yI)ethanol (1K): To a stirred solution of (S)-2-tert-butoxy-2-(7chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)ethyl pivalate (1 J) (22 mg, 0.045 mmol) in THF and methanol (3 mL/Ι mL) was added 1 M NaOH solution (1 mL, excess) at 0 °C. The mixture was stirred at room température for 16 hours and diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtaîned residue was purified by flash chromatography to provide the desired product 1K (11 mg, 61%). LCMS-ESI⁴10 (m/z): 404.2,406.2 (M+H)⁴.

Example 2: Préparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7dimethylquinoIin-6-yl)acetic acid (2K)

(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-diniethylqumolin-6-yl)acetÎc acid (2K) was prepared following the procedure used to préparé compound IL of Example l, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-65 yi)ethanol (2J) was used instead of compound 1K. ^lII-NMR 300 MHz, (CD₃OD) δ

8.31 (d, IH), 7.97 (s, IH), 7.73 (d, IH), 7.70-7.60 (m, 3H), 7.42-7.38 (m, IH), 5.25 (s, IH), 2.96 (s, 3H), 2.78 (s, 3H), 0.98 (s, 9H); LCMS-ESl⁺ (m/z); [M+H]⁺ calcd for C23H25CINO3: 398.9; Found: 398.2, 400.1.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-diTnethylquinoIin-6yl)ethanol (2 J):

Step l.

Préparation of 2,7-dimethylquinolin-6-ol (2B): Compound 2B was prepared following the procedure used to préparé compound lBof Example l, except that 4amino-2-methyIphenol (2A) was used instead of compound IA. LCMS-ESI* (m/z):

174.2 (M+H)*.

Step 2.

Préparation of 5*bromo-2,7-dimethylquinolin-6-ol (2C) ; Compound 2C was prepared following the procedure used to préparé compound ID of Example 1, except that 2,7-dimethylquinolin-6-ol (2B) was used instead of compound IC, LCMS-ESI* (m/z): 252.2, 254.2 (M+H)⁺.

Step 3.

Préparation of 5-(4-chlorophenyl)-2,7-dimcthy'quinolin-6-ol (2D): Compound

2D was prepared following the procedure used to préparé compound 1E of Example 1, except that 5-bromo-2,7-dimethylquinoIin-6-oI (2C) was used instead of compound ID. LCMS-ESI* (m/z): 284.2,286.2 (M+H)*.

Step 4.

Préparation of 5-(4-chlorophenyl)-2_I7-dimethylquinolin-6-yl trifluoromethanesulfonate (2E): Compound 2E was prepared following the procedure used to préparé compound 1F of Example 1, except that 5-(4-chlorophenyl)-2,7dimethylquinolin-6-oI (2D) was used instead of compound 1E. LCMS-ESI* (m/z): 416.0, 418.0 (M+H)*.

Step 5.

Préparation of 5-i4-chlorophenyl)-2,7-dimethyl-6-vinylquinoline (2F):

Compound 2 F was prepared following the procedure used to préparé compound IG of Example 1, except that 5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate (2E) was used instead of compound 1F. LCMS-ESI* (m/z):

294.3, 296.3 (M+H)*.

Step 6.

Préparation of (S)-l -(5-(4-chlorophenyl)-2,7-dimcthylquinolin’6-yl)eÎhaiie-l ,2diol (2G): Compound 2G was prepared following the procedure used to préparé t - 146 compound IH of Example l, exceptthat 5-(4-chlorophenyl)-2,7-dimethyl-6vinylquinolÎne (2F) was used instead of compound IG. LCMS-ESf (m/z): 328.2,330.2 (M+Hf.

Step 7.

Préparation of (S)-2-(5-(4-ch]orophenyl)-2,7-dimethylquinolin-6-yl)-2hydroxyethyl pivalate (2H): Compound 2H was prepared following the procedure used to préparé compound II of Example 1, except that (S)-l-(5-(4-chlorophenyl)-2,7dimethylqumoliii-6-yl)ethane-l,2-diol (2G) was used instead of compound 1Π. LCMSESf (m/z): 412.3, 414.3 (M+H)⁺.

Step 8.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chloτophenyl)-2,7-diπιethylquînolin-6yl)ethyl pivalate (21): Compound 21 was prepared following the procedure used to préparé compound 1J of Example l, except that (S)-2-(5-(4-chloiOphenyl)-2,7dimethyIquinolin-6-yl)-2-hydroxyethyl pivalate (2H) was used instead of compound II.

LCMS-ESf (m/z): 468.3,470.3 (M+H)⁺.

Step 9.

Préparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-2,7-dimethylquinolin-6yl)ethanol (2J) ; Compound 2J was prepared following the procédure used to préparé compound 1K of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,720 dimethylquinolin-6-yl)ethyl pivalate (21) was used instead of compound IJ. LCMSESf (m/z): 384.2, 386.2 (M+Hf.

l 47

Example 3: Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin6-yl)acetic acid (3L).

(S)-2-tert-butoxy-2-(5-(4-chJorophenyl)-7-methylquinolin-6-yl)acetic acid (3L) 5 was prepared following the procedure used to préparé compound IL of Example 1, except that (S)-2-tert-butoxy-2-(5 -(4-chlorophenyl)-7-methylquinolin-6-yl)ethanol (3K) was used instead of compound IL. 'H-NMR 300 MHz, (CDC1₃) 5 8.89-8.86 (m, IH), 7.98 (s, IH), 7.75-7.65 (m, 2H), 7.58-7.50 (m, 2H), 7.30-7.20 (m, 2H), 5.30 (s,

148

IH), 2.66 (s, 3H), 1.02 (s, 9H); LCMS-ESI* (m/z): (M*HJ* calcd for C22H23CINO3: 384.9; Found:384.1, 386.1.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6yljethanol (3K):

Step 1.

Préparation of 6-methoxy-7-methylquinoline (3B): l-methoxy-2-methyl-4nîtrobenzene (3A) (5 g, 30.0 mmol), 3-amino-l-propanol (0.57 mL, 7.5 mmol), isopropanol (3.43 mL, 4.5 mmol), ruthenium(III) chloride hydrate (156 mg, 0.75 mmol), triphenylphosphine (588 mg, 2.24 mmol), and tin(II) chloride dihydrate (1.69 g, 10 7.5 mmol) in dioxane/H₂(J (67 mL/7 mL) were placed in a stainless steei pressure vessel. After the System was flushed with argon, the mixture was stirred at 180 °C for 20 hours. The reaction mixture was filtered through a short silica gel column (ethyl acetate/chloroform mixture) to eliminate inorganic compounds and concentrated under reduced pressure. The organic layer was poured into saturated brine, extracted with chloroform, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residual oily material was separated by column chromatography to give the product 3B (200 mg, 15%). LCMS-ESI* (m/z): 1742 (M+H)*.

Step 2.

Préparation of 7-methylquinolin-6-ol (3C): Compound 3C was prepared following the procedure used to préparé compound IC of Example 1, except that 6methoxy-7-methylquinoline (3B) was used instead of compound IB. LCMS-ESI* (m/z): 160.2 (M+H)*.

Step 3.

Préparation of 5-bromo-7-methylquinolin-6-ol (3D): Compound 3D was prepared following the procedure used to prépare compound ID of Example 1, except that 7-methylqumolin-6-oI (3C) was used instead of compound IC. LCMS-ESI* (m/z):

238.1,240,1 (M+H)*.

Step 4.

Préparation of 5-(4-chlorophenyl)-7-methylquinolin-6-ol (3E): Compound 3E 30 was prepared following the procedure used to préparé compound 1E of Example 1, except that $-bromo-7-methylquïnolin-6-ol (3D) was used instead of compound ID. LCMS-ESI* (m/z): 270.2, 272.2 (M+H)*.

Step 5.

Préparation of 5-(4-chlorophenyl)-7-methylquinolin-6-yl trifluoromethanesuifonate (3F): Compound 3F was prepared following the procedure used to préparé compound 1F of Example 1, except that 5-(4-chloro-phenyl)-7methyIquinoIin-6-oI (3E) was used instead of compound 1E. LCMS-ESI* (m/z): 402.0, 404.0 (M+H)*.

Step 6.

Préparation of 5-(4-chlorophenyl)-7-methyl-6-vinylquinoline (3G): Compound 3G was prepared following the procedure used to préparé compound IG of Example 1, except that 5-(4-chIoropherfyl)-7-methylquinolin-6-yl trifluoromethanesuifonate (3F) was used instead of 1F. LCMS-ESI’ (m/z): 280.2,282.2 (M+H)*.

Step 7.

Préparation of (S)-l -(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethane-l ,2-diol (3H): Compound 3H was prepared following the procedure used to préparé compound IH of Example I, except that 5-(4-chlorophenyl)-7-niethyl-6-vinyl-qumoline (3G) was used instead of compound IG. LCMS-ESI* (m/z): 314.2,316.2 (M+H)*.

Step 8.

Préparation of (S)-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yI)-2hydroxyethyl pivalate (31): Compound 31 was prepared following the procedure used to préparé compound II of Example 1, except that (S)-l-(5-(4-chlorophenyl)-7methylquinolin-6-yl)ethane-l,2-diol (3H) was used instead ofcompound IH. LCMSESI* (m/z): 398.2, 400.2 (M+H)*.

Step 9.

Préparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6yl)ethyl pivalate (3J): Compound 3J was prepared following the procedure used to préparé compound lJof Example 1, except that (S)-2-(5 -(4-chlorophenyl)-7methyIquinolin-6-y!)-2-hydroxyethyl pivalate (31) was used instead of compound II. LCMS-ESI* (m/z); 454.3,456.3 (M+H)*.

Step 10.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-7-methylqumolm-6yl)ethanol (3K): Compound 3K was prepared following the procedure used to préparé compound 1K of example 1, except that (S)-2-tert-bütoxy-2-(5-(4-chlorophenyl)-7149

C

150 methylquinolîn-6-yl)ethyl pivalate (3J) was used instead ofcompound IJ. LCMS-ESf (m/z): 370.2, 372.2 (M+H)*.

Example 4: Préparation of (S)-2-tert-butoxy-2-(8-(4-vhlorcphenyVj-6-mctliylquinolin

7-yl)acetic acid (4J).

a	Cl
Λ
O	T
,N.A/OH — Ί1Ί	^nJLob
ζΑΛ	ΑΛΑ -
4C	40

4E 4F 4G

4H

4J (S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolm-7-yl)aceticacid (4J) was prepared following the procedure used to préparé compound IL of Example 1, 10 except that (S)-2-tert-butoxy-2-(8-(4-chlorophcnyl)-6-mcthylquinoliii-7-yl)ethancl (41) was used instead of compound IK.¹ H-NMR 300 MHz, (CDjOD) δ 8.97-8.91 (m, 1H), 8.86-8.82 (m, 1H), 8.11 (s, 1H), 7.95-7.90 (m, 1H), 7.72-7.65 (m, 3H), 7.50-7.45 (m, 1H), 5.23 (s, 1H), 2.73 (s, 3H), 0.99 (s, 9H); LCMS-ESI* (m/z): [M+H]* calcd for C₂₂H_BC1NO₃: 384.9; Found: 384.1,386.1.

Préparation of (S)-2-tert-butoxy-2-(8-(4-chJorophenyl)-6-methylquinolin-7yl)ethanol (41):

Step 1.

Préparation of 8 -(4-chlorophenyI)-7-methoxv-6-methyl quinoline (4B):

Compound 4B was prepared following the procedure used to préparé compound 1E of Example 1, except that 8-bromo-7-methoxy-6-methylquinoline (4A) was used instead of compound ID. LC MS-ES F (m/z): 284.2,286.2 (M+H/.

Step 2.

Préparation of 8-(4-chlorophenyl)-6-methylquinolin-7-ol (4C): Compound 4C was prepared following the procedure used to préparé compound IC of Example 1, except that 8-(4-chlorophenyl)-7-methoxy-6-methylquinoline (4B) was used instead of compound IB. LCMS-ESÏ* (m/z): 270.2,272.2 (M+H)⁺.

Step 3.

Préparation of 8-(4-chlorophenyl)-6-methylquinolin-7-yl trifluoromethanesulfonate (4D): Compound 4D was prepared following the procedure used to préparé compound 1F of example I, except that 8-(4-chloro-phenyl)-6methylquinolin-7-ol (4C) was used instead of compound 1E. LCMS-ESI’ (m/z): 402.0,

403.9 (M+H/.

Step 4.

Préparation of 8-(4-chlorophenyl)-6-methyt-7-vmylquinoline(4E): Compound

4E was prepared following the procedure used to préparé compound IG of Example 1, except that 8-(4-chlorophenyl)-6-methylquinolin-7-yl trifluoromethanesulfonate (4D) was used instead of compound 1F. LCMS-ESI⁺ (m/z): 280.2, 282.2 (M+H/. Step 5.

Préparation of (S)-1 -(8-(4-chloropheny l)-6-methylqumolin-7-yl)ethane-1,2-diol (4F): Compound 4F was prepared following the procedure used to préparé compound IH of Example 1, except that 8-(4-chlorophenyl)-6-methyl-7-vinyl-quinoline (4E) was used instead of compound IG. LCMS-ESf (m/z): 314.1, 316.1 (M+H/.

Step 6.

Préparation of (S)-2-(8-(4-chlorophenyi)-6-methylquinolin-7-yl)-2hydroxyethyl pîvalate (4G): Compound 4G was prepared following the procedure used to préparé compound II of example 1, except that (S)-l-(8-(4-chlorophenyl)-616294

C )52 methy!quinolin-7-yl)ethane-l,2-dibl (4F) was used instead of compound 1H. LCMSESI* (m/z): 398,2,400,2 (M+H)*.

Step 7.

Préparation of (S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-75 yl)ethyl pivalate (4H): Compound 4H was prepared following the procedure used to préparé compound IJ of example l, except that (S)-2-(8-(4-chlorophenyl)-6methylquinoIin-7-yl)-2-hydroxyethyl pivalate (4G) was used instead of compound II. LCMS-ESI* (m/z): 454,3, 456.3 (M+H)*.

Step 8.

Préparation of (S)-2-tert-butoxy-2-(8-(4-chloTOplienyl)-6-methylquinolin-7yl)ethanol (41): Compound 41 was prepared following the procedure used to préparé compound 1K of Example I, except that (S)-2-teit-butoxy-2-(8-(4-chlorophenyl)-6methylquinolin-7-yl)ethyl pivalate (4H) was used instead of compound IJ. LCMS-ESf (m/z): 370.2, 372.1 (M+H)*.

Example 5: Préparation of (S)-2-tert-butoxy-2-((S)-5-{2,4-dichlorophenyI)-2,7dimethylquinolin-6-yI)acetic acid (SJ).

1t>3

To a stirred solution of (S)-ethyl 2-tert-butoxy-2-((S)-5-(2,4-dichlorophenyl)-

2,7-diinethylquinolin-6-yl)acetate (SI) (15 mg as TFA sait, 0.027 mmol) in THF and methanol (3 mL/Ι mL) was added 1 M NaOH solution (1 mL, excess) at 0 °C. The mixture was stirred at 50 ^CC for 4 hours and diluted with water. The mixture was

extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by Prep-HPLC to provide the desired isomer of 5J as a TFA sait (l 1 mg, 77%). 'H-NMR 300 MHz, (CD₃OD) δ

8.14 (d, IH), 8.03 (s, IH), 7.74 (d, IH), 7.72 (d, IH), 7.52 (dd, IH), 7.25 (d, IH), 5.36 (s, 1 H), 2.96 (s, 3H), 2.90 (s, 3H), 1.11 (s, 9H); LCMS-ESf (m/z): [M+H]⁺ calcd for

C2ÎH24CI2NO3: 433.3; Found: 432.1, 434.1.

The (S,R) isomer of 5J was obtained using the same procedure described above except that the (S,R) isomer of SI was used in the reaction. ’H NMR 300 MHz, (CD3OD) δ 8.18 (d, 1H), 7.99(s, IH), 7.80 (d, JH), 7.77 (d, IH), 7.73 (d, IH), 7.6610 7.62 (m IH), 5.17 (s, IH), 2.95 (s, 3H), 2.80 (s, 3H), 1.05 (s, 9H); LCMS-ESf (m/z):

[M+H]⁺ calcd for C_2ÎH24C1₂NO₃:433.3; Found: 432.1,434.1

Préparation of (S)-ethyl 2-tert-butoxy-2-((S)-5-(2,4-dîchlorophenyl)-2,7dîmethylquinolin-6-yl)acetate (SI):

Stepl.

Préparation of 5-bromo-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate (SA): Compound SA was prepared following the procedure used to prépare compound 1F of Example 1, except that 5-bromo-2,7-dimethyIquinolin-6-ol (2C) was used instead of compound IE. LCMS-EST (m/z): 383.9,385.9 (M+H)⁺.

Step 2.

Préparation of 5-bromo-2,7-dîmethyl-6-vinylquinoline (SB): PdCl₂(PPh₃)2 (207 mg, 0.30 mmol) was added to a mixture of 5-bromo-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate (SA) (1.13 g, 2.95 mmol), tributyl(vinyl)stannane (0.95 mL,

3.25 mmol) and lithium chloride (375 mg, 8.85 mmol) in DMF (30 mL). The reaction 25 mixture was flushed with argon, heated at 80 °C for 4 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with NaHCO₃ solution, water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide 5B (678 mg, 88%). LCMS-ESf (m/z): 262.1,264.1 (M+H)⁺.

Step 3.

Préparation of(S)-l-(5-bromo-2,7-dimelhylquinolin-6-yl)ethane-l,2-diol (SC): Compound 5C was prepared following the procedure used to préparé compound IH of

Example l, except that 5-bromo-2,7-dimethy!-6-vinylquinoline (SB) was used instead of compound IG. LCMS-ESI⁺ (m/z): 296.1,298.1 (M+H)⁺.

Step 4.

Préparation of (S)-2-(5-bromo-2,7-dimethyIquinolm-6-yl)-2-hydroxyethyl pivalate (5D): Compound 5D was prepared following the procedure used to préparé compound II of Example I , except that (S)-l-(5-bromo-2,7-dimethylqumolin-6yl)ethane-I,2-diol (5C) was used instead of compound IH. LCMS-EST (m/z): 380.2,

382.2 (M+H)⁺.

Step 5.

Préparation of (S)-2-(5-bromo-2,7-dimethylquinoIin'6-yl)-2-tert-butoxyethy] pivalate (5E): Compound 5E was prepared following the procedure used to préparé compoundl J of Example l, except that (S)-2-(5-bromo-2,7-dimethylquinolin-6-y')-2hydroxyethyl pivalate (5D) was used instead compound II, LCMS-ESf (m/z): 436.2,

438.2 (M+H)⁺.

Step 6.

Préparation of (S)-2-(5-bromo-2,7-dimethylquinol in-6-y l)-2-tcrt-butoxyethanol (5F): Compound 5F was prepared following the procedure used to préparé compound 1K of Example I, except that (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tertbutoxyethyl pivalate (5E) was used instead of compound 1 J. LCMS-ESI* (m/z): 352.2,

354.2 (M+H)⁺.

Step 7.

Préparation of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid (5G): Compound SG was prepared following the procedure used to préparé compound IL of Example 1, except that (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2tert-butoxyethanol (5F) was used instead of compound 1K LCMS-ΕδΓ (m/z): 366.1,

368.1 (M+H)⁺.

Step 8.

Préparation of (S)-ethy 1 2-(5-bromo-2,7-djmcthylq’jinolin-6-yl)-2-tertbutoxyacetate (5H): To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6yl)-2-tert-butoxyacetic acid (5G) (180 mg, 0.49 mmol) in DMF (15 mL) was added césium carbonate (321 mg, 0.98 mmol) at 0 °C. After being stirred for 10 min iodoethane (0.059 mL, 0.74 mmol) was added. The mixture was stirred at room

56 température for 2 hours and quenched by the slow addition of a NaHCO₃ solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography to give the pure product 5H (168 mg, 87%). LCMS-ESÎ (m/z). 394.1,396.1 (M+Hf Step 9.

Préparation of (S)-ethyl 2-tert-butoxy-2-((S)-5-(2,4-dichIorophenyl)-2.7dimethylquinolin-6-yl)acetate (51); Pd₂(dba)₃ (3.5 mg, 0.006 mmol) was added to a mixture of (S)-ethyl 2-(5-bromo-2,7-dimethylqumolin-6-yl)-2-tert-butoxyacetate (5H) (24 mg, 0.061 mmol), 2,4-dichlorophenylboronic acid (23 mg, 0.12 mmol), 2dicyclohexylphosphino-2’,6’-dimethoxybiphenyI (“Sphos, 5 mg, 0.012 mmol) and K3PO4 (39 mg, 0.18 mmol) intoiuenc (1.5 mL). The réaction mixture was flushed with argon, heated at 110 °C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO₃solution, water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The obtained residue was purified by prep-HPLC to provide two isomers of 51 as white solids. Each was obtained as aTFA sait (desired (S,R)enantiomer:18 mg, 53%). LCMS-ESI⁺ (m/z): 460.2,462.2 (M+H)⁺.

Example 6: Préparation of (S)-2-tert-butoxy'2-((R)-5-{2,3-dihydropyrano[4,3,2de]quinoIin-7-yI)-2,7-dimethylquinolin-6-yl)acetic acid (6D).

(S)-2-tert-butoxy-2-((R)-5-(2₎3-dÎhydropyrano[4,3,2-de]qumolin-7-yl>2,7dimethylquinolin-6-yl)acetic acid (6D) was prepared following the procedure used to préparé compound IL of Example 1 except that (2S)-2-tert-butoxy-2-(5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-dimethylquinolin-6-yl)ethanol (6C) was used instead of compound IK. ’H-NMR 300 MHz, (CD-,OD) δ 8.59 (d, IH), 8.05 (s, IH), 7.94 (d, IH), 7.65 (d, IH), 7.54 (d, IH), 7.48 (d, IH), 7.27 (d, IH), 5.25 (s, IH), 4.70-4.55 (m, 2H), 3.52-3.45 (m, 2H), 2.90 (s, 3H), 0.91 (s, 9H); LCMS-ESI* (m/z); [M+H]⁺ calcd for 457.5; Found: 457.1.

Préparation of (2S)-2-tert-butoxy-2-(5-(2,3-dihyiropyrano[4,3,2-de]quinolin-7y 1)-2,7-dimethylquinolin-6-yI)ethanol (6C):

Step 1.

Préparation of(2S)-2-tert-butoxy-2-(5-(2,3-dihyiropyrano[4,3,2-de]quinolin-7yl)-2,7-dimethylquinoIin-6-yl)ethyl pivalate (6B); Pd(P?h₃)₄ (4 mg, 0.0037 mmol) was added to a mixture (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (5E) (16 mg, 0.037 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (6A) (23 mg, 0.073 mmol) and K₂COj (0.083 mL 2 M in water,

1.66 mmol) in 1,2-dimethoxyethane (2 mL). The reaction mixture was flushed with nitrogen, microwaved at 120 °C for 90 min and the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with NaHCO; solution, water and brine, dried over Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by prep-HPLC to provide 6B as a white solid (4 mg as TFA sait, 18%). LCMS-ESf (m/z); 527.3 (M+H)⁺.

Step 2.

Préparation of (2S)-2-tert-butoxy-2-(5-(2,3-dihydropyrajio [4,3,2-de]quinolin-7yl)-2,7-dimethylquinolin-6-yl)ethanol (6C): Compound 6C was prepared following the 10 procedure used to préparé compound 1K of Example 1 except that (2S)-2-tert-butoxy2-(5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-dimethylquinolin-6-yl)cthyi pivalate (6B) was used instead of compound 1 J. LCMS-ESf (m/z): 433.3 (M+H)*.

Example 7: Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-215 (trifluoromethyl)quinolin-6-yl)acetic acid (7J).

159

7J (S)-2-tert-Butoxy-2-(5-(4-chloropheny])-7-methyl-2-(trifluoroinethyl)quinolin6-yl)acetic acid (7J) was prepared following the procedure used to préparé compound IL of Example 1 except that (S)--2-iert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-25 (trifluoromethyl)quinolin'6-yl)ethanol (71) was used instead of compound 1 K. ^]HNMR 300 MHz, (CD₃OD) δ 8.01(s, IH), 7.95 (d, IH), 7.71 (d, IH), 7.65-7.55 (m, 2H),

7.35 (d, IH), 5.24 (s, IH), 2.71 (s, 3H),0.99 (s, 9H); LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₃H22C1F₃NO₃:452.9; Found; 452.1,454.1.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-7-methyl-2(trifluoromethyl)qui noIin-6-yl)ethanol (71);

Step 1.

Préparation of 5-bromo-7-methyl-2-(trifliioroniethyl)quinolin-6-ol (7B): Compound 7B was prepared following the procedure used to préparé compound IC of

Example l, except that 5-bromo-6-methoxy-7-{nethyl-2-(trifluoromethyl)quinoline (7A) was used instead of compound IB. LCMS-ESf (m/z): 306.1, 308.1 (M+H)⁺. Step 2.

Préparation of 5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl trifluoromethanesulfonate (7C)‘. Compound 7C was prepared following the procedure used to préparé compound 1F of Example 1 except that 5-bromo-7-methyl-2(trifluoromethyi)quinolin-6-ol (7B) was used instead of compound 1E. I CMS-ESI' (m/z): 437.8,439.8 (M+H)⁺.

Step 3.

Préparation of 5-bromo-7-methyi-2-(trifluoromethyl)-6-vinylquinoline (7D): Compound 7D was prepared following the procedure used to préparé compound SB of Example 5, except that 5-bromo-7-methyl-2-(trifluoromethyI)quinolin-6-yl trifluoromethanesulfonate (7C) was used instead of compound 5A. LCMS-ESE (m/z):

316.1,318.1 (M+H)⁺.

Step 4.

Préparation of (S)-l-(5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6yl)ethane-l,2-diol (7E): Compound 7E was prepared following the procedure used to préparé compound IH of Example 1, except that 5-bromo-7'inethyl-2(trifluoromethyl)-6“Vinylquinoline (7D) was used instead 7of compound IG. LCMSESI⁺ (m/z): 350.1,352.1 (M+H)⁺.

Step 5.

Préparation of (S)-2-(5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl)-2hydroxyethyl pivalate (7F): Compound 7F was prepared following the procedure used to préparé compound Π of Example 1 except that (S)-l-(5-bromO'7-methyl-2(trifluoromethyl)quinolin-6-yl)ethane-l,2-diol (7E) was used instead of compound IH. Step 6.

Préparation of(S)-2-(5-bromo-7-methyl-2-(trifluoroniethyl)qumolin-6-yl)-2tert-butoxyethyl pivalate (7G): Compound 7G was prepared following the procedure used to préparé compound IJ of Example I except (S)-2-(5-bromû-7-methyl-2(trifluoromethyl)quinolin-6-yl)-2-hydroxyethyl pivalate (7F) was used instead of compound II. LCMS-ESI* (m/z): 490.2,492.2 (M+H)⁺.

Step 7.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(trifluoromethyl)quinolin-6-yl)ethyl pivalate (7H): Compound 7H was prepared following the procedure used to préparé compound IE of Example l except that (S)-2(5-bromo-7-methyl-2-(trifluoromethyl)qumolin-6-yl)-2-tert-butoxyethyl pivalate (7G) 5 was used instead of compound 1D. LCMS-ESI⁴ (m/z): 522.2, 524.2 (M+H)⁴.

Step 8.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(trifluoromethyl)quinolin-6-yl)ethanol (71): Following the procedure used to préparé compound 1K of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-710 methyl-2-(trifluoromethy])quinolin-6-yl)ethyl pivalate (7H) was used instead of compound IJ. LCMS-ESI⁺ (m/z): 438.2,440.2 (M+H)⁴.

Example 8: Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-

1,2-dihydroquinolin-6-yl)acetic acid (8L).

A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (l l .4 g, 50.0 mmol) and chromium trioxide (23 mg, l .2 mol %) in wet acetonitrile (0.75% II₂O) to a volume of 114 mL. This stock solution (0.40 mL) was added to a solution of (S)-6-(l-tert-butoxy-2-hydroxyethyl)-5(4-chlorophenyI)-7-methylquinolin-2(lH)-one (8K, 4.4 æg) in wet acetonitrile (1.5 mL, 0.75% H₂O) at 0 °C. After stirring for 60 min at 0 °C, the reaction was quenched with

1.5 Μ K₂HPO₄ solution and extracted with ethyl acetate(2x). The combined organic layer was washed with 1:1 brine/H₂O (2x), saturated NaUSOj/brinc. and was dried (MgSO₄). Concentration and purification by prep-HPLC gave (S)-2-tert-butoxy-2-(5

C

163 (4-chlorophenyl)-7-methyl-2-oxo-l,2-dihydroquinolin-6-yl)acetic acid (8L) (2 mg). ’HNMR 300 MHz, (CDjOD) δ 7.56-7.53 (3 H, m), 7.35 (1 H, d, J = 9.7 Hz), 7.28 (1 H, d, J = 8.2 Hz), 7.22 (1 H, s), 6.43 (1 H, d, J = 9.8 Hz), 5.06 (1 H, s), 2.55 (3 H, s), 0.95 (9 H, s). LCMS-ESI* (m/z): [M+H]* calcd for CaHaCINO,: 400.9; Found: 400.2; LCMS-ESI' (m/z): [M-H]' calcd for C₂₂H₂₁C1NO4:398.9; Found: 397.9.

Préparation of (S)-6-( l-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7methylquinolîn-2(lH)-one (8K):

Step 1,

Préparation of 4-methoxy-3-methylaniline (SB): To the solution of 1-methoxy-

2- methyl-4-nitrobenzene (10 g, 60 mmol) in EtOH and EtOAc (250 mL, 3:2) was added 10% Pd/C (2 g). The mixture was stirred for 24 h under one atmosphère of hydrogen. Celite was added and the mixture was stirred for 10 min. The mixture was filtered through a pad of celite. Concentration under reduced pressure gave 4-methoxy-

3- methyIaniline (8B) (8.2 g). LCMS-ESI* (m/z): 138.2 (M+H)*.

Step 2.

Préparation of 6-methoxy-7-methylquinoline (3B): To 4-methoxy-3methylaniline (6.7 g) was added concentrated H₂SO4(12.4mL), followed by glycerin (21.1 g), m-nitrobenzenesulfonic acid (6.53 g), H3BO3 (3.4 g) and FeSÛ4*7H₂O (3.2 g). The mixture was stirred at 140 °C for 1 h. The reaction was cooled to 25 °C, quenched with ice-water and neutralized with 30% KOH. The mixture was extracted with DCM (2x), and the combined extracts dried with Na₂SO4 and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc) to give 6-methoxy-7methylquinoline (4.3 g) LCMS-ESI* (m/z): 174.1 (M+H)*.

Step 3.

Préparation of 5-bromo-6-methoxy-7-methylquinolîne (SC) : To the solution of 6-methoxy-7-methylquinoline (4.28 g, 24.6 mmol) in 50 mL of concentrated H₂SÛ4 was added NBS (4.41 g, 14.6 mmol) at 15 °C, and the reaction was stirred at 15 °C for

3.5 hours. The réaction mixture was poured into ice-water (600 mL). Theaqueous mixture was adjusted with a 50% KOH solution to pH -10, and then extracted with

DCM (3X). The combined extract was dried with sodium sulfate. Concentration under reduced pressure gave 5-bromo-6-methoxy-7-methylquinoline (6.3 g). LCMS-ESI' (m/z): 252.1,254.1 (M+H)*.

Step 4.

Préparation of 5-bromo-7-methylquinolin-6-ol (3D): To the solution of 5bromo-6-methoxy-7-methylquinoline (6.5 g, 25.8 mmol) in DCM (150 mL) was added BBr₃ slowly (77.3 mL, 1.0 M in DCM, 77.3 mmol). The mixture was stirred for 3 hours and cooled to 0 °C. Methanol (40 mL) was added slowly and the mixture was stirred for 20 minutes. The solvents were removed under reduced pressure. The solid was dissolved in methanol (100 mL) and was treated with 1.0 N sodium hydroxide solution (50 mL) (pH~ 12). The mixture was stirred for 12 hours and acetic acid was added to adjust pH to between 4-5. The mixture was fîltered and washed with water. The gray solid was dried under reduced pressure to give 5-bromo-7-methylqumolin-6ol (5.0 g). LCMS-ESI* (m/z): 238.2, 240.1 (M+H)*, 236.1, 238.0 (M-H).

Step 5.

Préparation of 5-bromo-7-methylquinolîn-6-yl trifluoromethanesulfonate (8D): To the solution of 5-bromo-7-methylquinolin-6-ol (238 mg, 1.0 mmol) in dichloromethane (10 mL) and pyridine (2 mL) was added Tf₂O (0.34 mL, 2.0 mmol) at -30 °C. The mixture was stirred and warmed to 0 °C over a period of2 hours. The réaction was quenched with slow addition of NaHCOj solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate. LCMS-ESI* (m/z): 369.9, 371.9 (M+H)*. Step 6.

Préparation of 5-bromo-7-methyl-6-vinylquinoline (SE): A mixture of 5-bromo7-methylquinolin-6-yl trifluoromethanesulfonate (230 mg, 0.62 mmol), tributyl(vinyl)stannane (200 pL, 0.68 mmol), lithium chloride (78 mg, 1.86 mmol) and PdCl₂(PPh₃)₂ (43 mg) in DMF (10 mL) was heated at 80 °C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO₃ solution, water and brine, dried over Na₂SO<f, fîltered and concentrated in vacuo. The residue was purified by flash chromatography

165 (hexanes/EtOAc) to provide 5-bromo-7-methyl-6-vinyIquinoIine ( 120 mg). LCMSESf (m/z): 248.2, 250.2 (M+H)⁺.

Step 7.

Préparation of (S)-l-(5-bromo-7-methylquinolm-6-yl)ethane-l,2-diol (8F):

AD-mix-a (0.7 g) was added to a mixed solvent of t-butanol and water (2.5 mL/2.5 mL) and stirred at 25 °C for 5 min, cooled to 0 °C. The mixture was transferred to another flask containing 5-bromo-7-methyl-6-vinylquinoline (I20 mg) and stirred at 0 °C for 48 hours. The mixture was diluted with ethyl acetate, washed with NaHCO; solution, water and brine, dried over NajSCh, filtered and concentrated in vacuo. The 10 residue was purifîed by flash column chromatography (EtOAc) to provide (S)-l -(5bromo-7-methyIquinolin-6-yi)ethane-l,2-diol (118 mg). LCMS-ESf (m/z): 282.1,

284.1 (M+H)⁺.

Step 8.

Préparation of (S)-2-(5-bromo-7-methylquinolin*6-yl)-2-tert-butoxyethyl pivalate (8G): To a stirred solution of (S)-l-(5-bromo-7-methylquinolin-6-yl)ethane-

1,2-diol (118 mg, 0.42 mmol) in dichloromethane (5 mL) and pyridine (1 mL) was added trimethylacetyl chloride (100 pL, 0.84 mmol) at 0 °C. The mixture was stirred at room température for 12 hours, quenched with slow addition of NaHCO₃ solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO4. Concentration gave the intermediate (124 mg) m/z 366.1,368.1 (M+H)⁴. To the solution of above intermediate (124 mg, 0.34 mmol) in t-butylacetate (3 mL) was added 70% perchloric acid (67 uL, 1.1 mmol) at 25 “C. The mixture was stirred at 25 °C for 2 hours, quenched with slow addition of NaHCO₃ solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purifîed by flash chromatography (hexanes/EtOAc) to provide (S)-2-(5-bromo-7-methylquinoIin-6-yl)-2-tert-butoxyethyl pivalate (133 mg). LCMS-ESf (m/z): 422.1, 424.2 (M-H)*.

Step 9.

Préparation of (S)-2-(2-acetoxy-5-bromo-7-methylquinolin-6-yl)-2-tert30 butoxyethyl pivalate (8H): To the solution of (S)-2-(5-bromo-7-methylquinolin-6-yl)2-tert-butoxyethyl pivalate (130 mg, 0.31 mmol) in DCM (2 mL) was added mCPBA (70%, 95 mg, 0.39 mmol). The mixture was stirred for 12 hours. The mixture was

diiuted with EtOAc, washed with saturated sodium bicarbonate solution, water and · brine, and dried over sodium sulfate. Concentration under reduced pressure gave the intermediate N-oxide (147 mg). LCMS-ESI* (m/z): 438.2,440.2 (M+H)*. To the above intermediate was added acetic anhydride (5 mL). The mixture was heated at 140 °C for

10 hours. The excess reagents were removed under reduced pressure. The mixture was diiuted with EtOAc, washed with saturated sodium bicarbonate solution, water and brine, and dried over sodium sulfate. Concentration gave (S)-2-(2-acetoxy-5-bromo-7methylquinoIin-6-yl)-2-tert-butoxyethyl pivalate (130 mg). LCMS-ESI* (m/z): 480.0, 482.0 (M+H)*.

Step 10.

Préparation of (S)-2-(5-bromo-7-methyl-2-oxo-l,2-dihydroquinolin-6-yl)-2-tertbutoxyethyl pivalate (81): To the solution of (S)-2-(2-acetoxy-5-bromo-7methyIquinolin-6-yl)-2-tert-butoxyethyl pivalate (130 mg) in éthanol (7.5 mL) was added aqueous methyl amine solution (0.5 mL, 50%). The mixture was heated at 78 °C for 80 min. Concentration and purification gave (S)-2-(5-bromo-7-methyl-2-oxo-l,2dihydroquinolin-6-yI)-2-tert-butoxyethyl pivalate (68 mg). LCMS-ESI* (m/z): 438.2,

440.2 (M+H)*.

Step 11.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-l ,220 dîhydroquinolin-6-yl)ethyl pivalate (8J): The mixture of (S)-2-(5-bTomo-7-methyl-2oxo-l,2-dihydroquinoIin-6-yl)-2-tert-butoxyethyl pivalate (34 mg, 0.078 mmol), Pd(PPh₃)₄ (9 mg), 4-chlorophenylboronic acid (16 mg, 0.1 mmol), aqueous K₂CO₃solution (0.15 mL, 2 M, 0.3 mmol) in 1,2-dîmethoxyethane (2 mL) was heated at 100 °C for 90 minutes. The residue was diiuted with ethyl acetate (100 mL), washed with

NaHCOj solution, water and brine, dried over NajSO^ Concentration and purification gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-l,2-dihydroquinolin-6yl)ethyl pivalate (22 mg). LCMS-ESI* (m/z): 470.3 (M+H)*.

Step 12.

Préparation of (S)-6-(l -tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-730 methylquinolin-2(lH)-one (8K): To the solution of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-oxo-l,2-dihydroquinolin-6-yl)ethyl pivalate (5.8 mg) in THF and méthanol (1.5 mL/0.5 mL) was added 1 M NaOH solution (0.6 mL). The mixture d

C

167 was stirred at 25 °C for 16 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Concentration gave (S)-6-( i-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7methylquînolin-2(lH)-one (4.4 mg). LCMS-ESI⁺ (m/z): 386.2 (M+H)⁺.

Example 9: (S)-2-tert-butoxy-2_r(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7 methylquinolin-6-yl)acetic acid (9).

mCPBA chloroform 0°C, th (S)-2-(5-bnomo-2,7-dimethytquinolin-6-yl)2-fer/-butoxyethyl pivalate

PhSOjCI toluene 110°C1h (S)-54womQ-6-(1-fert-but0xy2-(pivaloylcxy}ethyl)-2,7dimethykjuinoiine 1-oxîde

NHMe₂methanol

Pd{PPhj)₄

K₂CO₃ 2M

DME, 110 °C

Cl

8(OH)₂ (S)-2-(5-bronio-2-(chloromethyl)7-methy1quinolin-8-yl)-2-terf· butoxyethyt pivalate (S)-2-(5-bromo-2((di m ethyla min o)methy l)-7-m eth y Iquinolîn6-yi)-2-ter i-butoxy ethyl pivalate

chforciphenyl).2((dimethyla mino}methy I) -7methylquinolin-6-yl) ethyl pivalate

(S)‘2-fert-butoxy-2-[5-(4-chlOK>phenyl)2-((dim ethyl ami no) methyl)-7fnethylquinolin-6-yl)ethanol

Préparation of (S)-5-bromo-6-(l -tert-butoxy-2-(pivaloyloxy)ethyl)-2,7dimethylquinoline l -oxide: To a .stirred solution of (S)-2-(5-bromo-2,7dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (SE) (118 mg, 0,31 mmol) in chloroform (5 mL) was added mCPBA (209 mg, 77%, 0.93 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour before quenched with NaHCO₃ solution. The mixture was extracted with DCM (30 mL), washed with NaHCOj solution, water and brine, dried over Na₂S€>4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (52 mg, 37%). LCMS-ESI* (m/z):

452.1,454.1 (M+H)*.

Préparation of (S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6yI)-2-tert-butoxyethyl pivalate: To a stirred solution of(S)-5-bromo-6-(l-tert-butoxy-2(pivaloyloxy)ethyl)-2,7-dimethylquinoline 1-oxide (25 mg, 0.055 mmol) in toluene (3 mL) was added benzenesulfonyl chloride (0.06 mL, 0.24 mmol). The mixture was stirred at 110 °C for 16 hours, then cooled to room température. Dimethylamine (2 mL 2 M solution in méthanol, excess) was added. The mixture was stirred at room température for 16 h, then diluted in ethyl acetate (30 mL), washed with NaHCO₃solution, water and brine, dried over Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a white solid (II mg, 42%). LCMS-ESI* (m/z): 479.3,481.3 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2((dÎmethylamino)methyl)-7-methylqumoTin-6-y))ethyl pivalate: Pd(PPh₃)4 (2.5 mg, 0.002 mmol) was added to a mixture (S)-2-(5-bromo-2-((dimethylammo)methyl)-7methylquinoim-6-yl)-2-tert-butoxyethyl pivalate (11 mg, 0,023 mmol), 425 chlorophenylboronic acid (7 mg, 0.046 mmol), K₂CO₃ (0.06 mL 2 M in water, 0.13 mmol) in 1,2-dimethoxyethane (1 mL). The reaction mixture was flushed with nitrogen, heated at 110 °C for 30 min under microwave, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO] solution, water and brine, dried over Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a white solid (5.6 mg, 48%). LCMS-ESI* (m/z): 511.3,513.3 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2((dimethylamino)methyl)-7-methylquinolin-6-yi)ethanol: To a stirred solution of (S)-2tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-inethylquinolin-âyl)ethyl pîvalate (5.6 mg, 0.011 mmol) in THF and methanol (l .5 mL'0.5 mL) was added 2 M NaOH solution (0.5 mL, excess) at 0 °C. The mixture was stirred at 50 °C for 3 hours, diluted with water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by prep-HPLC to provide the desired product (3.0 mg, 64%). LCMS-ESI* (m/z): 427.3,429.2 (M+H)⁺.

Préparation of (S)-2-tert-butoxy-2-(5-(4-ch]orophenyl)-2((dimethy!amino)methyl)-7-methylquinolin-6-yl)acetic acid (9): A stock solution of periodic acïd/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (l L4 g, 50.0 mmol) andchromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H₂O) to a volume of 114 mL. This stock solution (0.50 mL) was added to a solution of (S)-2-tcrt-butoxy-2-(5-(4<hiorophcnyl)-2((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol (3 mg, 0.007 mmol) in wet acetonitrile (2.0 mL, 0.75% H₂O) at 0 °C. Reaction mixture was stirred for 30 minutes at 0 °C and quenched with NaHCO₃ solution. Ethyl acetate was added and organic layer separated and washed with l:l brine/H₂O (2x), then saturated NaHSO₃ /brine. The organic layer was dried (MgSCh), concentrated and purified by reverse phase HPLC to give the product as TFA sait (2.5 mg, 81%). ’H-NMR 300 MHz, (CD₃OD) 5

7.97 (s, lH), 7.78 (d, IH), 7.65-7.55 (m, 3H), 7.40-7.30(m, 2H), 5.22 (s, IH), 4.65 (s, 2H), 3.04 (s, 6H), 2.68 (s, 3H), 0.98 (s, 9H); LCMS-ESf (m/z): [M+H]⁺ calcd for C₂₅H₂9C1N₂O₃: 441.9; Found: 441.2,443.3.

Example 10: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyI)~7-methyl-2((methylamino)methyl)quinolin-6-yl)acetic acid (10).

170

(S>2-(5-bromo-2,7dimethylquinotin-6-yl)-2tert-butoxyethyl pîvalate (S)-2-terf-butoxy-2-(5-(4· chlorophenyf)-2,7' dimethylquinolin-6-yl)ethyl pîvalate mCPBA chloroform 0 °C,1h

1. PhSO₂CI toluene 11O^QC1h _t

2. NH₂Me methanol

2N NaOH THF/MeOH (S)-6-(1 -tert-butoxy-2(pivaloyioxy)ethyl)-5-(4chlorophenyl)-2,7dimethylquinoline 1-oxide (S)-2-tert-butoxy-2-(5-(4chlorophBnyt)-7-methyl-2((methylamino)methyt)quin ol in-6-yl)ethyl pîvalate

(S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyt-2((metbylamino)methyi)qui nolin-6-yl)ethanol (S)-2-fert-butoxy-2-(5-(4chloropheny()-7-methyl-2((methylamir»)nnethyl)quin olin-e-yllacetic acid

Préparation of (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-65 yl)ethyl pîvalate: Pd(PPh₃)4 (69 mg, 0.06 mmol) was added to a mixture (S)-2-(5bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyI pîvalate (5E) (325 mg, 0.75 mmol), 4'Chlorophenylboronic acid (175 mg, 1.1 mmol), K₂CO₃ (1.3 mL 2 M in water,

2.6 mmol) in 1,2-dimethoxyethane (10 mL). The reaction mixture was flushed with nitrogen, heated at 110 °C for 30 min under microwave, and then the volatile

component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO₃ solution, water and brine, dried overNa₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (256 mg, 73%). LCMS-ESI* (m/z): 468.3, 469.3 (M+H)*.

Préparation of (S)-6-(l-tert-Butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-

2,7-dimethyIquinoline l-oxide: Following the procedure used to préparé compound (S)-

5- brcmo-6-(l-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-djmethylquÎnoline l-oxide of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-

6- yl)ethyl pivalate was used instead of (S)-2-(5-bronio-2,7-dimethylquinoliri-6-yl)-2- tert-butoxyethyl pivalate. LCMS-ESI* (m/z): 484.3,486.3 (M+H)⁺.

Préparation of (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2((methylamino)methyl)quinolin-6-yl)ethyl pivalate: Following the procedure used to préparé compound (S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)2-tert-butoxyethyl pivalate of Example 9, except that (S)-6-(l-tert-butoxy-215 (pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline l-oxide was used instead of (S)-5-bromo-6-(l -tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline l oxide, and methylamine solution was used instead of N,;V-dimethylamine solution. LCMS-ESI* (m/z): 497.3,499.3 (M+H)*.

Préparation of (Sj-Z-tert-Butoxy^-ÎS-^-chlorophenylX-methyl^20 ((methylamino)methyI)quinolin-6-yl)ethanol; Following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)niethyl)-7methylquinolin-6-yl)ethanol of Example 9, except that(S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-((methylaniino)methyl)quinolin-6-yI)ethyl pivalate was used instead of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-725 methylquinoIin-6-yl)ethyi pivalate. LCMS-ESI* (m/z): 4I3.3,415.3 (M+H)*.

Préparation of (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2((methylamino)methyl)quinolin-6-yl)acetic acid (10): Following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-230 ((dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid (9) of Example 9, except that (S)-2-tert-butoxy-2 -(5-(4-chlorophenyl)-7-methyl-2((methylamino)methyl)quinolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-

I72 (5-(4-chlorophenyl)-2-((diinethylamino)methyI)-7-methylqumolin-6-yl)ethanoi. ’HNMR 300 MHz, (CDîOD) δ 7.95 (s, IH), 7.74 (d, IH),7.65-7.55 (m, 3H), 7.35-7.28 (m, 2H), 5.22 (s, IH), 4.51 (s, 2H), 2.88 (s, 3H), 2.67 (s, 3H), 0.98 (s, 9H); LCMS-ESI* (m/z): [M+H]* calcd for C24H27CIN2O3: 427.9; Found:427.2,429.2.

Example 11 : (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-lylmethyl)quinolin-6-yl)acetîc acid: (11).

(S)-6-(1 -Îert-butoxy-2(p rvaloyloxy Je thy 1)-5-(4chloropheny()-2,7dimethylquinoiine 1-oxide

1. PhSO₂CI totuene

110 ^eC 1h _r

2. MeOH

O-

(S)-2-tert-butoxy-2-(5-(4chlorophenylJ-T-methyW-Îpiperidin1 -ylmethy0quinolin-6-yl)ethana!

(SJ-2-terf-butoxy-2-(5-(4ctilorophenyl)-7-methyl-2(piperidin-1-ylmethyl)quinolri-6yljethyl pivalate

(S)-2-fert-buloxy'2-(5(+ chlorophenyl)-7-methyl-2-(piperidin1 -ylmethy ijiquînol i n-6-y IJacetic acid

Préparation of (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin1 -ylmethyl)quinolin-6-yl)ethyl pivalate: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7methyl-2-(piperidin-l-ylmethyl)quinolin-6-yl)ethyl pivalate was prepared following the procedure used to préparé compound (S)-2-(5-bromo-2-((dimethyIamino)methyl)-7methylquinolin-6-y!)-2-tert-butoxyethyl pivalate ofExample 9, except that (S)-6-(l15 tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide was used instead of (S)-5-bromo-6-(l-tert-butoxy-2-(pivaloyloxy)ethyl )-2,7dimethylquinoline 1-oxide, and piperidîne was used instead of AW-dimethy lamine solution. LCMS-ESI* (m/z): 551.3, 553.3 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1 ylmethyI)quinolin-6-yl)ethanol: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(piperidin-l-ylmethyl)quinolin-6-yl)ethanol was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-25 ((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol of Example 9, except that (S)2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-l-ylmethyl)qumolîn-6yl)ethyl pivalate was used Înstead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2((dimethylanûno)methyl)-7-methylquinolin-6-yl)ethyl pivalate. LCMS-ESf (m/z):

467.4, 469.3 (M+H)*.

ί 0 Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidm-1 ylmethyl)quinoIin-6-yl)acetic acid (11): (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7methyl-2-(piperidin-l-ylmethyl)quinolin-6-yi)acetic acid was prepared following the procedure used to préparé compound (S)-2-tcrt-butoxy-2-(5-(4-chlorophenyl)-2((dimethylamino)methyl)-7-methylquinolin-6-yl)aceticacid (9) of Example 9, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-inethyI-2-(piperidin-l yImethyl)quinoIîn-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-2-((dimethylamino)methyl)-7-methylqwnolin-6-y])ethanol. ’lI-NMR 300 MHz, (CDjOD) δ 7.97 (s, IH), 7.77 (d, IH), 7,65-7.58 (m, 3 H), 7.40-7.30 (m, 2H),

5.22 (s, IH), 4.61 (s, 2H), 3.60-3.20 (m, 4H), 2.69 (s, 3H), 2.00-1.90 (m, 4H), 1.80-1.65 (m, 2H), 0.98 (s, 9H); LCMS-ESf (m/z): [M+H]⁺ calcd for C₂8H₃îCIN₂O₃: 482.0;

Found: 481.3,483.3.

Example 12: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyI)-7methylquinolîn-6-yl)acetic acid: (12).

(r

174

(5)-6-(1 -tert-butoxy-2(pivaloyloxy)ethyl)-5-(4chlorophenyl)-2,7dimethylquinoline 1-oxide

1. PhSO₂CI toluene 110 °C

---------------«

2. MeONa methanol

3. water

(S)-2-ferf-butoxy-2-(5-{4chiorophenyl)-2(methoxymethyl)-7methylquinolin-6-yl)ethanol

(S)-2dert-butoxy-2-(5-(4chlorophenyI)-2-(methoxycarbonyl)7-methyiquinolin-6-y))acetic acid

Préparation of (S)-2-tcrt-butoxy-2-(5 -(4-chlorophenyl)-2-(methoxyTncthyl)-7methylquinoIin-6-y])ethanol: To a stirred solution of (S)-6-( I -tert-butoxy-25 (pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide (compound of Example 10) (14 mg, 0.03 mmol) in toluene (2 mL) was added benzenesulfonyl chloride (0.04 mL, 0.29 mmol). The mixture was stirred at 110 °C for 16 hours, then cooled to room température. Sodium methoxide (1 mL 25% solution în methanol, excess) was added. The mixture was stirred at room température for 16 hours, then water (1 mL) was added. The mixture was stirred at 60 °C for 1 hour. The reaction mixture was diluted in ethyl acetate (30 mL), washed with NaHCO₃ solution, water and brine, dried over Na₂SO4, filtered and concentrated in vacuo. The obtaîned residue was purified by HPLC to provide the desired product as TFA sait (4.8 mg, 33%). LCMSESI⁴ (m/z): 414.2, 416.2 (M+H)⁴.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyl)-7methylquinolin-6-yl}acetic acid (12): A stock solution of periodic acid/chromium

I75 trioxide was prepared according to WO 99/52850 by dissolving periodic acid (l 1.4 g, 50.0 mmol) and chromium trioxide (23 mg, l .2 mol %) in wet acetonitrile (0.75% H₂O) to a volume of 114 mL. This stock solution (0.50 mL) was added to a solution of (S)-2tert-butoxy-2-(5-(4-chlorophenyi)-2-(methoxymethyl)-7-metliylquinolin-6-yl)ethanol (4.8 mg, 0.01 mmol) in wet acetonitrile (2.0 mL, 0.75% H₂O) at 0 °C. The reaction mixture was stirred for 1 hour at 0 °C and quenched with Nal ICO; solution. Ethyl acetate was added and the organic layer separated and washed with 1:1 brine/H₂O (2x), then saturated NalISOj /brine. The organic layer was dried (MgSO₄) and concentrated and purified by reverse phase HPLC to give the product as TFA sait (2.7 mg, 61%). ^lIL

NMR 300 MHz, (CD₃OD) Ô 8.10-8,00 (m, 2H), 7.90 (d, 1H), 7.70-7.57 (m, 3H), 7.35 (d, 1H), 5.23 (s, IH), 4.03 (s, 3H), 2.70 (s, 3H), 0.98 (s, 9H); LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C₂₄H_2SC1NO_S: 442.9; Found:442.2,444.2.

Example 13: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxycarbonyl)-715 methylquinolin-6-yl)acetic acid (13).

(S)-6-(1-tert-butoxy-2(piva!oyloxy)ethyl)-5-(4-chlorophenyt)2,7-dimethy(quinoîine 1-oxide

(S)-2-tert-butoxy-2-(5-(4chlorophenyl)-2-{ethoxymethyi}7-methylquinofin-6-yl)ethano)

(S)-2-Îert-butoxy-2-(5-(4ctilorophenyl)-2-(ethoxycarbony!)-7methy Iquinolin-G-y IJacetic acid

176

Préparation of (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7methylquinolin-6-yl)ethanol: (S)-2-tcrt-Butoxy-2-(5-(4-ch]orophenyl)-2(ethoxymethyl)-7-methyIquinoIin-6-yl)ethanol was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-

7-rnelhylquinolin-6-yl)ethanol of Example 12. except that sodium ethoxide in éthanol solution was used instead of sodium methoxide in methanol solution. LCMS-EST (m/z): 428.2,430.2 (M+H)⁺.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(ethoxycarbonyl)-7methylquinolin-6-yl)acetic acid (13): (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2(ethoxycarbonyl)-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-i'5-(4-chiorophenyl)-2(methoxycarbonyl)-7-mcthylquinolin-6-yl)acetic acid of Example 12, except that (S)-2tert-butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-mcthylquinolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7mcthyiquinolin-6-yl)ethanol. ’H-NMR 300 MHz, (CDjOD) δ 8.10-8.00 (m, 2H), 7.90 (d, 1H), 7.70-7.57 (m, 3H), 7.35 (d, 1H), 5.23 (s, 1H), 4.50 (q, 2H), 2.70 (s, 3H), 1.46 (t, 3H) 0.98 (s, 9H); LCMS-ESf (m/z): [M+Hf calcd for C₂5H₂₆CINO₅:456.9; Found:

456.2,458.2.

Example 14: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-incthyl-2((methyl(phenyl)amino) methyl)quinolin-6-yl)acetic acid (14).

177

(S)-ethyl 2-(5-bromo-2,7dimethylquinolin-6-yf)-2tert-b utoxy acetate

Cl

Β(ΟΗ)₂

Pd(PPh₃)₄

K_ZCO₃ 2M

DME, MW110°C

mCPBA DCM (S)-ethy) 2-fflzt-butOxy-2-(5(4-chlorophenyl)-2,7dimethy I quinolin-6-yl)acetate

(S)-6-(1 -terf-butoxy-2-ethoxy-2oxoethyl)-5-(4-chÎorophenyl)2,7-dimethylquinoltne 1-oxide

1. PhSO₃C! toluene 90°C 1h

2. K₂CO₃EtOH

(S)-ethyl 2-fert-bjloxy-2-{5(4-cti loropheny l)-7-methy!-2((mat hy l(phenyi) aminojmettiy I )q uinclin-é-yl)acetate

2N NaOH MeOH/THF

(S)-2-/err-butoxy-2-(5(4chlo ropheny l)-7-methyl-2( (mettiy l(pheny l)a mino)metti yl)quinolin-6-yt)acelic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7dimethylquinoIin-6-yl)acetate: Pd(PPhî)^ (68 mg, 0.06 mmol) was added to a mixture of (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (230 mg,

0.59 mmol) and 4-chlorophenylboronic acid (183 mg, 1.17 mmol), K2CO3 (1.0 mL 2 M in water, 2.06 mmol) in 1,2-dimethoxyethane (8 mL). The reaction mixture was flushed with nitrogen, heated at i 10 °C for 30 min under microwave, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCOi solution, water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (200 mg, 80%). LCMS-ESI⁺ (m/z): 426.2, 428.2 (M+H)⁺.

C

178

Préparation of (S)-6-(l -tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-

2,7-dimethylquinoline 1-oxide: To a stirred solutîonof(S)-cthyl2-tert-butoxy-2-(5-(4chlorophenyl)-2,7-dimethylquinolin-6-yl)acetate (100 mg, 0.25 mmol) in dichloromethane (5 mL) was added a solution of mCPBA (114 mg, 77%, 0.51 mmol) 5 in DCM (2 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour before quenched with NaHCO₃ solution. The mixture was extracted with DCM (30 mL), washed with NaHCOj solution, water and brine, dried over Na₂SOi, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product ( 104 mg, 94%). LCMS-ESI* (m/z): 442.2,444.3 (M+H)*.

Préparation of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2((methyl(phenyl) amino)methyl)quinolin-6-yl)acetate: To a stirred solution of (S)-6-(ltcrt-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chloropheny])-2,7-dimethy!quinoline 1-oxide (13 mg, 0.029 mmol) in toluene (2 mL) was added benzenesulfonyl chloride (0.2 mL, excess). The mixture was stirred at 80 °C for 1 hour, then cooled to room température.

N-methylaniline (0.2 mL, excess) and K₂CO₃ (250 mg, excess) were added. The mixture was stin-edat 60 °C for 16 h, then diluted in ethyl acetate (3 û mL), washed withNaHCO₃ solution, water and brine, dried over Na-SCL, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (12 mg, 78%). LCMS-ESI⁴ (m/z): 531.3,533.2 (M+H)*.

Préparation of (S)-2-tert-Butoxy-2-(5-(4-chlorophcnyl)-7-methyl-2((methyl(phenyl)amino) methyl)quinolin-6-yl)acetic acid (14): To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2((methyl(phenyl)amino)methyi)quinolin-6-yl)acetate (12 mg, 0.023 mmol) in THF and methanol (2 mL/Ι mL) was added 2 M NaOH solution(0.5 mL, excess) at 0 °C. The 25 mixture was stirred at 50 °C for 3 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by prep-HPLC to provide the desired product as TFA sait (9.0 mg, 65%). ‘H-NMR 300 MHz, (CD₃0D) δ 8.21 (d, 1H), 8.07 (s, 1 H), 7.70-7.55 (m, 4H), 7.40-7.32 (m, 1H), 7.26-7.18 (m, 2H), 6.90-6.75 (m, 3H), 5.24 (s,

1H), 5.01 (s, 2H), 3.17 (s, 3H), 2.77 (s, 3H), 0.98 (s, 9H); LCMS-ESI* (m/z)·. [M+HJ* calcd for C₃₀HpCIN_?O₃: 504.0; Found: 503.3, 505.2.

179

Example 15: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2((methyî(phenyl)amino) methyl)quînolin-6-yl)acetic acid (15).

(S)-6-(1-tert-butoxy-2-ethoxy-2oxoethylp5-(4-chlorophenyl)2,7-dimethylquincline 1-oxide

(S)-2-tert-butoxy-2-(5-(4chiorDphenyi)-2-(ethoxymethyl)7-methylquinolin-6-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymcthyl)-7methylquinolin-6-yl)acetic acid (15): To a stirred solution of(S)-6-(l-tert-butoxy-2ethoxy-2-oxoethyl)-5-(4-ch!orophenyl)-2,7-dimethylquinoline 1-oxide (compound of Example 14) (12 mg, 0.027 mmol) in toluene (2 mL) was added benzenesulfonyl chloride (0.2 mL, excess). The mixture was stirred at 80 °C for 1 hour, then cooled to room température. Sodium ethoxide (0.5 mL 21% éthanol solution, excess) was added. The mixture was stirred at 60 °C for 16 h. Water (1 mL) was added, and the mixture was stirred at 60 °C for another 4 hours. The reaction mixture was diluted in ethyl acetate (30 mL), washed with NaHCOj solution, water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The obtained residue was purified by prep-IIPLC to provide the desired product as TFA sait (3.0 mg, 21%). 'H-NMR 300 MHz, (CD₃OD) δ 8.19 (d, IH), 8.06 (s, IH), 7.73 (d, IH), 7.70-7.60 (m,3H), 7.40-7.35 (m, IH), 5.24 (s, IH), 4.95 (s, 2H), 3.75 (q, 2H), 2.75 (s, 3H), 1.32 (t, 3H), 0.98 (s, 9H); LCMS-ESF (m/z): [M+H]‘ calcd for C_I5H2₉C1NO₄: 442.9; Found: 442.2,444.2.

Example 16: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimcthylcarbamoyl;-7methyIquinolin-6-yI)acetic acid: (16).

l 80

(S)-ethyl 2-(2-(acetoxymethy))-5-(4chlorophenyl}-7-melhyiquinolin-6yl)-2-tert-butoxyacetate (S)-6-(1-fert-butoxy-2-ethoxy-2oxoettiyl)-5-(4-chtorophenyl)2,7-dîmethylquinoline 1-oxide

(S)-ethyl 2-/erf-butoxy-2-(5-(4chiorophenyl)-2-(hydroxymethyi)7-methylquinoltn-6-yl)acetate

(S)-6-( l-terf-butoxy^-ethoxy^oxoethylbS-tA-chloropheriyiXmeûiylquindine^-carboxylic acid

HATU DIPEA

DMF

(S)-ethyl 2-tert-butoxy-2-(5-(4chlorophenyi)-2-(dimethytcafbamoyl)7-methylquinolin-6-yl)acetate

{S)-2-fer!-butoxy-2-(5-(4chlorophenyl)-2-(dirnethylcarbamoyl)7-rnethylquinolin-6-yl)acetic acid

Préparation of (S)-ethyl 2-(2-(acetoxymethy])-5-(4-chlorophenyl)-7methylquinolm-6-yl)-2-tert-butoxyacetate'. Acetic anhydride was added to a flask containing (S)-6-(l-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2_J75 dimethylquinoline 1-oxide (compound of Example 14) (42 mg, 0.095 mmol). The mixture was stirred at 80 °C for 1 hour. Acetic anhydride was removed under vacuum. The residue was dissolved în ethyl acetate (50 mL). The organic layer was washed with NaHCO j solution and water, dried and concentrated in vacuo. The obtained residue was used for next step reaction without purification. LCMS-ESI⁺ (m/z): 484.2, 486.2 (M+H)⁺.

Préparation of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2(hydroxymethyl)-7-methylquinolin-6-yl)acetate: To a stirred solution of (S)-ethyl 2-(2-

181 (acetoxymeÜiyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-buloxyacetate (0.095 mmol) in methanol (2 mL) was added 2 M K1CO3 (0.5 mL, excess) at room température. The mixture was stirred at room température for 1 hour, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (26 mg, 62%). LCMS-ESI* (m/z):

442.2, 444.2 (M+H)*.

Préparation of (S)-6-( 1 -tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-7methyIquinoline-2-carboxylîc acid: (S)-6-(l-tert-Butoxy-2-ethoxy-2-oxoethyl)-5-(410 chlorophenyl)-7-methylquinoline-2-carboxylîc acid was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2((dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid of Example 9, except that (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methyIquinolin-6yl)acetate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-215 ((dimethylamino)methyl)-7-methylquinolin-6-yl)etha]iol. LCMS-ESI* (m/z): 4 56.2,

458.2 (M+H)*.

Préparation of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2(dimethylcarbamoyl)-7-methylquinolin-6-yl)acetate: To a stirred solution of (5)-6-(1tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chiorophenyl)-7-methylquinoline-2-carboxylic acid (14 mg, 0.032 mmol), dimethylamine HCl sait (13 mg, 0.16 mmol) and DIPEA (0.056 mL, 0.32 mmol) in DMF (1 mL) was added HATU (61 mg, 0.16 mmol) at 0 °C. The mixture was stirred for 2 hours at ambîent température. The mixture was diluted with ethyl acetate (30 mL) and washed with water and brine, then dried over NajSOi. Concentration and purification by column chromatography provided the product (7 mg,

45%). LCMS-ESI* (m/z): 483.2,485.3 (M+H)*.

Préparation of (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)7-methylquinolin-6-yl)acclic acid (16): (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2(dimethylcarbamoyl)-7-methylquinolin-6-yl)aceiic acid was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-730 methyl-2-((methyl(phenyl)amino) methyl)quinolin-6-yl)acetic acid of Example 14, except that (S)-ethyl 2-tcrt-butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7methylquinolin-6-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(5-(416294

182 chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl) quinolin-6-yl)acetate. ’HNMR 300 MHz, (CD₃OD) δ 7.91 (s, IH), 7.87 (d, ÎH), 7.65-7.58 (m, 3H), 7.50 (d, 1H),

7.40-7.32 (m, 1H), 5.23 (s, 1H), 3.18 (s, 3 H), 3.05 (s, 3H), 2.69 (s, 3H), 0.99 (s, 9H); LCMS-ESI* (m/z): [M+H]* calcd for Cj^eCl^C^: 455.9; Found: 455.2, 457.2.

Example 17: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(methyl(phenyl)carbamoyl) quinolin-6-yl)acetic acid: (17).

Cl

OH

(S)-ethyl 2-tert-butoxy-2-{5-(4chlorophenyl)-7-methyP2(methyl(phenyl)carbamoyt)qui nolin-6-yt)acetate (S)-6-(1 -terf-butoxy-2-ethoxy-2oxoethyl)-5-(4-ch[orophenyl)-7methylquinoline-2-carboxylic acid

(S)-2-tôrt-butoxy-2-(5-(4chloropheny l)-7-methy 1-2(methyl(phenyl)carbamoyl )quinolin-6-y!)acetic acid

Préparation of (S)-ethy 12-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(methyl(phenyl)carbamoyl) quinolin-6-yl)acctate: (S)-Ethyl 2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl)quinolin-6-yl)acetate was prepared following the procedure used to préparé cornpound (S)-ethyl 2-tert-butoxy-216294

183 (5-(4-chlorophenyl)-2-(dimethylcarbarnoyi)-7-inethyIquinolin-6-yI)acetate of Example 16, except that IV-methylaniline was used instead of dimethylamine HCl sait. LCMSESf (m/z): 545.2, 547.2 (M+H)⁺.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-25 (methyl(phenyl)carbamoyl) quinoiin-6-yl)acetic acid (17): (S)-2-tert-butcxy-2-(5-(4chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl) quinolin-6-yl)acetic acid was prepared following the procedure used to préparé compound (S)-2-tert-Butoxy-2-(5-(4chlorophenylJ-T-methyl^-itmethyUphenyOammo) methyl)quinolin-6-yl)acetic acid of Example 14, except that (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-210 (methy l(phenyl)carbamoy l)quinolin-6-y l)acetate was used instead of (S)-ethy 12-tertbutoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl) quînolin-6yljacetate. ‘H-NMR 300 MHz, (CD₃OD) δ 7.80-7.50 (m, 6H), 7.40-7.10 (m, 6H),5.16 (s, IH), 3.54 (s, 3H), 2.62 (s, 3H), 0.95 (s, 9H); LCMS-ESE (m/z): [M+H]⁺ calcd for C₃oH3oC1N20₄: 518.0; Found: 517.2, 519.2.

Example 19:2-(5-(Biphenyl-4-yl)-2,7-dimethylquinolm-fi-yl)-2-tert-butoxyaceticacid (19).

184

2-(5-(b<phenyl-4-y1)-2,7dimethylquinolin-6-yl)-2fert-butoxyacetic acid

Préparation of ethyl 2-(5-(biphenyl-4-yl)-2,7-dimethylqumolin-6-yl)-2-tert5 butoxyacetate: Ethyl 2-(5-(biphenyI-4-yl)-2,7-dimethylquinolin-6-yl)-2-tertbutoxyacetate was prepared following the procedure used to préparé compound (S)ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)acetate of Example 14, except that biphenyl-4-ylboromc acid was used instead of 4chlorophenylboronîc acid. LCMS-ESf (m/z): 468.3 (M+H)⁺.

Préparation of 2-(5-(biphenyl-4-yl)-2,7-dimethylquinolin-6-y])-2-tertbutoxyacetic acid (19): 2-(5-(Biphenyl-4-yl)-2,7-dimethylquinolin-6-y])-2-tertbutoxyacetic acid was prepared following the procedure used to préparé compound (S)2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino) methyl)quinolin-6-yl)acetic acid of Example 14, except that ethyl 2-(5-(biphenyl-4-yl)15 2,7-dimethylqumo[in-6-yI)-2-tert-butoxyacetate was used instead of (S)-ethyl 2-tertbutoxy-2-(5-(4-chIorophenyl)-7-methyl-2-((methyl(phenyl)aniino)methyl) quinolin-6yl)acetate. ^lH-NMR 300 MHz, (CD₃OD) δ 8.40 (d, IH), 7.96 (s, IH), 7.95-7.90 (m,

X

185

2H), 7.70-7.60 (m, 4H), 7.55-7.40 (m, 4H), 5.39 (s, 1H), 2.96 (s, 3H), 2.80 (s, 3H), 0.98 (s, 9H); LCMS-ESf (m/z); [M+HJ* calcd for C»H₃oN0₃:440.6; Found: 440.2.

Example 20: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyiano[4,3^-de]quinolin-7-yl)-25 ((dimethylamino)methyi)-7-methylquinoIin-6-yl)acetic acid (20).

186

(S)-ettiyl 2-(5-bromo-

2,7-dimethylquinotin-5- ylj-2-tert-butoxyacetate

ethoxy-2-oxoettiyl)-2,7dimethylquiretine 1-oxide

AcjO °C 1h

2N K_ZCO₃methanol rt 1h (ff)-6-((S)-1-fert-butoxy-2-ethoxy2-oxoethyl)-5-(2,3dihydropyrano[4,3,2-de}quinafin-7yl)-2,7-dimethylquinoline 1-oxide (SRethyl 2-((R)-2(acetoxymethy 1)-5-(2,3dihydropyrano(4,3,2-de]quinolin7-^)-7-methyÎquino(in-6-yl)-2-terfbutoxyaœtate

(S)-ethy 12-ferf-butoxy-2-((R)-5- 2 Μβ,ΝΗ (2.3-dhydropyrano[4.3,2- methanol dejquinolin-7-yt)-2(hydroxymethyl)-7-rnethytqufnoiin-

(S)-ethyl 2-fert-bu1oxy-2-((fî)-5-(2,3tiihyctropyrano[4,3.2-£i'e]qüinDlin-7y ))-2- ( (dimethy lami no) methyl)-7methytquinolin-ft-yl)acetate (S)-2-ferf-butoxy-2-((R)-5-(2.3<fihydropyrano[4,3,2-(Je]quinoîin-7yl)-2-{(dimethylamino)methyl)-7methytquinolirv6-yl)acetic acid

Préparation of (S)-5-brorno-6-( l-tert-butoxy-2-ethoxy-2-oxoet?iy 1)-2,7dimethylquinoline 1-oxide: To a stirred solution of (S)-ethyl 2-(5-bromo-2,7dimethylquinolin-6-yI)-2-tert-butoxyacetate (5H) (248 mg, 0.63 mmol) in

dichloromethane (8 mL) was added a solution of mCPBA (283 mg, 77%, L26 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at 0 °C for l hour before quenched with NaHCOj solution. The mixture was extracted with DCM (30 mL), washed with NaHCOî solution, water and brine, dried over Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (212 mg, 82%). ICMS-ESJ' (m/z): 410.2,412.2 (M+H)⁴.

Préparation (R)-6-((S)-l-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(2,3dihydropyrano[4,3_I2-de]quinolin-7-yl)-2,7-diinethylquinoline 1-oxide: Pd(PPh₃)₄ (36 mg, 0.03 mmol) was added to a mixture (S)-5-bromo-6-(l-tert-butoxy-2-ethoxy-2oxoethyl)-2,7-dimethyIquinoline 1-oxide (86 mg, 0.21 mmol), 2,3dihydropyranoi4,3,2-de]quinolin--7-ylbc>ronic acid hydrochloride (105 mg, 0.42 mmol), K₂CO₃ (0.47 mL 2 M in water, 0.95 mmol) in N J^-dimethylacetamide (3 mL). The reaction mixture was flushed with nitrogen, heated at 90 °C for 16 hours. The mixture was dissolved in ethyl acetate (50 mL), washed with NaHCO₃ solution, water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo, The obtained residue was purified by HPLC to provide the desired product (87 mg, 69%). LCMS-ESI⁴ (m/z):

501.2 (M+H)⁴.

Préparation of (S)-ethyl 2-((R)-2-(acetoxymethyl)-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-methylquinolin-6-yI)-2-tert-butoxyacetate: (S)-Ethyl 2-((R)-2(acetoxymethyl)-5-(2,3-dihydropyTano[4,3,2-de]quinolin-7-yl)-7-inethylquinolin-6-yl)2-tert-butoxyacetate was prepared following the procedure used to préparé compound (S)-ethyl 2-(2-(acetoxymethyI)-5-(4-chlorophenyl)-7-niethylquinolin-6-yl)-2-tertbutoxyacetate of Example 16, except that (R)-6-((S)-1 -teit-butoxy-2-ethoxy-2oxoethyl)-5-(2,3-dihydropyrano[4,3,2-de]quinoIm-7-yl)-2,7-dimethylquinoline 1-oxide was used instead of 2-ethoxy-2-oxoethyl)-5-(4-ch]orophenyl)-2,7-dimethylquinoline 1oxide. LCMS-ESI⁴ (m/z): 543.1 (M+H)⁴.

Préparation of (S)cthyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2de] quinolin-7-yl)-2-(hydroxymethyl)-7-methylqui nolin-6-yl)acetate: (S)-Ethy! 2-tertbutoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(hydroxymethyl)-7methylquinolin-6-yI)acetate was prepared following the procedure used to préparé compound (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-

- - 188 methylquinolin-6-yI)acetate of Exampïe 16, except that (S)-ethyl 2-((R}-2(acetoxymethy^,i)'5-(2,3-dihydropyrano[4.3,2-dc]quinolin-7-yi)-7-mcdiylquinolin-6-yl)2-tert-butoxyacetate was used instead of (S)-ethy 1 2-(2-(acetoxymethyl)-5-(4chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate. LCMS-ESI* (m/z): 501.2 (M+H)*.

Préparation of (S)-ethy 1 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2de]quinoÎin-7-yl)-2-((dimethylamîno)methyl)-7-methylquinolin-6-yl)acetate: To a stirred solution of (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3 -dihydropyrano [4,3,2de]quinolin-7-yl)-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate (15 mg, 0.03 mmol) and D1PEA (0.013 mL, 0.075 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (6.8 mg, 0.06 mmol) at 0 °C. The mixture was stirred at room température for 3 hours before the addition of Ν,Ν-dimethylamine in méthanol (0.5 mL 2 M, excess). The mixture was stirred at room température for another 1 h, then diluted in ethyl acetate (30 mL), washed with NaHCO₃ solution, water and brine, dried over

Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by

HPLC to provide the desired product as TFA sait (18 mg, 97%). LCMS-ESI* (m/z):

528.3 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-((R)-5 -(2,3-dihydropyrano[43,2-de]quinolin7-yI)-2-((dimethylamino)methyl)-7-methylquino]in-6-yl)acetic acid (20): (S)-2-tert20 Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2((dimethylamino)methyI)-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7methyl-2-((methyl(phenyl)amino) methyl)quinoTm-6-yl)acetic acid of Example 14, except that (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano [4,3,2-de]quinolin-725 yl)-2-((dimethylamino)methyl)-7-methylquînolm-6-yl)acetate was used instead of (S)ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl) quinolin-6-yl)acetate. ’H-NMR 300 MHz, (CD₃OD) δ 8.70 (d, IH), 8.20 (s, IH), 7.83-

7.75 (m, 2H), 7.51 (d, IH), 7.42 (d, IH), 7.29 (d, IH), 5.26 (s, 1 H), 5.75-5.68 (m, 2H),

4.66 (s, 2H), 3.64 (t, 2H), 3.05 (s, 6H), 2.85 (s, 3H), 0.93 (s, 9H); LCMS-ESI* (m/z):

[M+H]* calcd for C₃₀H₃4N₃O₄: 500.6; Found: 500.2.

I89

ExampleZl: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolm-7-yi)-2(hydroxymethyl)-7-methyIquinolin-6-yl)acetic acid (21).

(S)-ethy 12-tert-butoxy-2-((R)-5(2,3-dihydropy rano[4,3,2- de]qurnolin-7-yl)-2(hydroxymethyl)-7-methylquinolin6-yl)acetate

(S)-2-fert-butoxy-2-((R}-5-(2,3dihydropyrano[4,3,2-de}quinolin7-yl)-2-(hydroxymethyl)-7methylquinolh-6-yl)acetic acid

Préparation (S)-2-tcrt-butoxy-2-((R)-5-(2.3-dihydropyrano[4,3,2-dc]qüinolin-75 yl)-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetic acid (21): To a stirred solution of (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4_!3,2-de]quinoiin-7-yl)-2(hydroxymethyI)-7-methylquinolin-6-yl)acetate (compound of Example 20) (10 mg, 0.02 mmol) in THF and methanol (2 mL/Ι mL) was added 2 M NaOH solution (0.5 mL, excess). The mixture was stirred at 50 °C for 3 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by prep-HPLC to provide the desired product as TFA sait (9.0 mg, 79%). 'H-NMR 300 MHz, (CD₃OD) δ

8.66 (d, 1H), 8.27 (s, 1H), 7.94 (d, 1H), 7.67 (d, 1H), 7.70-7.60 (m, 2H), 7.37 (d, 1H),

5.26 (s, 1H), 5.06 (s, 2H), 4.75-4.65 (m, 2H), 3.57 (t, 2H), 2.90 (s, 3H), 0.93 (s, 9H);

LCMS-ESf (m/z): (M+Hf calcd for C_2!H_mNïO₄: 473.5; Found: 473.1.

Example 22: (R)-6-((S)-tert-butoxy(carboxy)methyI)-5-(2,3-dihydropyranû[4,3,2de]quinolin-7-yI)-2,7-dimethylquinoline 1-oxide (22).

(R)-6-((S)-1-tert-butoxy-2-ethoxy-2oxoethyt)-5-(2,3dihydropyrano[4,3,2-c/e]quinoltn-7yl)-2,7dimethylquinoline 1-oxide

ΟΘ (R)-6-((S)-feributoxytcarboxyJmethyQ-S-fZ.adihydropyranofH^^-delqutnclin-?· yl}-2,7-dirnethylquinoline 1-oxide (R)-6-((S)-tert-Butoxy(carboxy)methyl)-5-(2,3-dihydropyrano[4,3,2de]quino!in-7-yI)-2,7-dimethylqumoline 1-oxide (22) was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-((R)-5-(2,35 dihydropyrano[4,3,2-de]quinolin-7-yI)-2-(hydroxymcthyl)-7-methylqumolm-6yl)acetic acid of Example 21, except that (R)-6-((S)-l-tert-butoxy-2-ethoxy-2oxoethyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-diniethylquinoline 1-oxide was used instead of (S)-ethyl 2-teri-butoxy-2-((R)-5-(2,3-dihydropyrano [4,3,2de]quinoIin-7-yI)-2-(hydroxymcthy])-7-methylquinolin-6-yl)acetate. ^lH-NMR 300

MHz, (CD₃OD) δ 8.78-8.70 (m, 2H), 7.85 (d, 1 H), 7.78 (d, 1 H), 7.44 (d, IH), 7.35 (d, IH), 7.11 (d, IH), 5.23 (s, IH), 5.75-5.65 (m, 2H), 3.65 (t, 2H),2.88 (s, 3H), 2.70 (s, 3H), 0.93 (s, 9H); LCMS-ESI⁺ (m/z): [M+H]⁺ calcd fbrC_2gH;!9N₂O₅:473.5; Found:

473.2.

Example 23: (S)-2-tert-Butoxy-2-((S)-5-(2,3-dihydropyTano[4,3_J2-de]quinolin-7-yl)-

2,7-dimethylquinolin-6-yl)acetic acid (23).

191

(S)-ethyl 2-(5-bromo-2,7dimethylq uinolin-6-y 1)-2terf-butoxyacetate

(S)-ethyl 2-tert-butoxy-2-((S)5-(2,3-dihydropyrano[4,3,2deIquinoiin-7-y1)-2,7dîmethylquinolin-6-yl)acetate

2N NaOH THF/MeOH

Pd(PPh₃)₄

K₂CO₃2M

DMA. 90 °C, ON

(S)-2-tert-butoxy-2-((S)-5-(2,3dihydrapyrano[4,3,2c/e]quinolin-7-yl)-2,7dirnethylquinolin-6-yl)acetîC acid

Préparation of (S)-ethyl 2-tert-butoxy-2-((S)-5-(2,3-dihydiopyrano[4,3,2de]quinolin-7-yl)-2,7-dimethyIquinolin-6-yl)acetate: Pd(PPh₃)4 (103 mg, 0,09 mmol) was added to a mixture (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin“6-yI)-2-tert5 butoxyacetate (5H) (350 mg, 0.89 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7ylboronic acid hydrochloride (447 mg, 1.78 mmol), K₂CO₃ (2.0 mL 2 M in water, 4.0 mmol) in N,N-dimethylacetamide (10 mL). The reaction mixture was flushed with nitrogen, heated at 90 °C for 16 h. The mixture was dissolved in ethyl acetate (150 mL), washed with NaHCO₃ solution, water and brine, dried over Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (407 mg, 43%). LCMS-ESI* (m/z): 485.2 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-((S)-5-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-2,7-dimethylquinolin-6-yl)acetic acid (23): (S)-2-tert-Butoxy-2-((S)-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-dimethylquinolin-6-yl)acetic acid was prepared following the procedure used to préparé cornpound (S)-2-tert-butoxy-2-((R)-

5-(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl)-2-(hydroxymethyl)-7-methylquinolin-6yl)acetic acid of Example 21, except (S)-ethyl 2-tert-butoxy-2-((S)-5-(2,3-

C

192 dihydropyrano{4,3,2-de]quinolîn-7-yl)-2,7-dimethylquinoIin-6-yl)acetate was used

S ' ~ instead of (S)-ethy 12-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate. ’H-NMR 300 MHz, (CD₃0D) δ 8.51 (d, 2H), 8.02-7.95 (m, 3H), 7.54 (d, IH), 7.36 (d, IH), 7.28 (d, IH), 5.28 (s, IH), 4.60 (ΐ, 2H), 3.43 (t, 2H), 2.93 (s, 3H), 2.83 (s, 3H), 0.72 (s, 9H); LCMS-ESf (m/z): [M+H]⁺ calcd for C2SH2SN2O4:457.5; Found: 457.1.

Example 24: (S)-6-(tert-Butoxy(carboxy)niethyl)-5-(4-chlûrophenyl)-7methylquinoIine-2-carboxylic acid (24).

2. MeOH

1. PhSO₂C1, toi 110°C1h

-terf-butoxy-2(pivatoyloxy)ethyl)-5-(4-chfarcphenyl)2,7-dimethylquinoline 1-oxide

OPiv THF/MeOH (S)-2-ier/-butoxy-2-(5-(4ctitorophenyl)-7-fnethyl-2((methyl(phenyl)amino) methy l)q trinGlin-6-y Ijéthyl pivalate

(S)-2-tert-butoxy-2-(5-(4cFil orop herty i)-7-methyt2 ((methyl(ptienyl)amino)met hy 1)qu i notin-6-y l)ethanol

(S)-6-(fer(-bvtoxy(carboxy)methyf)5-(4-chlo rophe ny 1)-7melhylquinoline-2-carboxyiic acid

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2((methyl(phenyl)amino)methyl) quinolîn-6-yl)ethyl pivalate: (S)-2-tert-Butoxy-2-(5-(4chlorophenyl)-7-methyl-2-((metfiyl(phenyl)amino)methyl) quinolin-6-yl)ethyl pivalate was prepared following the procedure used to préparé compound (S)-ethyl 2-tert15 butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyI(phenyl) amino)methyl)quinolin-6yl)acetate of Example 14, except that (S)-6-(l-tert-butoxy-2-(pi valoyloxy)ethy 1)-5-(4chlorophenyl)-2,7-dimethylqumoline 1-oxide was used instead of (S)-6-(l-tert-butoxy-

192

193

2-ethoxy-2-oxoethyI)-5-(4-chlorophenyl)-2,7-dimethylquinoline l -oxide. LCMS-ESI* (m/z): 573.3,575.4 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-ch]orophenyl)-7-methyl-2((methyl(phenyl)amino)methyl)quinolin-6-yI)ethanol: (S )-2-tert-Butoxy-2-(5-(45 chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl) quinolin-6-yl)ethanol was prepared following the procedure used to préparé compound S)-2-tert-butoxy-2-((R)-5(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl)-2-(hydroxymethyl)-7-methylquinolin-6yl)acetic acid of Example 21, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7methyl-2-((methyl(phenyl)amino)methyl) quinolin-6-yl)ethyl pivalate was used instead of (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2(hydroxymethyI)-7-methylquinolin-6-yl)acetate. LCMS-ESI* (m/z): 489.3,491.3 (M+H)*.

Préparation of (S)-6-(tert-butoxy(carboxy)methyl)-5-(4-chIorophenyl)-7methylquinoline-2-carboxylic acid (24): (S)-6-(tert-Butoxy(carboxy)methyl)-5-(415 chlorophenyl)-7-methyIquinoline-2-carboxylic acid was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2(methoxycarbony])-7-methylquinolin-6-yl)acetic acid of Example 12, except that (S)-2tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)niethyl) quînolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-220 (methoxymethyl)-7-methylqumolin-6-yl)ethanol. '1I-NMR 300 MHz, (CD₃0D) δ 8.158.05 (m, 2H), 7.93 (d, 1 H), 7.70-7.60 (m, 3H), 7.40-7.35 (m, 1 H), 5.24 (s, 1H), 2.70 (s, 3H), 0.99 (s, 9H); LCMS-ESI* (m/z): [M+H]* calcd for C23H23CINO5: 428.9; Found:

428.1,430.1.

Example 25: (S)-2-tert-butoxy-2-(5-cyclohexenyl-2-((dimethylaniiTio)methyl)-7methyIquinolin-6-yî)acetic acid (25).

C

194

(HO)_ZB

Pd(PPh₃)₄

K₂CO₃2M

DMA, 90 °C, ON

( S)-6-(1 -terf-butoxy-2-ethoxy-2oxoethyl)-5-cyclohexenyl-2,7dimethylquinoline 1-oxide (S)-5-bromo-6-{ t-tert-butoxy-2ethoxy-2-oxoethy l)-2,7dimethylquinoiine 1 -oxide

1. MsCI DIPEA DCM (S)-ethyl 2-{2-(acetoxymethyl>5cyclohexenyl-7-methyfquinolin-6yl)-2-tert-butoxyacetate (S)-ethyl 2-tert-butoxy-2-(5- 2. Me_zNH cyclohexenyl-2-(hydroxymethyl)- methanol 7-methylquinolin-6-yl)acetate

2N NaOH THRMeOH (S)-ethy 12-tert-butoxy-2-(5cyclohexenyl-2((dinnethylamino)methyl)-7methylquinolîn-6-yf)acetate

(S)-2-terf-butoxy-2-(5cycfohexenyl-2((dimethylamino)methyl)-7methylquinolin-6-yl)acetic acid

Préparation of (S)-6-(l -tert-butoxy-2-ethoxy-2-oxoethyl)-5-cyclohexenyl-2,75 dimethylquinoline l-oxide: Pd(PPh₃)<i (6 mg, 0.006 mmol) was added to a mixture (S)-

5-bromo-6-(l-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dîmcthylqumoIîne i-oxide (compound of Example 20) (20 mg, 0.05 mmol), cyclohexenylboronic acid (12 mg, 0.1 mmol), K₂CO j (0.09 mL 2 M in water, 0.17 mmol) in 1,2-dimethoxyethane (1 mL). The reaction mixture was flushed with nitrogen, heated at 85 °C for overnight, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with NaHCO₃ solution, water and brine, dried over Na₂SO₄.

C

195 filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (17 mg, 68%). LCMS-ESf (m/z): 412.3 (M+H)*.

Préparation of (S)-ethy 1 2-(2-(acetoxymethyl)-5-cyclohexenyl-7methylquinolin-6-yl)-2-tert-butoxyacetate: (S)-Ethyl 2-(2-(acetoxymethyl)-55 cyclohexeπyl·7-methylquinolin-6-yl)-2-tert-butoxyacetate was prepared following the procedure used to préparé compound (S)-ethyl 2-(2-(acetoxymethyl)-5-(4chlorophenyI)-7-methylquinolin-6-yl)-2-tert-butoxyacetate of Example 16, except that (S)-6-(l-tert-butoxy-2-ethoxy-2-oxoethyl)-5-cycIohexenyl-2,7-dimethylquinoIine 1oxide was used instead of 2-cthoxy-2-oxocthyl)-5-(4-chlorophenyl)-2,710 dimethylquinoline i-oxide. LCMS-ESf (m/z): 454.3 (M+HT.

Préparation of (S)-ethyl 2-tert-butoxy-2-(5-cyclohexenyl-2-(hydroxyinethyl)-7methylquinolin-6-yl)acetate: (S)-Ethyl 2-tert-butoxy-2-(5-cyclohexenyl-2(hydroxymethyl)-7-methylquinolin-6-yl)acetate was prepared following the procedure used to préparé compound (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-215 (hydroxymethyl)-7-methylquinolin-6-yl)acetate of Example 16, except that (S)-ethy 12(2-(acetoxymethyl)-5-cyclohcxenyl-7-inethylquinolin-6-yl)-2-tert-butoxyacetaÎe was used instead of (S)-ethyl 2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6yl)-2-tert-butoxyacetate. LCMS-ESI⁺ (m/z): 412.3 (M+H)⁺.

Préparation of (S)-ethyl 2-tert-butoxy-2-(5-cyclohexenyl-220 ((dimethylamino)methyi)-7-methylquinoIin-6-yl)acetate; (S)-Ethyl 2-tert-Butoxy-2-(5cyclohexenyl-2-((dimethylamino)methyl)~7-methylquinolin-6-yl)acetate was prepared following the procedure used to préparé compound (S)-ethyl 2-tert-butoxy-2-((R)-5(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((dimethylamino)methyl)-7methylquinolin-6-yI)acetate of Example 20 except that (S)-ethyl 2-tert-butoxy-2-(525 cyclohexenyl-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2(hydroxymethyl)-7-methylquinolin-6-yl)acetate. LCMS-ESf (m/z): 439.4 (M+H)⁺.

Préparation of(S)-2-tert-butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)7-methylquinoIin-6-yl)acetic acid (25): (S)-2-tert-Butoxy-2-(5-cyclohexenyl-230 ((dimethyIamino)methyl)-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophcnyl)-7methyI-2-((methyl(phenyl)amino) methyl)quinolm-6-yl)acetic acid of Example 14,

196 except that (S)-ethyl 2-tert-buloxy-2-(5-cyciohexenyi-2-('(diir.ethylamino) methyl)-7mcthylquinoIin-6-yl)acctatc was used instead of (S)-ethyl 2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-((inethyl(pheny))amino)niethyl) quinolin-6-yl)acetate. ’HNMR 300 MHz, (CD₃OD) δ 8.40-8.30 (m, 1H), 7.85-7.78 (m, 1H), 7.42 (d, 1H), 6.04,

5.70 (br, br, 1H), 5.80, 5.64 (s, s, 1 H),4.65 (s, 2H), 3.04 (s, 6H), 2.68-2.56 (m, 4H),

2.40-1.80 (m, 6H), 1.30-1.20 (m, 9H); LCMS-ESI* (w/z): [M+H]* calcd for C25H₃4N₂O₃: 411.6; Found: 411.3.

Example 26: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-610 yl)acetic acid (26).

Tf_zO DCM/pyridine (S)-2-tert-butoxy-2-(5-C4chlorophenyl}-7-fnethyl-2-oxo~1,2dihydroquinolin-6-yl)ethy! pivalate

( S)-2-/erf-but oxy-2-(5-(4dilDfophenyt)-7-methy1-2(trifluoromelhylsuifonytoxyjq uinolin-6-yl)ethyf pivalate

PdCI₂(PPh₃)₂LiCI

DMF

(S)-2-/er^,f-butoxy-2-(5-(4chloroptienyl)-7-methyî-2vinylquinolin-(î-yl)ethyl pivalate

2N NaOH THF/MeOH

(S)-2-fert-butoxy-2-(5-(4chtorophenyl)-7-methy1-2vinylquinotin-6-yl)ettianol

RWAIzOî Hz éthanol

(S)-2-terf-birtoxy-2-(5-(4chlorophenyt)-2-ethyl-7methy Iq uinoltn-6-y l)etha nol

(S)-2-terl-hjtoxy-2-(5-(4di)orophenyl)-2-ethy1-7methylquinolîn-6-yl)acetic acid

C

- 197

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(trifluoromethylsulfonyloxy) quinolin-6-yi)ethy] pivalate: To a stirred solutionof(S)-2tert-butoxy-2-(5-(4-chloropheny I )-7-methy l-2-oxo-1,2-dihydroquinolin-6-y l)ethyl pivalate (8J) (200 mg, 0.43 mmol) în dichloromethane (10 mL) and pyridine (0.35 mL) 5 was added Tf₂O (O.I mL, 0.87 mmol) at -78 °C. The température was slowly raised to 0 °C. The mixture was stirred at 0 °C for 2 hours, quenched with slowly addition of NaHCOj solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to provide a brown coiored solid. The obtained residue was purified by flash chromatography to provide the desired product 10 (200 mg, 77%). LCMS-ESI* (m/z): 602.0,604.0 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2vinylquinolin-6-yl)ethyl pivalate: PdCl₂(PPh3)₂ (3 mg, 0.004 mmol) was added to (S)2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-

6-yl)ethyl pivalate (25 mg, 0.04 mmol), tributyl-vinyl-stannane (0.024 mL, 0.08 mmol) 15 and lithium chloride (7 mg, 0.16 mmol) in DMF (2 mL). The reaction mixture was flushed with nitrogen, heated at 90 °C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCOj solution, water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as 20 TFA sait (14 mg, 59%). LCMS-ESI* (m/z): 480.3,482.3 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2vinylquînoIin-6-yl)ethanol: To a stirred solution of(S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyI-2-vinylquinolin-6-yl)ethyl pivalate TFA sait (14 mg, 0.024 mmol) in THF and methanol (3 mL/Ι mL) was added 1M NaOH solution (0.5 mL, 25 excess). The mixture was stirred at 0 °C for 6 hours and diluted with water. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was used in the next reaction without purification. LCMS-ESI* (m/z): 396.2,398.2 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-730 methylquinolin-6-yl)ethanol: A balloon filled with hydrogen was connected to a degassed mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolm-

6-yl)ethanoI (9 mg, 0.024 mmol) and Rhodium on activated alumina (2 mg, cat.) in

X

éthanol. The mixture was stirred at room température for 2 hours, filtered and s '1.

concentrated to dry. The obtained residue was used on next step reaction without purification. LCMS-ESf (m/z): 398.2, 400.2 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7methylquinolin-6-yl)acetîc acid (26): (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-ethyl 7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to prépare compound teri-butoxy-[7-chioro-5-(4-chioro-phcnyl)-2-methyl-qumolin-6-yl]acetic acid of Example 1, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl7-methylquinolin-6-yl)ethanol was used instead 2-ter/-butoxy-2-[7-chloro-5-(4-chlorophenyl)-2-methyi-quinoIin-6-yl]-ethanol. 'H-NMR 300 MHz, (CD₃OD) δ 8.31 (d, 1 H),

7.98 (5, IH), 7.76 (d, IH), 7.70-7.60 (m, 3H), 7.42-7.35 (m, IH), 5.25 (s, IH), 3.21 (q, 2H), 2.78 (s, 3H), 1.48 (t, 3H), 0.98 (s, 9H); LCMS-ESf (m/z): [M+HJ* calcd for C24H27CINO3:412.9; Found: 412.2, 414.2.

Example 27 : (S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid (27).

199

(S)-2-ierf-bu:ûxy-2-(5-(4chlorophenyl>7-rT>ethyl-2(trifluoromethylsulfanyloxy)q uinoiîn-6-y l)ethyl pivalate

(S)-2-(2,5-bis(4-chloropheny!)7-melhylquinolin-6-yl)-2-tertbutoxyethyl pivalate

(S)-2-(2,5-bis(4<blorophenyl)-7methylquinolin-6-yl)-2-terl· butoxyethanol

HjlOs/CrOa wet CH₃CN

(S)-2-(2,5-bis(4-chioropheny I)7-methylquinolir>-6-yl)-2-terfbutoxyacetic acid

Préparation of (S)-2-(2,5-bis(4-chlorophcnyl)-7-methylquinolin-6-yl)-2-tertbutoxyethyl pivalate: Pd(PPh₃)₄ (4.6 mg, 0.004 mmol) was added to a mixture (S)-25 tert-butoxy-2-(5-(4-chlorophenyI)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6yl)ethyi pivalate (compound of Example 26) (25 mg, 0.04 mmol), 4chlorophcnylboronic acid (13 mg, 0.08 mmol), Na₂CO₃ (0.14 mL 1 M in water, 0.14 mmol) in 1,2-dimethoxyethane (2 mL). The reaction mixture was flushed with nitrogen, heated at 90 °C for 16 hours, and then the volatile component was removed in vacuo.

The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO₃ solution, water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a TFA sait (15 mg, 55%). LCMS-ESI* (m/z): 564.3, 566.3, 568.3 (M+H)*.

Préparation of (5)-2-(2,5-bis(4-ch)orophenyl)-7-methylquinolin-6-yl)-2-tert15 butoxyethanol: (5)-2-(2,5-Bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tertbutoxyethanol was prepared following the procedure used to préparé compound (S)-216294

- 200 tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)ethanot (compound of Example 26), except that (S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinoIin-6-ylX2-tertbutoxyethyl pivalate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7methyl-2-vinylquînolin-6-yl)ethyl pivalate. LCMS-EST (m/z): 480.2,482.2,484.2 (M+H)*.

Préparation of (S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2“tertbutoxyacetic acid (27): (S)-2-(2,5-Bis(4-chlorophcnyl)-7-rnethylquinolir.-6-yl)-2-tcrtbutoxyacetic acid was prepared following the procedure used to préparé compound (S)2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)acetic acid (compound of Example 26), except that (S)-2-(2,5-bis(4-clilorophenyl)-7methylquinolin-6-yl)-2-tert-butoxyethanol was used instead (S)-2-tert-butoxy-2-(5-(4chiorophenyl)-2-ethyl-7-methylquinolin-6-yl)ethanol. ’H-NMR 300 MHz, (CD₃0D) 5 8.15-8.02 (m, 4H), 7.98 (d, IH), 7.70-7.60 (m, 5H), 7.38 (d, IH), 5.24 (s, IH), 2.74 (s, 3H), 0.98 (s, 9H); LCMS-ESI* (m/z): [M+H]* calcd for C_2sH₂sCl₂NO₃: 495.4; Found:

494.2,496.2,498.2.

Example 28: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2<yclopropy!-7-methylquinolin6-yl)acetic acid (28).

201

(S)-2-tert-butcxy-2-(5-(4chlorophenyl)-7-niethyi-2(trifluoromethylsulfonytoxy)q uinolin-6-yl)ethyl pîvalate

2N NaOH THF/MeOH (S)-2-terf-buto>cy-2-{5'(4chtorophenyl)-2-cyclopropyl-7methy lquinolin-6-yl)ethy! pîvalate

HjlOe/CrOg wet CH₃CN (SJ-2-terf-butoxy-2-(5-(4ch(orophenyl)-2-cyciopropyl-7methylquinolin-6-yl)ettiancl

(S)-2-tsrt-butoxy-2-{5-{4chlorophe nyl)-2-cyclopropyl-7methylquinolin-6-yl)acetic acid

Préparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-2-cyclopropyl-7methylquinoIîn-6-yl)ethyl pîvalate: Pd(PPh₃)₄ (4.7 mg, 0.004 mmol) was added to a mixture (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-25 (trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pîvalate (compound of Example 26) (25 mg, 0.04 mmol), cyclopropylboronic acid (7 mg, 0.08 mmol), KF (8 mg, 0.14) and NaBr (6 mg, 0.06 mmol) in toluene (2 mL). One drop of water was added to the mixture. The reaction mixture was flushed with nitrogen, heated at 90 C for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO, solution, water and brine, dried over Na₂SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product as a TFA sait (11 mg, 47%). LCMS-ESI⁺ (m/z):

494.3,496.3 (M+H)⁺.

Préparation of (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7methylquinoIin-6-yl)ethanol: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7methylquinolin-6-yl)ethanol was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chJoropheny])-7-methy]-2-vinylqumolin-6-

202 yl)ethanol, (compound of Example 26) except that (S)-2-tert-butoxy-2-(5-(4t chlorophenyl)-2-cyclopropyI-7-methylquinolin-6-yl)ethyl pivalate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquii)olin-6-yl)ethyl pivalate. LCMS-ESI* (m/z): 4103, 4I2.2 (M+H)*.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7methyIquînolin-6-yI)acetic acid (28): (S)-2-tcrt-buîoxy-2-(5-(4-chlorophenyl)-2cyclopropyl-7-methylquinolîn-6-yl)acetic acid was prepared following the procedure used to préparé compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7methylquinolin-6-yl)acetic acid (compound of Example 26) except that(S)-2-tertbutoxy-2-(5-(4-chIorophenyl)-2-cycIopropyl-7-metbylquinol m-6-yl)ethanol was used instead (S)-2-tert-butoxy-2(5-(4-chIorophenyl)-2-cthy'-7-methylquino!in-6-yl)ethanol. ¹ H-NMR 300 MHz, (CD₃OD) S 8.19 (d, IH), 7.96 (s, IH), 7.70-7.58 (m, 3H, 7.40-7.30 (m, 2H), 5.23 (s, IH), 2.77 (s, 3H), 2.58-2.48 (m, IH), 1.65-1.55 (m, 2H), l.42-1.36 (m, 2H), 0.98 (s, 9H); LCMS-ESE (m/z); [M+H]* calcd for C_2ÎH_KC1NO₃:424.9; Found:

424.2,426.2.

Example 29: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolm6-yl)acetic acid (29).

ΓΛ HN O \/

DME/80 C

(S)-2-ierf-butoxy-2-(5-(4-ch)orûphenyi)

-7-rnethyl-2-mofph ol inoq uinol in-6-y l)eth y! pivalate (S)-2-(e»'f-butoxy-2q5-(4-chlorophenyl) -7-methyt-2-(trifluoromethylsu(fonyloxy) qutnoSr»-6-yl)ethy! pivalate

( S) -2-/erfbutoxy-2-(5^4-ch Icwpheny I ) -7 -methyl-2-morpholinoqu i noii n-6-y I Jeth a nol

( S)-2-f erfbutoxy-2-(5-(4 -ch lo rophenyl ) -7 -methyl-2-motphQlinoquinolin-6-yl)acetic add

203

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2morpholinoquinolin-6-yl)ethyl pivalate: A mixture of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-inethyl-2-(trinuoromcthy]su]fonylux.yiquinolin-6-yl)e;hyl pivalate (l 2 mg, prepared as in Example 26) and morpholine (0.2 mL) in DME was heated at 80 °C 5 for 12 hours. Concentration in vacuo gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7methyl-2-morphoIinoquinolin-6-yl)ethyl pivalate (15 mg). LCMS-ESI* (m/z): [M+H]* calcd forC_3IH4oClN₂0₄: 539.3; Found: 539.4.

Préparation of (S)-2-tcrt-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2morpholmoquinoIin-6-yl)ethanol: To the solution of (S)-2-îcrt-butoxy-2-(5-(410 chlorophenyl)-7-methyl-2-rnorpholinoquinolin-6-yl)ethyl pivalate (15 mg) in THF/MeOH (1 mL/Ι mL) was added sodium hydroxide solution (1.0 N, 1 mL). The mixture was heated at 50 °C for 16 hours and was diluted with water. The aqueous was extracted with ethyl acetate, and the organic phase was washed with brine, and dried over sodium sulfate. Concentration under reduced pressure gave (S)-2-tert-butoxy-215 (5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol (10 mg). LCMSESI¹ (m/z): [M+H]* calcd for C₂₆H₃₂C1N_ZO₃: 454.2: Found: 455.3.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-7-niethyl-2morpholinoquinoIin-6-yl)acetic acid (29): A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 20 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H₂O) to a volume of 114 mL. This stock solution (0.40 mL) was added to a solution of (S)-2tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol ( 10 mg) in wet acetonitrile (1.5 mL, 0.75% H₂O) at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C. Filtration and purification by reverse phase HPLC (0.1%TFA/CH3CN-0.1%TFA/H20) gave(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7methyl-2-morphotinoquinoIin-6-yl)acetic acid (7.2 mg). ’H-NMR 400 MHz, (CD₃OD) Ô. 7.76 (m, 2 H), 7.62 (m, 3 H), 7.30 (m, 2 H), 5.14 (s, 1 H), 3.89 (m, 8 H), 2.66 (s, 3 H), 0.97 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C₂₆H₃₀CIN₂O₄: 469.2; Found: 469.3; LCMS-ESI' (m/z): [M-H]' calcd for C^ClNjO^ 467.2 Found: 467.0.

Example 30: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropylamino)-7methyIquinolin-6-yi)acetic acid (30).

204

{S)-2'iert-butoxy-2-(5-(4-chloropbenyl)

-2-{cyclopropyÎaniino)-7-methyÎqutnolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropylamino)-7methylquinolin-6-yl)acetic acid (30) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorOphenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using cyclopropylamine instead of morpholine. ’H-NMR 400 MHz, (CDjOD) δ.7.82 (m, l H), 7.61 (m, 4 H), 7.30 (d, J = 7.6 Hz, l H), 6.80 (m, 1 H), 5.12 (s, 1 H), 2.90 (m, 1 H), 2.67 (s, 3 H), 1.10 (m, 2 H), 0.97 (s, 9 H), 0.81 (m, 2 H); LCMS-ESI* (m/z); [M+HJ* calcd foi CasHaCINzOj: 439.2; Found: 439.2; LCMSESI' (m/z): [M-H]' calcd for C₂$H₂₆ClW)f 437.2; Found: 437.0;

Example 31 : (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyi-2(methylamino)quinolin-6-yl)acetic acid (31).

(S)-2-teri-butoxy-2-(5-(4-chlorophenyl) -7-methyl-2-(methylamino)quinolin^-yl)acetic add (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methylamino)quinolin-615 yl)acetic acid (31) was prepared in a similar manner as compound (S)-2-tert-butoxy-2(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using methylamine instead of morpholine. ’H-NMR 400MHz, (CD3OD) δ. 7.7 (m, 1 H), 7.58 (m, 4 H), 7.30 (d, J = 8.4 Hz, 1 H), 6.82 (m, 1 H), 5.11 (s, 1 H), 3.19 (s,

205

H), 2.64 (s, 3 H), 0.97 (s, 9 H);_LÇMS-ES1* (n/z): [Μ+1ΪΓ calcd for CnHaCttfeQ: 413.2; Found: 413.2.

Example 32: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylaniino)-75 methylquinolin-6-yl)acetic acid (32).

(SF2-fert-butaxy-2'{5-(4-chlorophenyl)

-2-(dimethylamino)-7-methylquinolin-6-|fl)aceticacîd (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylamino)-7-methylquinolin6-yl)acetic acid (32) was prepared in a sîmilar manner as compound (S)-2-tert-butoxy2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquino]in-6-yl)acetic acid of Example 29 10 except using dimethylamine instead of morpholine. ¹ H-NMR 400 MHz, (CD3OD)

5.7.79 (s, 1 H), 7.71 (d, J = 10 Hz, 1 H), 7.60 (m, 3 H), 7.31 (d, J = 8 Hz, 1 H), 7.16 (d, J = 10.4 Hz, 1 H), 5.13 (s, 1 H), 3.42 (s, 6 H), 2.66 (s, 3 H), 0.97 (s, 9 H); LCMS-ESf (m/z): [M+H]⁺ calcd for C₂₄H28C1N₂O₃:427.2; Found: 427.2; LCMS-ESL (m/z): [ΜΗ]* calcd for C₂₄H_MC1N₂O₃; 425.2; Found: 425.0.

.

Example 33: (S)-2-tert-Butoxy-2-(5-(4-chlorophcnyi)-7-methyl-'2-(pynd:n9ylmethylamino)quinolin-6-yl)acetic acid (33).

206

(S)-24ert-butoxy-2-(5-(4-chiorophBnyî)

-7-methyl-2-(pyridjn-4-ylme!hylamino)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chIorophenyl)-7-methyl-2-(pyridin-4ylmethylamino)quinolin-6-yI)acetic acid (33) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chIorophenyl)-7-melhyl-2-morpliolinoqumolin-65 yt)acetic acid of Example 29 except using pyridin-4-yLmetlianainime instead of morpholine. 'H-NMR 400 MHz, (CD3OD) δ 8.67 (m, 2 H), 7.72 (m, 3 H), 7.60 (m, 4 H), 7.31 (d, J = 8.4 Hz, 1 H), 6.97 (d, J =9.2 Hz, 1 H), 5.12 (s, 1 H), 5.0 (s, 2 H), 2.64 (s, 3 H), 0.96 (s, 9 H); LCMS-ESf (m/z): [M+H]⁺ calcd for C28H29CIN3O3: 490.2; Found: 490.2; LCMS-ESF (m/z): [M-H]'calcd for CjgF^ClNjOj'. 488.2; Found:

488.0.

Example 34: (S)-2-tert-Butoxy-2-(5-(4-chlorophcny!)-7-methyl-2-(2morpholinoethylamino) quinolin-6-yl)acetic acid (34).

(SJ^-tert-butoxy-S-fS-^-chforaphenyQ-î-niethyl^-^morpholinoethylamino)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyI)-7-methyl-2-(2morpholinoethylamino)quinolin-6-yi)acetic acid (34) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-mctbyl-2-moipholinoquiiiolin-

207

6-yl)acetic acid of Example 29 except using 2-morpholinoethananiine instead of morpholine. ’H-NMR 400 MHz, (CD₃OD) δ 7.73-7.55 (m, 5 H), 7.29 (d, J = 8 Hz, l

H), 6.90 (m, l H), 5.12 (s, i H), 4.05-3.81 (m, 6 H), 3.45-3.35 (m, 6 H), 2.65 (s, 3 H), 0.97 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C_2!H_îsClN₃O₄: 512.2; Found:

512.2; LCMS-ESI* (m/z): [M-H]' calcd for C_2ÏH₃₃C1N₃O4: 510.2; Found: 510.1,

Example 35: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(3-(2methoxyethoxy)propylamino)-7-niethylquinolin-6-yI)acetic acid (35).

(S)-2-tert-butoxy-2-(5-(4-chkxophenyl)-2-(3-(2methoxyethoxy)propylamino)-7-mettiytquinolin-6-yl)acetic acid ( (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(3-(2methoxyethoxy)propylamino)-7-methylquinolin-6-yi)acetic acid (35) was prepared in a similar manner as compound (SJ-2-tert-butoxy-2-(5-(4-cli]orophenyl)-7-inethyl-2morphoIînoquinolin-6-yl)acetic acid of Example 29 except using 3-(215 methoxyethoxy)propan-1 -amine instead of morpholine. ‘H-NMR 400 MHz, (CD₃OD) Ô 7.7-7.55 (m, 5 H), 7.30 (d, J = 8 Hz, 1 H), 6.85 (m, 1 H), 5.11 (s, I H), 3.7-3.5 (m, 8 H), 3.35 (s, 3 H), 2.65 (s, 3 H), 2.05 (m, 2 H), 0.97 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C₂₈H₃₆CIN₂0s: 515.2; Found: 515.3; LCMS-ESL (m/z): [M-H]' calcd foi C₂gH₃₄ClN₂O₅: 513.2; Found: 513.0.

Example 36: (S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (36).

Tf;O pyridine

-78 «C

(S)-245-brofrw-7-fnethyF2-oxo-1,Σόι hydroq uinolin-6-y tJ-2-tert-bu(oxyethy I pivata te (S)-2-Ierf-butcxy -24(/7)-5-(2,3-d ihydropyrano [4,3,2-de]q ui no<in-7-yi)-7-fflethyk2-OMj1,2-dihydroquino1irH5-yl)ethyt pivalate

tBuli/CuCN THF/-40 C (S)-2-tef Fbutoxy-2-((R)MZ3-dMro pyrano[4,3,2-de]quino!irt-7-yi)-7-metfiyl-2(trifluoromethyisutfonyioxy)quînolir>-6-yî)effiyi pivalate

( SF2-ferMjUoxy-2-((R)-2-/ert-tiutyl-5· (2,3-dihydropyrano(4,3i-Îfe]quinoÉn-7yf)-7-fliithylquinolin-6-yl)ethyl pivalate

NaOH MeOH/THF 50 ’C

(S)-2-(eri-butoxy-2-4(R)-2-fert-butyF5(2,3-dihydropyrano{4,3,2-dejqui nclin -7-y l)-7 -methy lquinolini-6-y i jeth anol (S)-24erf-butoxy-2-((i7}-2-tert-butyl -542,3-dihydfopy rano[4,3.2-de}quinolin· 7-yl)-7-rnethfiquinolin-6-yl)aœttc add

Préparation of (S)-2-tert-butoxy-2-((R)-5-(2,3 -d;hydropyrano[4,3,2-de]quinolin7-yl)-7-methyl-2-oxo-l,2-dihydroquinolin-6-yl)cthyl pivalate: (S)-2-tert-Butoxy-2((R)-5-(2,3-dihydropyrano[43,2-de]quinolin-7-yl)-7-iTiethyl-2-oxo-l,25 dihydroquinolin-6-yI)ethyi pivalate (800 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2dihydroquinoIin-6-yl)ethyl pivalate of Example 29 except using 2,3dihydropyrano[4,3_î2-de]quinolin-7-y]boronic acid hydrochloride instead of 4chlorophenylboronic acid. LCMS-ESI* (m/z): [M+H]*calcd for CfolIpNiOp 529.3;

Found: 529.0.

Préparation of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[43,2-de]quin.olm-

7-yl)-7-methyl-2-(trif[uoromcthylsu!fop.yloxy)qujnolin-6-yl)etbyl pivalate: (S)-2-tertButoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2(trifluoromethylsulfonyIoxy)quinolin-6-yl)ethyl pivalate was prepared în asimilar manner as compound (S)-2-ten-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(trifluoromethylsulfonyloxy) quinoiin-6-yi;ethyî pivalate of Example 29 except using (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolÎn-7-yl)-7-methy'l-2-0xo-

1,2-dihydroquinolin-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate LCMS-ESf (m/z): (M+Hf calcd for CjjlWWLS: 661.2; Found: 661.0.

Préparation of(S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2de]qumolin-7-yl)-7-methylqumolin-6-yl)ethyl pivalate: To a suspension of copper(I) cyanide (40 mg, 0.44 mmol) in THF (1 mL) at -40 °C was added tert-bulyllîthium (0.48 mL, 1.7 N, 0.82 mmol) slowly. The mixture was stirred for 5 minutes, and a solution 15 of (S)-2-tert-butoxy-2-((R)-5-(2₎3-dihydropyTano[4_l3,2-de]quinolin-7-yl)-7-methyl-2(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (40 mg, 0.06 mmol) in THF (0.5 mL) was added dropwise. The reaction mixture was kept at -45 to -35 °C for 4 hours, and warmed to 25 “C slowly and stiired for 12 hours. The réaction was quenched with water, and extracted with ethyl acetate. The organic layer was washed 20 with brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-((R)-2-tert-butyl-5(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)ethyl pivalate (14 mg). LCMS-ESf (m/z): [M+H]⁺ calcd for Cj^sNîOî 569.3; Found: 569.4.

Préparation of (S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,225 de]quinolm-7-yl)-7-methylquinolin-6-yl)ethanol: (S)-2-iert-Butoxy-2-((R)-2-tert-butyl-

5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)ethanol (13 mg) was prepared in a sîmilar manner as compound ((S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-morpholinoquinolîn-6-yl)ethanol of Example 29,except using(S)-2-tert-butoxy-2-((R)-2-tert-bulyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-730 yl)-7-methyIquinolin-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate. LCMS-ESf (m/z): [M+H]⁺ calcd for C₃iH₃₇N₂O₃: 485.2; Found: 485.1.

(f

210

Préparation of (S)-2-tert-butoxy-2-((R)-2-tert-butv 1-5-(2,3-dihydropyrano [4,3,2de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (36) : (S)-2-tert-Butoxy-2-((R)-2tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quinoiin-7-yl)-7-methylquinolin-6-yl)acetic acid (11.6 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(55 (4-chlorophenyi)-7-methyl-2-morpholinoquinolin-6-yi)acetic acid of Example 29, except using (S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydrepyrano[4,3,2de]quinolin-7-yl)-7-methylquinolin-6-yl)ethanol instead of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 'H-NMR 400 MHz (CDjOD) δ 8.62 (d, Ji = 4.8 Hz, I H), 8.27 (s, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.71 (d, J 10 = 8 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.59 (d, J = 5.2 Hz, ί H), 7.33 (d, J = 7.6 Hz, 1

H), 5.26 (s, 1 H), 4.66 (m, 2 H), 3.55 (m, 2 H), 2.89 (s,3 H), 1.54 (s, 9 H), 0.92 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C31H35N2O4:499.2; Found: 499.2; LCMSESf (m/z): [M-H]' calcd for CjiHjjhW 497.2; Found: 497.2.

Example 3 7: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-niethyl-2(phenylethynyl)quinolin-6-yl)acetic acid (37 A) and (S)-2-tert-birtoxy-2-(5-(4chlorophenyl)-7-methyl-2-(phenyIethynyl)quinolin-6-yl)acetic acid (37B).

211

(S)-2-iert-butoxy-2-(5-(4^h!oropbenyt) -7-methyl-2-(trifltKMometfiylsulfonyloxy) qtrirKiltn-6-yl)ettiyl pivalate

(S)-2-ierf-buioxy-2-{5-(4-cMwoph«iyi} -7-methyt-2-iphenytethynyf) quint>lin-6-yi)ethyi pivalate

(S)-2-iert-butoxy-2-(5-(4-cNorophenyi) -7-methy!-₂qphenytethynyl)quinolin-6-yf)ethano1

(S)-2-tart-butoxy-2-(5-(4<hiorophenyl) -7-fnethyl-2-phenethylquinolin-6-yf)eÎhanol

(S)-2-ted-butoxy-2-(5-(4-chioro pheny[)-7-methyi-2(phenyletfvnyt)qi4notin-6-y1]acetic add

CfO₃HsIQs CHjCN 0*C

(S)-2-1eff-twtoxy-2-(5-(4<hloropheny1) -7-meHiyi-2-pbenetnylquiiwim-6-yi)acelic add

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophcnyl)-7-methyl-2(phenylethynyl)quinolin-6-yl)ethyl pivalate: The solution of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-(trifïuoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (35 mg, 0.06 mmol), ethynylbenzene (8 pL, 0,08 mmol), and triethylamine (1 mL) in ethyl acetate (0.5 mL) wasdegassed with nitrogen. Copper(I) iodide ( 1 mg) and bis(triphenylphosphine)palladiuin (II) dichloride (7 mg) were added, and the mixture was stirred for 12 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and dried with sodium sulfate.

Concentration and purification by flash column chromatography (silica gel, ethyl acetate/hexanes) gave (S)-2-tert-butoxy-2-(5-(4-chloropbcny l)-7 -methy 1-2(phenylethynyI)quînolin-6-yl)ethyl pivalate. LCMS-ESf (m/z); [M+H]⁺ calcd for

C35H37CIW 554.2; Found: 554.3.

C 212

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyi-2(phenyIethynyi)quînoIin-6-yl)ethanoI: (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7methyl-2-(phenyIethynyl)quinolin-6-yl)eÎhanol ( 12 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-25 moiphoIinoquinoIin-6-yl)ethanol of Example 29 except using (S)-2-tert-butoxy-2-(5(4-chlorophenyl)-7-methyl-2-(phenyiethynyl)quinolin-6-yl)ethyl pîvalate instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyI-2-morpholinoquinolîn-6-yl)ethyl pivalate. LCMS-ESf (m/z): [M+Hf calcd for C_3CH,₉C1\O_;: 470.2; Found; 470.2.

Préparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-niethyl-210 (phenylethynyI)quinolin-6-yl)acetic acid (37A) : (S)-2-tert-Bütoxy-2-(5-(4chlorophenyl)-7-methyl-2-(phcnyîethynyl)quinolin-6-yl)acetic acid (4.9 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chloropheny!)-7methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-lertbutoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)q'jinolin-6-yl)ethanoI instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6yl)ethanol. 'H-NMR 400 MHz (CD₃OD) δ 7.95 (m, 1 H), 7.90 (s, 1 H), 7.7-7.6 (m, 6 H), 7.50 (m, 3 H), 7.37 (d, J = 8.8 Hz, 1 H), 5.23 (s, 1 H), 2.72 (s, 3 H), 0.99 (s, 9 H); LCMS-ESf (m/z): [M+H]⁺ calcd for C30H27CINO3:4842; Found: 484.2. Préparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl)ethanoI;

The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-7-metliyl-2(phenylethynyI)qumolin-6-yl)ethanol (6 mg) and rhodium on alumina (2 mg) in éthanol (1.5 mL) was stirred under 1 atm of hydrogen for 3 houis. Celite was added, and the mixture was filtered and washed with ethyl acetate. Concentration of the mother liquor under reduced pressure gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-225 phenethylquinolin-6-yl)ethanol (6. 5 mg). LCMS-ESf (m/z): [M+H]⁺ calcd for C₃₀H₃₃CtNO₂:474.2; Found: 474.3.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chIorophenyl)-7-methyl-230 phenethylquinoIin-6-yl)acetic acid (37B): (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7methyl-2-phenethylquinolin-6-yl)acetic acid (4.8 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-inethyl-2-niorpholinoquinolÎn'

C

213

6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7mefliyl-2-phenethylquinoIîn-6-yl)ethanol instead of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. *H-NMR 400 MHz (CD₃OD) δ 8.21 (d, J = 8 Hz, l H), 7.93 (s, 1 H), 7.7-7.6 (m, 4 H), 737 (d, J - 8 Hz, 1 H), 7.3-7.15 (m, 5 H), 5.24 (s, 1 H), 3.46 (d, J = 7.6 Hz, 2 H), 3.18 (d, J = 7.6 Hz, 2 H),

2.76 (s, 3 H), 0.96 (s, 9 H); LCMS-ESI* (m/z); [M+H]* calcd forC₃oH_3IC[N0₃: 488.2; Found: 488.2.

Example 3 8 : (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropy lelhynyl)-7methylquinolin-6-yl)acetic acid (38).

(S)-2-fer+butoxy-2-(5-(4-chlorophenyl) -2-(cyclopropy[ethynyi)-7-metiiyJqiiinolin-6-y1)aceticacid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropylethynyl)-7methylquinolin-6-yl)acetic acid (38) (5.5 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(phenylethynyl)quinolin-6-yl)acetic acid of Example 37 except using ethynylcyclopropane instead of ethynylbenzene. ’H-NMR 400 MHz (CD₃0D) δ 8.0 (m, 1 H), 7.84 (s, 1 H), 7.64-7.55 (4 H, m), 7.35 (d, J = 7.6 Hz, 1 H), 5.21 (s, 1 H), 2.72 (s, 3 H), 1.65 (m, 1 H), 1.13-1.02 (m, 4 H), 0.98 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C;7H27C1NO₃: 448.2; Found: 448.2.

Example 39: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(2-cyclopropylethyl)-7methylquinolîn-6-yl)acetic acid (39).

214

(S)-2-(tert-butoxy)-2-(5-(4-chlorophenyl)-2(2-cyctopropylethyl)-7-methy]quinoiîn-6-yl)aceac acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(2-cyclopropylethyl)-7methylquinolîn-6-yl)acetic acid (39) (5.7 mg) was prepared irr a sîmilar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquïnolin-65 yl)acetic acid of Example 37 except using ethynylcyclopropane instead of ethynylbenzene. ¹ H-NMR 400 MHz (CDjOD) δ 8.17 (d, J = 8.4 Hz, 1 H), 7.91 (s, l H), 7.66 (d, J = 8.8 Hz, 1 H), 7.6-7.5 (m, 3 H), 7.31 (m, 1 H), 5.18 (s, 1 H), 3.21 (m, 2 H), 2.71 (s, 3 H), 1.72 (m, 2 H), 0.92 (s, 9 H), 0.75 (m, 1 H), 0.41 (m, 2 H), 0.02 (m, 2 H); LCMS-ESI* (m/z): [M+H]⁺ calcd for CzîHjjCINOj: 452.2; Found: 452.2.

Example 40: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolîn-7-yl)-7methyl-2-(phenylethynyl)quinolin-6-yl)acetic acid: (40).

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4₎3,2-de]quînolin“7-yl)-7-metiiyl-2(phenylethynyl)quinolin-6-yl)aceticacid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4₎3,2-de]quinolin-7-yl)-715 methyl-2-(phenylethynyl)quînolin-6-yl)acetic acid (40) (4.9 mg) was prepared in a sîmilar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(phenylethynyl)quinolin-6-yl)acetic acid of Example 37 except using (S)-2-tert-butoxy2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2fi (trifluoromethylsulfonyIoxy)quinolin-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2'-L (5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate. ‘H-NMR 400 MHz (CD₃OD) δ 8.71 (d, J = 5.2 Hz, l H), 8.10 (s, I H), 7.9-

7.8 (m, 2 H), 7.65 (m, 2 H), 7.58 (m, 2 H), 7.45 (m, 4 H), 5.26 (s, l H), 4.75 (m, 2 H),

3.64 (m, 2 H), 2.85 (s, 3 H), 0.94 (s, 9 H); LCMS-ESf (m/z): [M+H]⁺ calcd for C_3iH_3lN₂O₄: 543.2; Found: 543.1; LCMS-ESf (m/z): [M-HJ* calcd for ε₃5Η»Ν₂Ο₄:

541.2.; Found: 541.0.

Example 41 ; (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolm-7-yl)-7methyl-2-phenethylquinolin-6-yl)acetic acid: (41).

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4₁3,2-<ie)qurnolin-7-yl)-7-methyl-2phene9iyiquinoiin-6-yi)acetic acid (S)-2-tert-Butox.y-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yI)-7methyl-2-phenethylquinolin-6-yI)acetic acid (41) (5.2 mg)was prepared in a similar manner as compound (Sj-Z-tert-butoxy^-tS-^-chloropheriyO-î-niethyl^phenethylquinolin-6-yl)acetic acid of Example 37 except using (S)-2-tert-butoxy-2((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2(5-(4-chlorophenyi)-7-methyl-2-(trifluoromethylsulfony]oxy)quinolin-6-yl)ethyl pivalate. ‘H-NMR 400 MHz (CD₃OD) δ 8.51 (d, J = 5.7 Hz, 1 H), 7.96 (s, I H), 7.80 (d, J = 8.8 Hz, 1 H), 7.59 (d, J = 7.6 Hz, 1 H), 7.45 (m, 2 H), 7.2-7.05 (m, 6 H), 5.15 (s, 1 H), 4.56 (m, 2 H), 3.35 (d, J = 6.8 Hz, 2 H), 3.22 (m, 2 H), 3.07 (t, J = 7.2 Hz, 2 H), 2.80 (s, 3 H), 0.82 (s, 9 H); LCMS-ESr (m/z): [M+Hf calcd for C_3SH₃₅N₂O₄: 547.2; Found: 547.2; LCMS-ESF (m/z): [Μ-ΗΓ calcd for 545.2; Found: 545.1.

Example 42: (S)-2-tert-butoxy-2-((R)-2-(cyclopropylethynyl)-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)accticacid (42).

2I6

(S)-2-te/-f-butoxy-2-((R)-2-(cyclopr(^ylethynyl)-S-(2,3-dihydropyranQ[4,3,2-de]quÎnolin-7-yl)-7methyfquinolin-6-yl)acetic acid (S)-2-tert-butoxy-2-((R)-2-(cyclopropy lethynyl)-5 -(2,3 -dihydropyrano[4,3,25 de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (42) (5.2 mg) was prepared in a similar manner as compound (S)-2-tcrt-butoxy-2-(5-(4-chhrophenyl)-7-mcthyl-2(phenylethynyl)quinolÎn-6-yI)acetic acid of Example 37 except using (S)-2-tert-butoxy2-((R)-5-(23'dihydropyrano(4,3,2-de]quÎnolin-7-yl)-7-methyI-2(trifluoromethylsuIfonyloxy)quinolin-6-yl)ethyl pivalate and ethynylcyclopropane instead of(S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-7-niethyl-2(trifluoromethylsulfonyloxy)quinoiin-6-yl)ethyl pivalate and ethynylbenzene. ’H-NNÎR 400 MHz (CDsOD) δ 8.68 (d, J = 5.6 Hz, 1 H), 8.0 (s, 1 H), 7.80 (d, J = 7.6 Hz, 1 H), 7.74 (d, J = 5.6 Hz, 1 H), 7.5 (d, J = 8,4 Hz, 1 H), 7.41 (d, J = 7.6 Hz, IH), 7.35 (d, J =

8.8 Hz, 1 H), 5.23 (s, 1 H), 4.70 (m, 2 H), 3.62 (m, 2 H), 2.83 (s, 3 H), 1.60 (m, 1 H),

1.05-0.88 (m, 4 H), 0.93 (s, 9 H); LCMS-ESI⁺ (m/z): [ΜΗ!]' calcd for CmHîiNîO^

507.2; Found: 507.1; LCMS-ESI* (m/z): [M+H]* calcd forCajHaNjO^ 505,2; Found:

505.1.

Example 43 : (S)-2-tert-Butoxy-2-((R)-2-(2-cyclopropylethy 1)-5-(2,320 dihydropyrano[4,3,2-de]quinoliîi-7-yl)-7-methylquÎnolin-6-yl)acetic acid (43).

217

(S)-2-fe/'t-butoxy-2q(R)-2-(2-cyctopropylethyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-

7-methylquinolin-6-yl) acetic acid (S)-2-tert-butoxy-2-((R)-2-(2-cyclopropylethyl)-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (43) (5.9 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-7-methyl-2- phenethylquînolin-6-yl)acetic acid of Example 37 except using (S)-2-tert-butoxy-2((R)-5 -(2,3 -dihydropyrano [4,3,2-de]quinoiin-7-yl)-7-methyl-2(trifluoromcthylsuIfonyIoxy)quinolin-6-yl)ethyl pîvalate and ethynylcyclopropane instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pîvalate and ethynylbenzene. ’H-NMR

400 MHz (CD₃OD) S 8.55 (m, 1 H), 8.03 (s, IH), 7.92 (d, J = 8.4 Hz, 1 H), 7.62-7.45 (m, 3 H), 7.23 (d, J = 7.6 Hz, 1 H), 5.19 (s, 1 H), 4.78 (m, 2 H), 343 (m, 2 H), 3.20 (m,

H), 2.84 (s, 3 H), 1.65 (m, 2 H), 0.84 (s, 9 H), 0.7 (m,l H), 0.4 (m, 2 H), 0.02 (m, 2 H); I.CMS-ESI⁺ (m/z): [M <1 if calcd for C₃₂H₃5N₂O₄·. 511.2; Found: 511.2; LCMSΕδΓ (m/z): [M-H]' calcd for C₃₂ll3₃N₂O₄:509.2; Found: 509.1.

Example 44: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dîhydropyrano[4,3,2-delquinolin-7-yI)-7methyl-2-(prop-I-ynyl)quinolin-6-yl)acetic acid (44).

218

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl) -7-mettiyl-2-(prop-1-ynyl)quÎnolin-6-yl)acetic acid (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-(prop-I-ynyl)quinolin-6-yl)acetic acid (44) (4.6 mg) was prepared în a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-25 (phenylethynyl)quinolin-6-y l)acetîc acid of Example 3 7 except using (S )-2-tert-butoxy2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin'7-yl)-7-mcthyl-2(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate and prop-1 -yne instead of (S)2-tert-butoxy-2-(5-(4-chlorophenyl)-7-metliyl-2-(trifluoromethylsulfonyloxy)quinoliii6-yl)ethyî pivalate and ethynylbenzene. ’H-N.MR 400 MHz (CD^OD) 5 8.67 (d, J = 5.6 10 Hz, 1 H), 8.02 (s, 1 H), 7.85-7.75 (m, 2 H), 7.5-7.4 (m, 1 H), 7.42 (d, 1= 8 Hz, 1 H),

7.35 (d, J = 8.8 Hz, I H), 5.23 (s, 1 H), 4.70 (m, 2 H), 3.62 (m, 2 H), 2.83 (s, 3 H), 2.15 (s, 3 H), 0.93 (s, 9 H); LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for CjoHkNjO^ 481.2; Found: 481.4; LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C30H27N2O4:479.2; Found: 479.1.

Example 45: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-rfe]quinolin-7-yl)-2ethynyl-7-methylquinolin-6-yl)acetic acid (45).

219

(S)-2-terFbutoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quiriolin~7-yl) ^-β^νηγΙ-Ζ-ΓΓίε^ιγΙςυιηοΙίη-θ-γΙ^^εύε acid (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2ethynyl-7-methylquinolm-6-yl)acetic acid (45) (5 mg) was prepared in a similar manner 5 as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(phenylethynyl)quinolin-6-yl)acetic acid of Example 37 except using (S)-2-tert-butoxy2-((R.)-5-(2,3-dihydropyrano(4,3,2-de]qumolin-7-yl)'7-methyl-2(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pîvalate and ethynyltrimethylsilane instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-210 (trifluoromethyIsulfonyloxy)quinolin-6-yl)ethyl pîvalate and ethynylbenzcne. ’ll-NMR

400 MHz (CDjOD) δ 8.69 (d, J = 5.6 Hz, l H), 8.07 (s, 1 H), 7.85-7.75 (m, 2 H), 7.5-

7.4 (m, 3 H), 5.24 (s, 1 H), 4.75 (m, 2 H), 3.98 (s, 1 H), 3.65 (m, 2 H), 2.83 (s, 3 H), 0.93 (s, 9 H); LCMS-ESI* (m/z): [M+H]⁺ calcd for 467.2; Found: 467.1 ;

LCMS-ESf (m/z): [M-H]‘ calcd for C29H25N2O4: 465.2; Found: 465.0 .

Example 46: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2îsopropyl-7-methylquinolin-6-yl)acetic acid (46).

220

(S)-2-ierf-butoxy-2-((ff)-5-(2,3dihydropyrano[4,3,2-cie]quinolm-7-yf)-7methyl-2-(trifluoromethylsuifonyloxy)quinolin6-y IJethyl pivalate

ÎPrMgSr

Fe(AcAc)3 THF/NMP

NaOH MeOH/THF 50’C (S)-2-iert-butoxy-2-((R)-5-(2,3ditiyd<Opyrano[4.3,2-</e]quif»lin-7-yl)-2isopropy1-7-methylquinolin-6-yQethyl pivalate

(S)-2-fe/7-butoxy-2-((R)- 5-(2,3ditiydrapyrano[4,3,2-Î/e}quinolin-7-yl)-2-isopropyl·

7-methyiquinolir>6-yl)ethanoi (S)-2-/ert-butoxy-2-((/?)-5-(2,3dihydiOpyrano[4_r3,2-de]quinolln-7-yl)2-isopropyP7-melhylqujnolin-6yljacetic acid

Préparation of (S)-2-tcrt-butoxy-2-((R)-5-(2,3-dihydropyTano[4,3,2-de]quinolin-

7-yl)-2-isopropyl-7-methylquinolin-6-yl)ethyl pivalate: To a solution of (S)-2-tertbutoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-niethyl-2- (trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 36) (40 mg, 0.06 mmol) in THF/NMP (0.75 mL/75 pL) was added iron (III) acetylacetonate (2 mg), followed by isopropylmagnesiumbromide (ΙΌ N, 0.14 mL, 0.14 mmol) slowly. The mixture was stirred for 30 minutes, and was quenched with water. Ethyl acetate was added, and the organic layeî was separated, washed with brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-((R)-5-(2,3dihydropyrano[4,3,2-de]quinoIin-7-yl)-2-isopropyl-7-methylquinolin-6-yl)ethyl pivalate (11 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for CsîRiNjO.,: 555.3; Found:

555.4.

Préparation of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-2-isopropyl-7-methylquinolin-6-yl)ethanol: (S)-2-tert-Butoxy-2-((R)-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-2-isopropyl-7-methylquinolin-6-yl)ethanol (8

_w η i

Ci I mg) was prepared in a similar manner as cornpound (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol of Example 29 except using (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyTano[4,3,2-de]quinoIin-7-yl)-2isopropyl-7-methylquinolin-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(45 ' chIorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate. LCMS-ESI⁺ (m/z); [M+H]⁺ calcd for C30H35N2O3: 471.3; Found: 471.3.

Préparation of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyraiio [4,3,2-dejquinolin7-yl)-2-isopropyl-7-methylquinolin-6-yl)acetic acid (46): (S)-2-tert-Butoxy-2-((R)-5(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-isopropyl-7-mcthyIquinolin-6-yI)acetic acid (7'mg) was prepared in a similar manner as cornpound ((S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolm-7-yl)-2isopropyl-7-methylquinolin-6-yl)ethanol instead of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. ’H-NMR 400 MHz (CD₃OD) 8 8.60 (d, J = 5.2 Hz, 1 H), 8.11 (s, I H), 7.98 (d, J = 9.2 Hz, 1 H), 7.7-7.6 (m, 2 H), 7.51 (d, J = 4.8 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 5.26 (s, 1 H), 4.64 (m, 2 H), 3.55-3.40 (m, 3 H), 2.90 (s, 3 H), 1.46(m, 6 H), 0.91 (s, 9H); LCMS-ESf (m/z): [M+H]⁺ calcd for CjoH^NaO^ 485.2; Found: 485.2; LCMS-ESI' (m/z): [M-H]‘ calcd for C3qH₃iN₂O4: 483.2; Found: 483.2.

Example 47: (S)-2-tert-butoxy-2-((R)-2-cydobutyl-5-(2,3-dihydropyrano[4,3,2de]quinoIin-7-yl)-7-methylquinolin-6-yl)acetic acid (47).

(S)-2-tert-butoxy-2-((R)-2<yclobutyl-5-(2,3-dihydropyrano [4.3,2-de)quînQlin-7-yl)~7-methyIquinolin-6-yl)acetic acid

ζ/2 (S)-2-tert-butoxy-2-((R)-2-cyclobutyl-5-(2,3-dihydropyraro[4,3,2-de]quinolm7-yl)-7-methylquinolin-6-yl)acetic acid (47) (ΙΟ mg) was prepared'in a similar manner as compound (S)-2 -tert-butoxy-2-((R)-5 -(2,3 -dihydropyrano[4,3,2-de] quînolin-7-yl)-2isopropyl-7-methylquinolin-6-yl)acetic acid of Example 46 except using cyclobutylmagnesium bromide instead of isopropylmagnesium bromîde.¹ H-NMR. 400 MHz (CD₃OD) δ 8.60 (m, 1 H), 8.10 (m, 1 H), 7.95 (m, 1 H), 7.65 (m, 2 H), 7.45 (m, 1 H), 7.24 (mj H), 5.25 (s, 1 H), 4.63 (m, 2 H), 3.5 (m, 2 H), 3.30 (m, 1 H), 2.90 (s, 3 H), 2.6-2.4 (m, 4 H), 2.3 (m, 1 H), 2.0 (m, 1 H), 0.91 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for CjjHjîNîCh: 497.2; Found: 497.2; LCMS-ESI' (m/z): [M-H]' calcd for C_3!H-,iN₂O₄:495.2; Found: 495.2.

Example 48: (S)-2-((R)-2-(but-3-enyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methylquinolin-6-yl)-2-tert-butoxyacetic acid (48).

( S)-2-((R)-2-(but-3-eny 1)-5-(2,3-dihydropyrano[4,3,2-de] quinolin-7-yl)-7-methylquinolin-6-yl)-24eri-t)utoxyacetic acid (S)-2-((R)-2-(but-3-enyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methylquinolin-6-yl)-2-tert-butoxyacetic acid (48) (12 mg) ) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-((R)-5-(2₎3 -dihydropyrano[4,3,2-de]quinolin7-yl)-2-isopropyl-7-methylquinolin-6-yl)acetïc acid of Example 46 except using but-320 enylmagnesîum bromide instead of isopropylmagnesium bromide. ’H-NMR 400 MHz (CD3OD) δ 8.62 (m, I H), 8.09 (s, 1 H), 7.94 (m, 1 H), 7.68 (m, 1 H), 7.57 (m, 2 H),

7.32 (m, 1 H), 5.90 (m, 1 H), 5.25 (s, 1 H), 5.08 (m, 2 H), 4.64 (m, 2 H), 3.52 (m, 2 H),

3.25 (m, 2 H), 2.90 (s, 3 H), 2.62 (m, 2II), 0.91 (s, 9 H); LCMS-ESI* (m/z): [M+H]⁺calcd for C₃₁H33N₂O₄:497.2; Found: 497.2; LCMS-ESI* (m/z): [M-H]’ calcd for

C₃₁H₃₁N₂O₄: 495.2; Found: 495.1.

Exampïe'49: (2S)-2-tert-Butoxy-2-((5R)-2-sec-buty 1-5-(2,3-dihydropyrano [4,3,2de]quinoIin-7-yI)-7-methylquinolin-6-yl)acetic acid (49).

(2S)-2-tert-butoxy-2-((5R)-2-sec-butyl-5-(2,3-dihydropyrano [4,3,2-de]quinotÎn-7-yl)-7-methylquinolin-6-yl)acetic acid (2S)-2-tert-butoxy-2-((5R)-2-sec-butyl-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (49) (9.4 mg) was prepared in a similar manner as compound (S)-2-teit-butoxy-2-((R)-5-(2,3-dihydropyiano [4,3,2de]quinolin-7-yl)-2-isopropyL7-methylquinolin-6-yl)acetic acid of Example 46 except using sec-butylmagnesium bromide instead of îsopropylmagnesium bromide. 'H-NMR

400 MHz (CD₃OD) δ 8.58 (d, J = 4.4 Hz, 1 H), 8.10 (s, 1 H), 7.96 (m, 1 H), 7.67-7.58 (m, 2 H), 7.48 (m, l H), 7.26 (d, J = 8 Hz, 1 H), 5.25 (s, 1 H), 4.62 (m, 2 H), 3.48 (m, 2 H), 3.2 (m, 1 H), 2.90 (s, 3 H), 1.85 (m, 2 H), 1.44 (m, 3 H), 0.91 (m, 12 H); LCMSESI* (m/z): [M+H]* calcd for C₃iH_3îN_zO₄: 499.2; Found: 499.2; LCMS-ESI’ (m/z):

[M-H]* calcd for C₃₁H₃₃N₂O₄: 497.2; Found: 497.2.

Example 50: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3₁2-de]quînolin-7-yl)-2isobutyI-7-methylquinolin-6-yl)acetic acid (50).

224

(S)-2-tert-butoxy'2-({ff)-5-{2,3-ciitiydropyrano(4,3,2-de] quÎnolin-7-yl)-2-isobutyb7-methylquinolin-6-yl)acetic acid (S)-2-tert-butoxy-2-((R)-5 -(2,3 -dibydropyrano[4,3,2-dc]quinolin-7-yl)-2isobutyl-7-methylquinolin-6-yl)acetic acid (50)(10 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,32-<le]qwnoliii5 7-yl)-2-isopropyI-7-methylquinolin-6-yl)acetic acid of Example 46 except using isobutylmagnesium bromide instead of isopropylmagnesium bromide. ¹ H-NMR 400 MHz (CD₃OD) δ 8.65 (d, J = 5.2 Hz, l H),8.12 (s, 1 H), 8.03 (d, J = 9.2Hz, 1 H),7.72 (d, J = 8 Hz, l H), 7.63-7.58 (m, 2 H), 7.33 (d, J = 8 Hz, 1 H), 5.26 (s, I H), 4.65 (m, 2 H), 3.55 (m, 2 H), 3.05 (d, J = 7.2 Hz, 2 H),2.92 (s, 3 H), 2.2 (m, 1 H), 1.02 (d, J= 6.8

Hz, 6 H), 0.92 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C₃iH_3JN₂O₄: 499.2; Found: 499.2; LCMS-ESI* (m/z): [M-H]’ calcd for C₃iH₃₃N_zO₄:497.2; Found: 497.2.

Example 51 : (S)-2-tert-Butoxy-2-((R)-2-cyclopenty 1-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yI)-7-methylquinoIin-6-yl)acetic acid (51).

(S)-2-ierf-butoxy-2-((R)-2-cydopentyi-5-(2,3-dihydropyrano l4,3₁2-de]quinolin-7-yl)-7-methylquinolin-6-y l)acetic acid (S)-2-tert-Butoxy-2-((R)-2-cyclopentyl-5-(2,3-dihydropyrano[4,3,2de]quinoIin-7-yI)-7-methylquinolîn-6-yl)acetic acid (51) (8 mg) was prepared in a

C

225 similar manner as compound (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2de]quinoiiii-7-yl)-2-isopropyl-7-methylquinolin-6-yl)acetic acid in ofExample 46 except using cyclopentylmagnesium bromide instead ofisoprapylmagnesium bromide. ’H-N'MR 400 MHz (CDîOD) δ 8.63 (m, l H), 8.12 (s, l H), 8.0l (d, J = 7.2 Hz, l H),

7.65 (m, 2 H), 7.54 (m, 1 H), 7.32 (m,'l H), 5.26 (s, 1 H), 4.65 (m, 2 H), 3.52 (m, 3 H),

2.91 (s, 3 H), 2.30 (m, 2 H), 2.0-1.8 (m, 6 H), 0.91 (s, 9 H); LCMS-ESf (m/z): [M+H]⁺calcd for (HH35N2O4: 511.2; Found: 511.1; LCMS-ESf (m/z): [M+H]⁺ calcd for C₃2H₃3N2O₄: 509.2 Found: 509.1.

i O Example'52: (S)-2-tert-Butoxy-2-((R)-2-cyclohcxyl-5-(2,3-dihydropjÎano[4,3,2de]quino!in-7-yI)-7-methylquinolin-6-yl)acetic acid (52).

(S)-2-tert-butoxy-2-((/?)-2-cyciohexyl-5-(2,3-dihydropyrano [4,3,2-de]qu;nojin-7-y!)-7-methylquir>olin-6-yl)acet:c acid (S)-2-tert-Butoxy-2-((R)-2-cyclohexyl-5-(2,3-dihydropyrano[4,32*de]quinolin15 7-yl)-7-methylquinolin-6-yl)acetic acid (52) (11 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinoli&-7-yl)-2isopropyl-7-methylquinolin-6-yl)acetic acid in ofExample 46 except using cyclohexylmagnesium bromide instead of isopropylmagnesium bromide. 'H-NMR 400 MHz (CD3OD) δ 8.62 (m, 1 H), 8.13 (s, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.65 (m, 2 H),

7.54 (m, 1 H), 7.30 (d, J = 8 Hz, 1 H), 5.26 (s, 1 H), 4.65 (m, 2 H), 3.50 (m, 2 H), 3.15 (m, 1 H), 2.91 (s, 3 H), 2.1-1.35 (m, 10 H), 0.91 (s, 9 H); LCMS-ESf (m/z): [M+H]⁺calcd for C33H37N2O4: 525.3 ; Found: 525.2; LCMS-ESf (m/z): [M-H]’ calcd for C3₃H3₅N₂O₄: 523.3; Found: 523.2.

226

Example 53: (S)-2-((R)-2-BenzyI-5-(2,3-dihydropyrano[4,3,2-de]quinolîn-7-yI)-7methylquinolin-6-yl)-2-tert-butoxyacetîc acid: (53).

ΌΗ ίο (5)-2-((Κ)-2-Βεηζν1-5-(2,3-άϊΗνάκ)ρνΓ3ηο[4,3,2-όε]ςώηο!ιη-7-ν1}-7mcthylquinolin-6-yl)-2-tert-butoxyacetic acid (53) (8 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-2-isopropyl-7-methylquinolin-6-yl)acetic acid of Example 46 except using benzylmagnesium bromide instead of isopropylmagnesium bromide. ’H-NMR 400 MHz (CD₃OD) δ 8.61 (m, 1 H), 8.13 (s, 1 H), 7.82-7.70 (m, 2 H), 7.60 (m, 1 H), 7.47.2 (m, 7 H), 5.24 (s, 1 H), 4.65 (m, 2 H), 4.45 (s, 2 H), 3.55 (m, 2 H), 2.89 (s, 3 H), 0.91 (s, 9 H); LCMS-ESl' (m/z): [M+H]⁺calcd for C₃4H_BN₂O₄: 533.3; Found: 533.2; LC MS-EST (m/z): [M-H]' calcd for CmHuN^; 531.3; Found: 531.1.

Example 54: (S)-2-tert-Butoxy-2-((R)-5-(2₎3-dihydropyrano[4,3_i2-de]quinolin-7-yI)-2(2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (54).

227

(S)-2-red-tutoxy-2-((fï)-5-(Z,3-dihydro pyrano[4,S,2-dejquino!itv7.yi).7-methy!-2(trifluor omethylsu Ifony foxy )qu ino!in-6-yl)eth yl piva late (S)-2-ferr-butoxy-24(fl)-5-(2,3-<litiydfopyrano J4,3,2-de]quinoin-7-y0-2-(2,6-dimethylphenyl ) •7-meth yiqut nolin-6-yIJethyI piv a laie

(SJ-2-tert-butoxy-2-((/7)-542,3-dïh ydrapyrano

K.3,2-de)quinoin-7-|rl)-242,B-dimeth)1phei>y1) -7-methyk]uinolÎr>-8-yl)a«tic acid (S)-24ei'(-butoxy-24(R)-5-(2,3-dihydrapyrano [4.3_r2-<fefauinoli(i-7-yi)-242.6-dsmetbyiphenyi) -7-melhy Iqu ino!in-6-yl)ethanol

Préparation of (S>2-tert-butoxy-2-((R)-5-(2,3-dihydropyTano[4,3,2de]quinolin-7-yl)-2-(2,6-dimethylphenyl)-7-methylquinolin-6-yl)ethyl pivalate: (S)-2tert-butoxy-2-((R)-5-(2,3 -dihydropyrano[4,3,2-dcJquinol în-7-yl)-2-(2,65 dimethylphcnyl)-7-rnethylquinolin-6-yl)ethyl pivalate (7.5 mg) was prepared in a similar mariner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-

1,2-dihydroquinolin-6-yl)ethyl pivalate of Example 8 except using (S)-2-tert-butoxy-2((R)-5-(2,3-dihydropyrano[4,3,2-dc]quinolm-7-yl)-7-niethyl-2(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate and 2,6- dimethylphenylboronic acid instead of (S)-2-(5-bromo-7-methyl-2-oxo-l ,2dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate and 4-chlorophenylboronic acid. LCMS-ESI* (m/z): [M+H]* calcd for C4QH45N2O4:6173; Found: 617.5.

Préparation of (S)-2-tert-butoxy-2-((R)-5-(23'dihydropyraiio[4,3,2de]qumoIin-7-yl)-2-(2,6-dimethylphenyl)-7-methylquinolÎn-6-yl)ethanol· (S)-2-tert15 butoxy-2-((R)-5-(23-dihydropyrano[43,2-dc]quinolin-7-yl)-2-(2,6-dimethylphenyl)-7methylquinolin-6-yl)ethanol (5.5 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-nioipholinoquinolin-6-yl)ethanol

- 228 of Example 29 except using (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano [4,3,2de]quinolin-7-yl)-2-(2,6-dimethylphenyl)-7-mcthylquinoiin-6-yl)etliyÎ pivalate instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyi pivalate. LCMS-ESI* (m/z): [M+H]* calcd for C35H37N2O3: 533.3; Found: 533.4.

Préparation of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyTajio[4,3,2de]quinolin-7-yl)-2-(2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (54): (S)2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(2₁6dimethylphenyl)-7-methylquinolin-6-yl)acetiç acid (3.5 mg) was prepared in a smilar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-210 morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2· ((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(2,6-dimethyIphenyl)-7' methylquînolin-6-yl)ethanol instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7methyl-2-morpholinoquinolin-6-yl)ethanol.¹ H-NMR 400 MHz(CDjOD) δ 8.66 (m, 1 H), 8.13 (m, 1 H), 7.95 (m, 1 H), 7.80 (m, 1 H), 7.64 (m, 1 H), 7.45 (m, 1 H), 7.4-7.25 (m, 2 H), 7.23 (m, 2 H), 5.29 (s, l H), 4.68 (m, 2 H)_t 3.57 (m, 2 H), 2.89 (s, 3 H) 2.06 (s, 6 H), 0.94 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C_3SH3₅N₂O<: 547.3;

Found: 547.2; LCMS-ESI (m/z): [M-H]' calcd for C35H33N2O4:545.3 ; Found: 545.2.

Example 55: (S)-2-tert-Butoxy-2-((R)-2-(3-chlorophenyl)-5-(2,3-dihydropyrano[4,3220 de]quinolin-7-yl)-7-methyIquinolin-6-yl)acetic acid (55).

(S)-2-terf-butoxy-2-((R)-2-(3-chlorophenyl)-5-(2,3-diliydropyrano[4,3_]2de]quinolîn-7-yl)-7-methy!quinolîn-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-2-(3-chlorophenyl )-5-(2,3-dihydropyrajio [4,3,2de]quinolin-7-yI)-7-methyiquinoIin-6-yl)acetic acid (55) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-((R)-5-(2,3-diliydropyrano[4,3,2-de]quinolin25 7-yl)-2-(2,6-dimethylphenyl)-7-methylquinolin-6-yi)acetic acid (3.5 mg) of Example i/

C

229 except using 3-chlorophenylboronic acid instead of 2,6-dimethylphenylboronic acid . Ή-NMR 400 MHz (CD₃OD) δ 8.71 (d, J = 5.6 Hz, 1 H), 8.23 (s, 1 H), 8.20 (s, 1 H), 8.04 (m, 1 H), 7.9-7.75 (m, 3 H), 7.6-7.4 (m, 4 H), 5.27 (s, I H), 4.74 (m, 2 H), 3.66 (m, 2 H), 2.86 (s, 3 H), 0.95 (s, 9 H); LCMS- LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C33H₃ûC1N₂O4: 553.2; Found: 553.1 ; LCMS-ESI' (m/z): [M-H]' calcd for C33H2JCIN2O4:551.2; Found: 551.1.

Example 56: (S)-2-tert-Butoxy-2-((R)-2-(4-chloropheny 1)-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (56).

ίο

.OH (S)-2-tert-Butoxy-2-((R)-2-(4-chlorophenyl)-5-(2,3-dihydropyrano[4,3,2de]quinoIin-7-yI)-7-methylquinolin-6-yl)acetic acid (56) was prepared in a sîmilar manner as compound (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-dc]quinoÎin7-yl)-2-(2,6-dimethylphenyI)-7-melhylquinolîn-6-yl)aceticacid (3.5 mg) of Example 54 except using 4-chIorophcnylboronic acid instead of2,6-dimethylphenylboronic acid . ’H-NMR 400 MHz (CDjOD) δ 8.70 (d, J = 5.2 Hz, 1 H), 8.22 (s, 1 H), 8.13 (d, J = 8.4 HZ, 2 H), 7.9-7.75 (m, 3 H), 7.6-7.5 (m, 2 H), 7.46 (d, J = 8 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 5.27 (s, I H), 4.75 (m, 2 H), 3.64 (m, 2 H), 2.86 (s, 3 H), 0.95 (s, 9 H). LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C₃₃H₃₀ClN₂O4: 553.2; Found; 553.1; LCMS-ESI' (m/z): [M-H]' calcd for CsîHîsCIN^: 551.2; Found: 551.1.

Example 57: (S)-2-tert-Butoxy-2-((R)-5-(23-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-phenylquinolin-6-yl)acetic acid (57).

fi

230

(S)-2-tert-Butoxy-2-((R)-5-(2 j-dihydropyrano[4,3.2-dc]quinolin-7-yl)-7mcthyl-2-phenyIquinoiin-6-yl)acetic acid (57) was prepared in a similar manner as compound (S)-2-tcrt-butoxy-2-((R)-5-(2_i3-dihydropyrano[4,3,2-de]qiiinûlin-7-yI)-25 (2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (3.5 mg) of Example 54 except using phenylboronic acid instead of 2,6-dimethylphenylboronîc acid. 'H-NMR 400 MHz(CD₃OD) δ 8.71 (m, l H), 8.24 (m, 1 H), 8.12 (m,2 H), 7.85 (m, 2 H), 7.75 (m,2 H), 7.60 (m, 3 H), 7.43 (d, J = 8 Hz, 1 H), 5.28 (s, 1 H), 4.69 (m, 2 H), 3.63 (m, 2 H), 2.88 (s, 3 H), 0.95 (s, 9 H); LCMS-ESI* (m/z): [M4-H]⁺ calcd forC₃₃H₃iN2O₄: 519.2;

Found: 519.1.

Exampie 58: (S)-2-tert-Butoxy-2-((R)-2-cyclopropyl-5-(2,3-dihydropyrano[4₎3,2de]quinolin-7-yl)-7-methylquinolm-6-yl)acetic acid (58).

(S)-2-tert-Butoxy-2-((R)-2-cyclopropyl-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-methylquînolin-6-yl)acetic acid (58) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quino]in7-yl)-2-(2,6-dimethylphenyl)-7-methylquinolin-6-yl)aceticacid (3.5 mg) of Example 20 54 except using cyclopropylboronic acid instead of 2,6-dimethylphenylboronic acid .

'H-NMR 400 MHz (CD₃OD) δ 8.65 (d, J = 5.2 Hz, 1 H), 8.07 (s, 1 H), 7.86 (d, J = 8.8

231

Hz, l H), 7.69 (d, J = 8 Hz, l H), 7.56 (d, J = 4.8 Hz, l H), 7.3l (d, J = 8.4 Hz, IH),

7.18 (d, J = 8?8 Hz, 1 H), 5.24 (s, ] H), 4.65 (m, 2 H), 3.51 (m, 2 H), 2.90 (s, 3 H), 2.50 (m, 1 H), 1.54 (m, 2 H), 1.30 (m, 2 H), 0.92 (s, 9 H); LCMS-ESI* (m/z): [M+H]⁺ calcd for CjcHîtNaCU: 483.2; Found: 483.2; LCMS-ESI' (m/z): [M-Hf calcd for

C30H29N2O4'. 481.2; Found; 481.2.

Example 59; (S)-2-(l,5-Bis(4-chlorophenyl)-7-methyl-2-oxo-l,2-dihydroquinolin-6yl)-2-tert-butoxyacetic acid: (59).

(S)-2-(1,5-bis(4-chiorcphenyt) -7-methyP2-oxo-1,2-d ihydroquin olîn -6-y1)-2-/ert-but«yethyi pivalate

NaOH MeOWTHF 50 *C

( S) -6-(1 -terf-butoxy-2-hydroxy ethy I) -1,5-bis(4-diÎoropÎienyl j -7-methyiquinolin-2(1 H)-one ( S )-2-( 1,5-b is (4-chl wopheny l>7-methy I

-2-OXC-1,2<ihydroqiiinolin-6-yl)-2-|eriq)utCMyacetic add

Préparation of (S)-2-(l,5-bis(4-chlorophenyl)-7-methyl-2-oxo-l,2dihydroquinoIin-6-yl)-2-tert-butoxyethyl pivalate: To the solution of (S)-2-tert-butoxy2-(5-(4-chlorophenyI)-7-methyl-2-oxo-l ,2-dihydroquinolm-6-yl)ethyl pivalate (8J) (23 mg, 0.05 mmol) and 4-chlorophenyIboronic acid (16 mg, 0.10 mmol) in dichloromethane (2 mL) was added copper (II) acetate (9 mg), followed by molecular

C

232 sieve 4Â and pyridine ( 82 pL). The mixture was stirred for.5 days, and filtered and washed with ethyl acetate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave(S)-2-(l,5-bis(4-chlorophenyl)-7-methyI-2oxo-l,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pîvalate (25 mg). LCMS-ESr (m/z): 5 [M+H]⁺ calcd for C₃3H₃₆C1₂NCÿ 580.2; Found: 580.0.

Préparation of ( (8)-6-( l-tcrt-butoxy-2-hydroxyethyl)-l,5-bis(4-chlorophenyl)7-methylquinoIîn-2( I H)-one: (S)-6-( l -lert-butoxy-2-hydroxyethyl)-1,5-b i s(4chlorophenyl)-7-methyiquinolîn-2(lH)-one was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morphoIinoquinolin-610 yl)ethanol of Example 29 except using (8)-2-(1,5-bis(4-chlorophenyl)-7-niethy 1-2-oxo- l,2-dihydroquinoIin-6-yl)-2-tert-butoxyethyl pîvalate instead of (S)-2-tert-butoxy-2-(5(4-chlorophenyI)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pîvalate. LCMS-ESI’ (m/z): [M+Hf calcd for C₂₈H₂₈C!₂NOy496.1; Found: 496.3.

Préparation of( (8)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,215 dihydroquinolin-6-yl)-2-tert-butoxyaceticacid(59): (S)-2-(l,5-bis(4-chlorophenyl)-7methyi-2-oxo-l,2-dîhydroquinolin-6-yl)-2-tert-butoxyacetic acid was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-6-(l-tert-butoxy2-hydroxyethyI)-l,5-bis(4-chlorophenyI)-7-methylquinolin-2(lH)-one instead of ((S)20 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-niethyl-2-morpholinoquinolin-6-yl)ethanol. ^:HNMR 400 MHz (CD3OD) δ 7.51 (m, 3 H), 7.46 (m, 2 H>, 7.25 (d, J = 9.6 Hz, 1 H), 7.27.15 (m, 3 H), 6.52 (d, J « 9.6 Hz, 1 H), 6.42 (s, 1 H), 5.05 (s, 1 H), 2.28 (s, 3 H), 0.93 (s, 9 H); LCMS-ESI* (m/z): [M+H]⁺calcd for C2gH₂₆Cl₂NO₄: 510.1; Found: 510.1.

Example 60: (S)-2-tert-Butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2isopropyl-8-methyIimidazo[l,2-a]quinolin-7-yl)acetic acid: (60).

233

1,4-dioxane

160 *C

(S>2-tert-butoxy-2-({R)-5-(2,3dîhydropyranc[4,3,2-deIquinotin-7-yi) J-methyl-2-(inflUDiOrnethyisififonyfoxy) qurnolin-6-yl)ethyl pivalate (S)-2-te/Î-butoxy-2-((ff)-5-(2.3dihydropyrano[4,3,2'delquinolin-7-y() ,1 -dmettwxy-3-fnelhyibutan -2-ylamino)-7-methylquir»lirv8-yi)ethy) pivalate

NaOH MeOH/THF 50’C (S)-2-tert-butoxy-2-({f?}-6-(2₁3-dihydropyrano [4,3,2-</e}quinolin-7-yl)-2-'sopropyl -8-methy!imidazo[1,2-aJquinolin-7-yl)ethyl pivalate

(S)-2-tert-butoxy-2-((R)-6-{2,3dihydropyrano[4,3,2-iie]quinolin-7-y1) -2-isopropyl-8-mettiyiimidazo [1,2-a]quinolin-7-yl)ethanol (S)-24ert-butoxy-2-((Ry8-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl) -2-isopropyl-8-methyliniidaM [1,2-a)quinolin-7-yl)acetc acid

Préparation of (S)~2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin7-y 1 )-2 - ((S) -1,1 -dirncthoxy-3-rnethy]butan-2-ylamino)-7-inethy lquincliu-6-y! )etiiy 1

234 pivalate: The mixture of (S)-2-tert-butoxy-2-((R)-5-(2_[3-dihydropyrano(4,3,2dejquinolin-7-yl)-7-methyl-2-(tri fluoromethylsulfonyloxy)qui]iolin-6-yl)ethyl pivalate (compound of Example 36) (30 mg) and (S)-l,l-dimethoxy-3-methylbutan-2-amine (70 mg) in 1,4-dioxane (1 mL) was heated at 160 °C for 10 hours. The solution was diluted 5 with ethyl acetate, and was washed with LO N sodium hydroxide solution and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanesÆtOAc) gave (S)-2-tert-butoxy-2-((R)-5-(2,3dihydropyTano[4,3,2-de)quinolin-7-yl)-2-((S)-1, ] -dimethoxy-3-methylbutan-2ylamino)-7-methylquinolin-6-yi)ethyl pivalate (22 mg). LCMS-ESI⁴ (m/z): [M+H]* '10 calcd for CjÿHiîNiOs: 658.4; Found: 658.3.

Préparation of(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-2-isopropyI-8-methylimidazo[l,2-a]quÎnolin-7-yl)ethyl pivalate: The mixture of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinoIin-7-yl)-2-((S)-1,1 dimethoxy-3-methylbutan-2-ylamino)-7-methylquinolin-6-yl)ethyl pivalate (22 mg) and acetic acid (0.1 mL) in xylene (2 mL) was heated at 180 °C for 90 minutes. The solution was diluted with ethyl acetate, and was washed with 1.0 N sodium hydroxide solution and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-((R)-6-(2,3dihydropyrano[4,3,2-de]quinolin-7 -y l)-2-isopropyl-8-methyliniidazo[ 1,2-a]quinolin-720 yl)ethyl pivalate (8.7 mg). LCMS-ESI* (m/z): [M+H]* calcd for C37H44N3O4: 594.3; Found: 594.4.

Préparation of(S)-2-tert-butoxy-2-((R)-6-(2,3-dîhydropyrano[4,3,2-de]quinolin7-y l)-2-i sopropyI-8-methylimîdazo[ 1,2-a]quÎnolin-7-yl)ethanol: (S)-2-tert-butoxy-2((R)-6-(2_î3-dihydropyrano[4₎3,2-de]quinolin-7-yl)-2-isopropyL8-mcthylimidazo[l,225 a]quinolin-7-yl)ethanol was prepared in a similar manner as compound ((S)-2-tertbutoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquino1in-6-yl)ethanol of Example 29 except using (S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7yl)-2-isopropyl-8-niethylimidazo[l,2-a]quinolin-7-yl)ethyl pivalate instead of (S)-2tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate.

LCMS-ESI* (m/z): [M+H]* calcd for C32H36N3O3: 510.3; Found: 510.3.

Préparation of (S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3_t2-de]quinolin7-yl)-2-isDpropyl-8-methylimidazo[l,2-a]quinolin-7-yl)acetic acid (60): (S)-2-tertb

235

Butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-isopropyl-8methylÎmÎdazo[l,2-a]quinoiîn-7-yl)acetic acid was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chloropheny))-7-methyl-2-morpholinoquinolin-6yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-((R)-6-(2,35 dihydropyrano[4₁3,2-de]quinolin-7-yl)-2-isopropyl-8-methylimidazo[l,2-a]quinolin-7yl)ethanol instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)~7-methyl-2morpholinoquinolin-6-yl)ethanol. ’H-NMR 400 MHz (CD₃OD)Ô 8.8 (s, l H), 8.65 (d, J = 5.2 Hz, 1 H), 8.58 (s, 1 H), 7.7 (m, 1 H), 7.6 (m, 1 H), 7.4-7.2 (m, 3 H), 5.23 (s, 1 H), 4.65 (m, 2 H), 3.55 (m, 2 H), 3.3 (m, 1 H), 2.93 (s, 3 H), 1.50 (d, J = 6.8 Hz, 6 H),

0.93 (s, 9 H); LCMS-ES1⁺ (m/z): [M < Hj* calcd for 524.3; Found: 524.2;

LCMS-ESI' (m/z): [M-HJ* calcd for C32H32N3O4: 522.3; Found: 522.1.

Example 61 : (S)-2-tert-Butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-8methyI-2-phenylimidazo[l,2-a]quinolin-7-yl)acetic acid (61).

( S)-2-tert-butoxy-2-((R)-6-(2₁3-dihydropyrano [4,3,2-de]quinoiin-7 -yl)-8-methyl -2-phenyirmidazo[1,2-a]quinolin-7-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-6-(2,3-dihydropyrano{4,3₃2-de]quinolni-7-yl)-8methyl-2-phenylimîdazo[l ,2-a]quinolin-7-yl)acetic acid (61) (2.9 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,220 de]quinoIin-7-yl)-2-isopropyl-8-methylimidazo[l,2-a]quinolin-7-yl)acetic acid of Example 60 except using 2,2-dimethoxy-l-phenyîethanamine instead of (S)-1,1 dimethoxy-3-methylbutan-2-amine. ’H-NMR 400 MHz(CÜ3OD) δ 9.34 (s, 1 H), 8.67 (m, 1 H), 8.60 (m, 1 H), 7.98 (m, 2 H), 7.7 (m, 1 H), 7.6-7.4 (m, 5 H), 7.3 (m, 2 H),

236

5.25 (s, l H), 4.66 (m, 2 H), 3.54 (m, 2 H), 2.95 (s, 3 H), 0.95 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C35H32N3O4: 558.2; Found: 558.2; LCMS-ESf (m/z): [M-H]' calcd for C35H30N3O4: 556.2; Found: 556.1.

Example 62: (S)-2-tert-Butoxy-2-(6-(4-chlorophenyl)-8-methylimidazo[l,2-a]quinolin7-yl)acetic acid (62).

(S)-2-terLbu:oxy-2-(6-(4<h!cropbenyl) -8-mefriyiimidazo[1,2-a]quinolin-7-yl}âceticaci<i (S)-2-tert-Sutoxy-2-(6-(4-chlorophenyl)-8-mcthylimidazo[l₎2-a]quinolin-7yl)acetic acid (62) was prepared in a similar manner as compound (S)-2-tert-butoxy-2((R)-6-(2_J3-dihydropyrano[4_i3,2-de]quinolm-7-yl)-2-isoprcpyl-8-methylimidazo[l,2a]quinolin-7-yl)acetic acid of Example 60 except using (S)-2-tert-butaxy-2-(5-(4chlorophenyl)-7-methy]-2-(trifluoromethylsulfonyloxy)qiiinolin-6-yl)ethyl pivalate and

2,2-dimethoxyethanamine instead of (S)-2-tcrt-butoxy-2-(( R)-5-(2,3dihydropyrano[4_J3,2-de]quinolin-7-yl)-7-methyl-2(trifluoromethylsulfonyIoxy)quinolin-6-yl)ethyl pivalate and (S)-l ₁1 -dimethoxy-3methylbutan-2-amine. ^lH-NMR 400 MHz (CD3OD) δ 8.92 (m, 1 H), 8.45 (m, 1 H),

8.10 (m, 1 H), 7.7-7.6 (m, 5 H), 7.38 (m, 1 H), 5.21 (s, I H), 2.80 (s, 3 H), 0.99 (s, 9 H);

LCMS-ESI* (m/z): [M+H]* calcd for Cj-d^ClNjO?: 423.; Found: 423.2; LCMS-ESI* (m/z): [M+H]* calcd for C24H22CIN2O3: 421.1; Found: 421.0.

Example 63: (S)-2-tert-butoxy-2-(6-(4-ch]orophenyl)-8 -methyl-[ 1,2,4]triazolo[4,3a]quinolin-7-yl)acetic acid (63).

237

( S)-2-fert-butoxy-2-(5-(4^hlorophenyl) -7-methyl-2-(trifluoromethy1 sulfonyloxy)quinaiin-6-yt)ethyl pivalate ( S)-2-ter t- b utoxy-2-(5-(4-cHoraphe nyl) -2-hy d razi nyl-7-m ethylquinolin-8-y I) ethyl pivalate

NaOH/HjO THF/MeOH 50°C

HjNHN

(S)-2-terf-butaxy-2-(5-(4-chlorophenyl) -2-hydrazfnyl-7-methylquinotin-&-yl)ethanol

(S)-2-/ert-butoxy-2-i6-(4-chloropheny!) 63

-e-melhyHI^ÂJtriazoit^.S-aJquincÎn-î-yl) éthanol (S)-2-tert-butoxy-2-(6-(4-chlorophenyl) -a-methyH1,2,4]tnazolo[4_l3-a]quinolin-7-yl) acetic acid

Préparation of (S)-2-tert-butoxy-2-(5-(4-chloropheny])-2-hydrazinyl-7methylquinolin-6-yl)ethyl pivalate: The mixture of (S)-2-tert-butoxy-2-(5-(45 chlorophenyl)-7-methyl-2-(trifluoromethylsuifonyloxy)qiiinolin-6-yl)ethyl pivalate (compound of Example 26) (10 mg) and hydrazine in THF (1.0 N, 1 mL, 1 mmol) was heated at 80 °C for 12 hours. Concentration under reduced pressure gave (S)-2-tertbutoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-yl)ethyl pivalate, which was used for next step without purification. LCMS-ESf (m/z): [M+H]⁺ calcd for C27H35CIN3O5: 484.2; Found: 484.3.

d.

L

- 238

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7methylquinolîn-6 yl)ethanoi: (S)-2-tert-butbxy-2-(5-(4-chlorophenyl)-2-hydrazinyl~7methylquinolin-6-yl)ethanol was prepared in a similar manner as compound ((S)-2-tertbutoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol of Exemple 5 29 except using (S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-2-hydrazmyl-7methylquinoIÎn-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)7-methyl-2-morphoIinoquinolin-6-yl)ethyl pivalate. LCMS-ESI ' (m/z): [M+H]⁺ calcd for C22H27CIN3O2: 400.2; Found; 400.2.

Préparation of (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-inethyl10 [l,2,4]tria2olo[4,3-a]quinolin-7-yl)ethanol:'The mixture of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-yl)ethanol and triethyl orthoformate (0.5 mL) in butanol (5 mL) was heated at 100 °C for 12 hours. The solution was diluted with ethyl acetate, and was washed with 1.0 N sodium hydroxîde solution and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8methyI-[l,2,4]triazoio[4,3-a]quînolin-7-yl)ethanol (3.3 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for CisH^ClNaOi: 410.2; Found: 410.2.

Préparation of (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl' [I,2,4]triazolo[4,3-a]quinolin-7-yl)acetic acid (63): (S)-2-tert-butoxy-2-(6-(4- chlorophenyl)-8-methyl-[l,2,4]triazolo(4,3-a]quinolin-7-yl)acetîc acid was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chbrophenyl)-7-methyI-2morpholinoquinolin-6-yl)acetîc acid of Example 29 except using (S)-2-tert-butoxy-2(6-(4-chlorophenyl)-8-methyl-[ 1,2,4]triazolo[4,3-a]quinolin-7-yl)ethanol instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol.

’H-NMR 400 MHz (CD₃OD) δ 9.95 (s, 1 H), 8.34 (s, 1 H), 7.6 (m, 3 H), 7.54 (m, 1 H),

7.35 (m, 2 H), 5.17 (s, 1 H), 2.75 (s, 3 H), 0.99 (s, 9 H); LCMS-ESC (m/z): [M+H]* calcd for C23H₂₃C1N₃O₃:424.1; Found: 424.2; LCMS-ESI (m/z): [M-H]'calcd for C₂₃H₂iC1N₃O₃: 422.1Found: 421.9.

Example 64: (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-niethyltetrazolo[1,5 -ajquinolin7-yl)acetic acid (64).

Scheme 9

L

239

(S)-2-f erf-butoxy-2-(5-(4-chloropheny I) -7-methyl-2-(tnf1uoromethyi suifonyloxy)quinclin-6-yl}ethyl pivalate

NaN₃DMF/90

Ci

N=N ( S)-2-fer f-buioxy-2-(6-(4-chlof oplwnyl) -S-methylletrazoto{1,5-aJqùnolm-7-yî) ethyl pivalate

(S)-2-iert-butoxy’2-(6-(4-chtorophenyf) -8-methyltetrazolo[1,5-a]quinolin-7-yl) éthanol

(S)-2-tert-butoxy-2-(6-(4-chlorophenyl) -S-melhyltetrazi)lo{1,5-ajquinolin-7-yi) acetic acid

S4

Préparation of (S)-2-tert-butoxy-2-(6-(4-ch]orophcnyl)-8-methyltetrazolo[ 1,5a]quinolin-7-yI)ethyI pivalate: The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)7-methyl-2-(trifluoromethylsulfonyloxy Jquinolin-6-yl)ethyl pivalate (compound of 5 Example 26)(30 mg) and sodium azidc (32 mg) in DMF (1 mL) was heated at 90 C for 4 hours. The mixture was diluted with ethyl acetate, and washed with water and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8methyItetrazolo[I,5-a]quinolin-7-yl)ethyl pivalate (5.9mg). LCMS-ESI* (m/z): [M+H]* 10 calcd for C27H32CIN4O3: 495.2; Found: 495.2.

Préparation of (S)-2-tert-butoxy-2-(6-(4-chlorophcnyl)-8-iiiethyltetrazolo[l ,5a]quinolin-7-yl)ethanol: (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-inethyltetrazolo[l,5a]quinolin-7-yl)ethanol (5 mg) was prepared in a similar manner as compound ((S)-2tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquiiiolin-6-yl)ethanol of

Example 29 except using (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8methyltetrazolo(l,5-a]quinolin-7-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y])ethyl pivalate. LCMS-ES1⁺ (wt/z): [M+H]* calcd for C22H24CIN4O2: 411.2; Found; 411.1.

240

Préparation of (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[l,5a]quinolin-7-yl)acetic acid (64): (S)-2-tert-bôfoxy-2-(6-(4-chIorophenyl)-8methyltetrazolo[l,5-a]quinolin-7-yl)acetic acid (4.9 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-25 morpholinoquinolin-6-yl)acetic acid ofExample 29 except using (S)-2-tert-butoxy-2(6-(4-chlorophenyl)-8-methyltetrazolo[l,5-a]quinolin-7-yl)ethanol instead of ((S)-2tert-butoxy-2-(5’(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanoI.. *HNMR 400 MHz (CD₃OD) δ 8.61 (s, 1 H), 7.75 {d, J = 9.6 Hz, 1 H), 7.67-7.55 (m, 4 H),

7.39 (d, J - 9.2 HZ, 1 H), 5.2 (s, 1 H), 2.79 (s, 3 H), 1.00 (s, 9 H); LCMS-ESf (m/z): 10' [M+H]⁴ calcd for C^H^ClbLiOj: 425.1; Found: 425.1.

Example 65: (5)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tertbutoxyacetic acid (65A) and (S)-2-(l-benzyl-5-(4-chlorophenyl)-7-inethyl-2-oxo-l ,2dihydroquinolin-6-yl)-2-tert-butoxyacetic acid (65B)

C

241

(S)-2-tert-butoxy-2-(5-(4-chlorophenyt) -7-methy ^-ax ο-1,2-d ihydroquin oIin-8-yl) ethyl pivalate

(S)-2-{2-(benzyloxypS(4ihforoptienyl) -7-meth ylqu inofn-6-yl)-2-ter f-butoxyethanol

(S)-1 -be nzy 1-6-(1 - ter f-butûxy -2-hydroxyethyl)-5-(4-ch lorophenyl) -7 -tnethyiqu inoli n-2( t H)-aie

CtOj HsJO_eCH₃CN 0*C

CrO₃h₅io₆CHjCN 0 °C

( SJ-2-(2-(beruy loxy )-5-(4 -chloropheny I) -7-mett)ylquinoBn-6-yl)-2-tert-butoxyaceticadti

(5)-2-( 1 -beniyl-5-(4-chlorophenyl) -7-methyÛ2-oxo1 Z-dihydroquinolin-B-yt) -2-fer t-buloxyacetic aùd

S5A

65B

Préparation of (S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7 -methylquïnolin-6-yl)2-tert-butoxyethanol and (S)-l-benzyl-6-(l-tert-butoxy-2-hydroxyethyl)-5-(4chlorophenyl)-7-methylquinolin-2(lH)-one: To the solution of(S)-2-tert-butoxy-2-(55 (4-chlorophenyl)-7-rnethyl-2-oxo-l,2-dihydroquinolin-6-yl)ethyI pivalate (SJ) (16 mg, 0.03 mmol) in DMF (1 mL) was added sodium hydride (7 mg, 60% oil, 0.17 mmol). The mixture was stirred for 30 minutes, and benzyl bromide (6 μ1-, 0.05 mmol) was added. The mixture was stirred another 90 minutes, and was quenched with water, and left for 12 hours. The mixture was extracted with ethyl acetate, and the organic layer 10 was washed with water and brine, and dried over sodium sulfate. Concentration and

242 purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-(2(benzyloxy)-5-(4-chlorophenyl)-7-methylquiriôlin-6-yl)-2-tcrt-butoxyethanol (3.1 mg). LCMS-ESI' (m/z): [M-H]' calcd for C₂₉H3₀ClNO₃: 476.2; Found: 476.1. (S)-lBcnzyl-6-( l -tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylqiiinolîn-2(l H)one was also isolated 6.1 mg LCMS-ESI* (m/z): [M+H]* calcd for LCMS-ESI* (m/z): [M+H]* calcd for C29H31CINO3: 476.2; Found: 476.2.

Préparation of (S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylqiiinolin-6-yl)2-tert-butoxyacetic acid: (S)-2-(2-(Benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6yl)-2-tert-butoxyacetic acid (65A) (3.3 mg) was prepared in a similar manner as cornpound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinoiin-6yl)acetic acid of Example 29 except using (S)-2-(2-(benzyIoxy)-5-(4-chlorophenyl)-7methylquinolin-6-yl)-2-tert-butoxyethanol instead of ((S)-2-tert-butoxy-2-(5-(4chlorophenyI)-7-rnethyl-2-rriorpholinoquinolin-6-yl)ethanol.. ’H-NMR 400 MHz (CDjOD) S 7.82 (d, J = 9.6 Hz, 1 H), 7.71 (s, 1 H), 7.80 (m, 3 H), 7.51 (m, 2 H), 7.41-

7.10 (m, 4 H), 7.12 (d, J = 9.6 Hz, 1 H), 5.58 (s, 2 H), 5.18 (s, 1 H), 2.66 (s, 3 H), 0.97 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd for C₂₉H₂₉CINO₄: 490.2; Found: 490.2.

Préparation of (S)-2-(l -benzyl-5-(4-chioiophenyl)-7-methyl-2-oxo-l,2dihydroquinoiin-6-yl)-2-tert-butoxyacetic acid; (S)-2-(l-Benzyl-5-(4-chlorophenyl)-7methyl-2-oxo-l ,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic acid (65B) (5.4 mg) was prepared in a similar manner as cornpound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7methyl-2-morpholïnoquinolin-6-yl)acetic acid of Example 29 exceptusing (S)-lbenzyl-6-( 1 -tert-butoxy-2-hydroxyethyl)-5-(4-chloropheny l)-7-methylquinolin-2( 1H)one instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2morphoIinoquinolin-6-yl)cthanol. . ’H-NMR 400 MHz(CD₃OD) δ 7.6-7.5 (m, 3 H),

7.4-7.2 (m, 8 H), 6.59 (d, J = 9.6 Hz, 1 H), 5.64 (s, 2 H), 5.02 (s, 1 H), 2.47 (s, 3 H), 0.94 (s, 9 H); LCMS-ESI* (m/z): [M+H]* calcd forC₂₉H₂₉ClN0₄: 490.2; Found: 490.2; LCMS-ESI* (m/z): [M+H]* calcd forC₂₉H₂₇ClN0₄:488.2; Found: 488.0.

Example 66: (S)-2-tcrt-butoxy-2-(5-(4-chlorophenyl)-2-methoxy-7-methylquinolin-6yljacetic acid: (66).

L

243

(S)-2-fert-butoxy-2-(5-(4-cbiQrcphenyi)-2-rnethoxy-7methy!quinolin-6-yi)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-methoxy-7-niethylquinolin-6yljacetic acid (66) (2.3 mg) was prepared in a sîmilar manner as compound ($)-2-(2(benzyloxy)-5-(4-chlorophenyI)-7-methylquinolm-6-yl)-2-tert-butoxyacetic acid of

Exemple 65 except using iodomethane instead of benzyl bromide. ’H-NMR. 400 MHz (CD₃OD) 8 7.68 (s, l H), 7.6-7.5 (m, 4 H), 7.30 (d, J = 8 Hz, 1 H), 6.87 (d, J = 9.6 Hz, 1 H), 5.16 (s, 1 H), 4.08 (s, 3 H), 2.62 (s, 3 H), 0.97 (s, 9 H); LCMS-ESI* (m/z): [M+H]⁺ calcd for CbHïsCINOî: 414.1 ; Found: 414.2; LCMS-ESI* (m/z): [M+H]⁺calcd for C23H23CINO4: 412.1; Found; 412.0.

Example 67: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-l,7-dimethyl-2-oxo-l ,2dihydroquinolin-6-yl)acetic acid (67).

S7 (S)-2-ferf-butoxy-2-(5-(4-chloTophenyl)-1,7-dimeihyi-2-oxo1,2-dihydroquinolin-6-yl)acetic acid (S)-2-teit-BuÎoxy-2-(5-(4-chlorophenyl)-l,7-dimethyl-2-oxo-1,2dihydroquÎnorm-6-yl)acetic acid (67) (2.0 mg) was prepared în a sîmilar manner as compound (S)-2-( 1 -benzyl-5-(4-chloropheny l)-7-methyl-2-oxo- l,2-dihydroquinolin-6yl)-2-tert-butoxyacetic acid of Example 65 except using iodomethane instead of benzyl

C

244 bromide. H-NMR 400 MHz (CD₃OD) δ 7.6-7.5 (m, 4 H), 7.3-7.26 (m, 2 H), 6.49 (d, J = 10 Hz, l H), 5.06 (s, l H), 3.78 (s, 3 H), 2.64 (s, 3 H), 0.97 (s, 9 H); LCMS-ESf (m/z): [M+H]⁺ calcd for C23H25CINO4: 4I4.1 ; Found: 414.2; LCMS-EST (m/z): [M-H] calcd for C23H23CÎNO4: 412.1; Found: 412.0.

Example 68: (S)-2-((R)-l-benzyl-5-(2,3-dihydropyrano[4,3,2'de]quinolin· 7-yl)-7methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacettc acid (68).

(S)-2-((R)-1 -benzyl-S(2,3-dîhydropyranc(4,3,2-iie] qjino!in-7-y!)-7-methyl-2-oxo-1,2-dihydrc<;uinolin-6-y1) -2-tert-butoxyacetic add (S)-2-((R)-1 -Benzyl-5-(2,3-dihydropyTano|4,3,2-de]quinciin-7-yl)-7-methyl-2oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic acid (68) (1.0 mg) was prepared in a similar manner as compound (S)-2-(l-benzyL5-(4-ch]orophenyI)-7-methyl-2-oxo-l,2dihydroquinolin-6-yi)-2-tert-butoxyacctic acid of Example 65 except using (S)-2-tertbutoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7'yI)-7-methyl-2-oxo-l,2dihydroquînolin-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(4-chiorophenyl)7-methyl-2-oxo-l,2-dihydroquinolin-6-yl)ethyl pivalate. 'H-NMR 400 MHz (CD₃OD) δ 8.68 (m, 1 H), 7.9 (m, 1 H), 7.75 (m, 1 H), 7.6 (m, 3 H), 7.43 (m, 4 H), 7.06 (d, J = 9.2 Hz, 1 H), 6.37 (d, J = 9.6 Hz, 1 H), 5.49 (s, 2 H), 5.07 (s, 1 H), 4.83 (m, 2 H), 3.50 (m, 2 H), 2.72 (s, 3 H), 0.90 (s, 9 H); LCMS-ESf (m/z): [M+H]⁺ calcd for C₃₄H3₃N2O5: 549.2; Found: 549.1 ; LCMS-ESf (m/z): [M-H]calcd for C34II31N2O5: 547.22; Found: 547.1.

Example 69: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7mcthyl-2-(thiophen-2-yl)quinolin-6-yl)acetic acid (69).

(Sp2-(erf-butoKy-2-((R)-5-(2,3-dihydropyranot4.3,2defa uinolir>-7-yl)-7-methyl-2(trifluo rometh y fc ulfony toxyjquirtalin-é-yl Jethyl pîvalate

(S>2-iert-butoxy-2-({ffyS(2.3dihydropyrarw(4,3.2-defauinol«i-7yî)-7-methyf-2«(thiophen-2yl)quinolin-6-yl)éthyt pîvalate

{S)-2-ierf-butoxy-2-((R)-5-(2,3dihydropyrano[4,3,2-<ïe]quino!iri7-yl)-7-methy(-2-(thiQiihen-2y l)q uînoïn-6-yl)ethanal

(S>2-fert-butoxy-2-((fff-5-(2,3-dSiytl ropy rano|4,32-de)quinolin-7yl)-7-methyî-2-(t)i>opfien-2-yl)quinoîin-6-yl)3œlie acid

Préparation of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyiano[4,3,2-dc]quinolin7-yl)-7-methyl-2-(thiophen-2-yI)quînolin-6-yl)ethyl pîvalate: To a solution of(S)-2tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3₎2-de]quinolin-7-yI)-7-methyl-25 (trifIuoromethylsuIfonyloxy)quinolin-6-yl)ethyl pîvalate (compound of Example 36) (50 mg, 0.08 mmol) in 1,2-dimethoxyethane was added thiophen-2-yIboronîc acid (15 mg, 0.114 mmol), 2 M potassium carbonate (0.15 mL, 0,30 mmol) and Pd(PPh₃)₄ (9 mg, 0.008 mmol) and the resulting solution was degassed 5 minutes with argon. The mixture was then heated for 20 minutes at 110 °C in a microwave reactor. The crude reaction was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a brown film (23.2 mg). LCMS-ESf (m/z): [M+H]⁺calcd for C_3fcHj9N₂O₄S: 595.26; found: 595.48.

Préparation of (S)-2~tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-7-methyl-2-(thiophen-2-yl)quinolin-6-yl)ethano): To a solution of (S)-2-tert15 butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methy]-2-(Îhiophen.-2yl)quinolin-6-yl)ethyl pîvalate (23 mg, 0.039 mmol) in tetrahydrofuran and methanol (5:1,3 mL) was added 1 M sodium hydroxide (2 mL) and the réaction was heated to 45

CZ

246

C overnight. An additional 2 mL of l M sodium hydroxide was added and the reaction was stirred at room température over the weekend. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and then dried over sodium sulfate and concentrated to give a yellow film (14 mg). LCMS-ESI⁺ (m/z): [M+H]* calcd for CfiHjiNjOjS: 511.20; found: 511.40.

Préparation of(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydrQpyrano[4,3,2-de]quinolin7-yl)-7-methyl-2-(thiophen-2-yl)quinolin-6-yl)acetic ac;d (69): To a solution of(S)-2tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)~7-methyl-2-(thiophen2-yl)quînoIin-6-yI)ethanol in wet acetonitrile al 0 °C was added 0.4 M CrOj/HsIO^ ( 0.206 mL, 0.082 mmol). The solution was stirred at 0 “C for 3 hours, and an additional 0.082 mmol of 0.4 M CiOj/HîIOé was added. The reaction was quenched with l M NaH₂PO4’2H₂O and extracted with ethyl acetate. The organic layer was concentrated and purified by reverse phase HPLC (Gemini, 10-55% A.CN7H₂O + 0.1% TFA). Product lyophiiized to give a yellow powder (4 mg). ’H-NMR: 400 MHz, (CDjCN) δ:

8.62 (d, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.76 (d, J = 3.2 Hz, 1H), 7.70 (d, J = 7.6 Hz, IH),

7.67 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 4.4 Hz, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 8 Hz, 2H), 7.17 (t, J = 3.2 Hz, 1Η), 5.19 (s, 1H), 4.62 (m, 2H), 3.48 (t, J = 6.0,2H),

2.72 (s, 3H), 0.92 (s, 9H).

LCMS-ESI* (m/z): [M+H]* calcd for CîiHjçNrOiS; 425.18; found: 425.25.

Example 70: (S)-2-lert-Butoxy-2-(5-(4-chlorophenyl)-7methyl-2-(l H-pyrazol-5yl)quinolin-6-yI)acctic acid (70).

(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-niethyl

-2-( I H-pyrazoI-5-y l)qu inolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(lH-pyrazol-5yl)quinolin-6-yl)acetic acid (70) was prepared using the procedure to préparé (S)-2-tert5 butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinoÎin-7-yl)-7-methyl-2-(thiophen-2yl)quinolîn-6-yi)acetic acid of Example 69 except that (Sf2-tert-butoxy-2-(5-(4chlorophenyî)-7-methyl-2-(trifluoromethylsulfonyloxy)quino]in-6-yl)ethyl pivalate was used instead of (S)-2-tert-butoxy-2-((R)-5-(2,3-dîhydrcpyrano[4,3,2-de]quinolin-7-yl)7-methyl-2-(trifluoroniethylsulfonyloxy)quinolin-6-yl)ethyl pivalate and lH-pyrazol-510 ylboronic acid was used instead of thiophen-2-ylboronic acid. Additionally, in the second step the crude extract was co-evaporated two times with acetonitrile and in the final step the CrOj/HsIOs was added in one portion and sti ne d 2 hours. ’H-NMR: 400 MHz, (CD₃CN) δ; 8.06 (s, IH), 7.98 (AB_q, J = 22.4, 8.S Hz, 2H), 7.78 (s, IH), 7.74 (d, J = 8.4 Hz, 1 H), 7.58 (m, 2H), 7.37 (d, J = 8.4 Hz, IH),7.33 (d, J = 7.2 Hz, IH), 7.20 15 (s, 1 H), 5.23 (s, 1 H), 2.64 (s, 3H), 097 (s, 9H). LCMS-ESf (m/z): [M+Hf calcd for

CîsHisCINaOj: 450.15; found: 450.62.

Example 71: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-(lH-pyrazol-5-yI)qumolin-6-yl)acelic acid (71).

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano|4,3,2-de]quinolin-7-yl) -7-methyl-2-(l H-pyrazol-5-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4₁3₎2-de]quinolin-7-yI)-725 methyI-2-(IH-pyrazol-5-yl)quinolin-6-yl)acetic acid (71) was prepared using the procedure to préparé (S)-2-tert-butoxy-2-((R)-5-(2,3-diliydropyrano[4,3,2-de]quinolin7-yl)-7-methyl-2-(thiophen-2-yl)quinolin-6-yl)acetic acid of Example 69 except that

248 lH-pyrazoI-5-ylboronic acid was used instcad of thiophen-2-ylboronic acid, in the second step the crude extract was co-evaporated two times with acetonitrile and in the final step the CrO₃/H₅lO6 was added in one portion and stirred for 2 hours. ^lH-NMR:

400 MHz, (CD₃CN)δ: 8.64 (d, J = 4.8 Hz, IH), 8.07 (s, IH), 7.80 (d, J = 8.8Hz, IH), ' 5 7.69 (d, J = 2.0 Hz, IH), 7.66 (d, J = 8.4 Hz, IH), 7.49 (m, 2H), 7.26 (d, J = 8.0 Hz,

IH), 7.09 (d, J = 2.0 Hz, l H), 5.19 (s, l H), 4.61 (m, 2H), 3.46 (t, J = 6.0 Hz, 2H), 2.74 (s, 3H), 0.91 (s, 9H). LCMS-ESI* (m/z): [M+H]*calcd for CaoHwWa:509.21; found: 509.26.

Example 72: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]qumoliii-7-yl)-7methyl-2-(pyrimidin-5-yl)quinolin-6-yl)acelic acid (72).

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4_!3_î2-de]quinolin-7-yl)7-methyl-2-(pyrimidin-5-yI)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2’((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-720 rnethyl-2-(pyrimidin-5-yl)quinolin-6-yl)acetic acid (72) was prepared using the procedure to préparé (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-7-methyl-2-(lH-pyrazol-5-yl)quinolin-6-y])acetic acid of Example 71 except that pyrimidin-5-ylboronic acid was used instead of lH-pyrazoI-5-ylboronic acid and the final reaction was stirred 1 hour. ’H-NMR: 400 MHz, (CD₃CN) δ: 9.43 (s, 2H), 9.19 (s, IH), 8.63 (d, J = 4.8 Hz, IH), 8.08 (s, 1 H), 7.76 (d, J= 8.8 Hz, IH), 7.71 (d, J - 8.8

Hz, III), 7.50 (d, J = 5.2 Hz, HI), 7.44 (d, J = 8.4 Hz, IH), 7.29 (d, J = 8 Hz, IH), 5.22

249 (s, l H), 4.62 (m, 2H), 3.48 (t, J = 5.6 Hz, 2H), 2.75 (s, JH), 094 (s, 9H). LCMS-ESI* (m/z): [M+H]⁺ calcd for 521.21; found: 521.18.

Example 73 : (S )-2-tert-butoxy-2-(5-(4-chloropheny!)-7-methyI-2-(pyridin-45 yl)quinoIin-6-yl)acetîc acid (73).

(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl2-(pyridin-4-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chIoiOphenyl)-7-nict]iyl-2-(pyridin-4-yl)quinolin-6yl)acetic acid (73) was prepared following the procedure used for (S)-2-tert-butoxy-2(5-(4-chlorophenyI)-7-methyl-2-(l H-pyrazoi-5-yl)quinolin-6-yl)acetic acid of Example 70 except that pyridin-4-yiboronic acid was used instead of lH-pyrazol-5-ylboronic acid and in the final step the reaction was stirred for 3 hours.

’H-NMR: 400 MHz, (CD3CN) Ô: 8.84 (s, 2H), 8.46 (d, J = 5.6 Hz, 2H), 8.03 (s, IH),

7.98 (d, J = 9.2 Hz, IH), 7.87 (d, J = 8.8 Hz, IH), 7.60 (m, 3H), 7.37 (d, J = 8 Hz, IH),

5.27 (s, IH), 2.66 (s, 3H), 0.99 (s, 9H). LCMS-ESI* (m/ty [M+H]⁺calcd for C₂₇H₂₅C1N₂O₃: 461.16; found: 461.64.

Example 74: (S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-7-methyl-2-(pyridin-3yl)quinolin-6-yl)acetic acid (74).

250 et

N .OH (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl2-(pyridin-3-yl)quinolin-6’yl)acetic acid (S)-2-tert-BuÎoxy-2-(5-(4-chlorophenyl)-7-methy]-2-(pyridin-3-yl)qiiiTiorm-6yl)acetic acid (74) was prepared following the procedure for(S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-(pyndin-4-yl)quÎnolin-6-yl)acelic acidof Example73 except that pyridin-3-ylboronic acid was used instead of pyridin-4-ylboronic acid. ’H-NMR: 400 MHz, (CDjCN) S: 9.49 (s, IH), 8.94 (d, J = 8.4 Hz, IH), 8.79 (s, lH), 7.91 (m, 2H), 7.80 (Abq, J = 26.2, 8.8 Hz, 2H), 7.58 (m, 3H), 7.34 (m, IH), 5.25 (s, 1 H), 2.61 (s, 3H), 0.97 (s, 9H). LCMS-ESf (m/z): [M+H]⁺calcd for C₂₇H26C1N₂O₃: 461.16; found: 461.00.

Example 75: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-(pyridin-4-yl)quinolin-6-yl)acetic acid (75).

OH (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de] quinolin-7-yl>7methyI-2-(pyridin-4-yl)qumolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4_t3,2-de]{|uinûlin-7-yl)-7methyl-2-(pyridin-4-yl)quinolin-6-yl)acetic acid (75) was prepared following the

- 25I procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3.2-de]quinolin-7-yI)-7methyl-2-( lH-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 71 except that pyridin-

4-yIboronic acid was used instead of lH-pyrazol-5-yIboronic acid and the final reaction was stirred for l hour. ^lH-NMR: 400 MHz, (CDjCN) δ: 8.82 (br s, 2H), 8.63 (d, J =

4.4 Hz, IH), 8.48 (d, J = 5.2 Hz, 2H), 8.10 (s, IH), 7.85 (d, J = 8.8 Hz, IH), 7.64 (d, J =

Hz, IH), 7.48 (d, J = 8.8 Hz, IH), 7.45 (d, J = 5.2 Hz, IH), 7.25 (d, J = 8 Hz, IH),

5.24 (s, IH), 4.60 (m, 2H), 3.44 (t, J = 6 Hz, 2H), 2.75 (s, 3H), 0.92 (s, 9H). LCMSESI* (m/z): [M+H]* calcd for CW+obLOp 520.22; found: 520.22.

- 10 Example 76: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(thiazol-4yl)quinolin-6-yI)acetic acid (76).

(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl2-(thiazol-4-yl)quÎnolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(thiazol-4-yl)quinolin-6yl)acetîc acid (76) was prepared following the procedure for (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyi-2-(lH-pyrazol-5-yl)quinoIÎn-6-yl)acetic acid of Exampïe 70 except that thiazol-4-ylboronic acid was used instead of lH-pyrazol-5-ylboronic acid 20 and the in the final step the reaction was stirred for 1.5 hours. ’H-NMR.: 400 MHz, (CD_aCN) δ: 9.07 (d, J = 2.0 Hz, IH), 8.58 (d, J = 2.0 Hz, IH), 8.17 (d, J= 9,2 Hz, IH), 8.02 (s, IH), 7.93 (d, J = 9.2 Hz, IH), 7.59 (m, 3H), 7.35 (d, J = 7.6 Hz, IH), 5.25 (s, IH), 2.64 (s, 3H), 0.98 (s, 9H).

LCMS-ESI* (m/z): [M+H]* calcd for C^ClNzOjS: 467.11; found: 467.49.

- 252

Example 77: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methy 1-2-( lH-pyrazol-4yl)quinolin-6-yl)acetic acid (77).

(S)-2-tert-butoxy-2-(5-(4-chlorophenyi)-7-methyl5 2-( l H-pyrazol-4-yl)quinolin-6-yl )acetic acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2 -( l H-pyrazol-4yl)quinolin-6-yl)acetic acîd (77) was prepared following the procedure for (S)-2-tertbutoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(IH-pyrazol-5-yl)quinoiin-6-yl)acetic acid of 10 Example 70 except that 4-(4,4,5,5-tetramethyl-1,3,2-dicxaborolan-2-yl)-1 H-pyrazole was used instead of lH-pyrazol-5-yIboronic acid and the in the final step the reaction was stirred for 1 hour. ^lH-NMR: 400 MHz, (CD₃CN) δ: 8.45 (s, 2H), 8.08 (s, IH), 7.89 (d, J = 8.8 Hz, IH), 7.73 9 (d, J = 8.8 Hz, IH), 7.59 (m, 3H), 7.34 (d, J = 7.2Hz, IH), 5.22 (s, IH), 2.63 (s, 3H), 0.97 (s, 9H). LCMS-ESI* (m/z): [M+H]*calcd for

CiîHiîClNîOy. 450.15; found: 450.53.

Example 78: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyI-2-(lH-pyrazoI-4-yl)quinolin-6-yl)acetic acid (78).

(S)-2-tert-butoxy-2~((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)16294 °53

7-methyl-2-(lH-pyrazoi-4-yl)quinolin-6-yl)acetic acid .

(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyi-2 (lH-pyrazol-4-yl)quinolin-6-yl)acetic acid (78) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y])-7methyl-2-(pyrimidin-5-yl)quinolin-6-yl)acetic acid of Example 71 exceptthat4(4,4,5,5-tetra.rncthyl-],3.2-dioxaborolan-2-yl)-iH-pyra2r)le was used instead of ÎHpyrazo!-5-yIboronic acid. ‘H-NMR: 400 MHz, (CD_?,CN) δ: 8.64 (d, J = 5.2 Hz, IH),

8.50 (br s, 2H), 8.23 (s, IH), 7.61 (m, 3H), 7.45 (d, J = 5.2 Hz, IH), 7.24 (d, J = 8.0 Hz, '10 IH), 5.20 (s, 1H),4.6O (m, 2H), 3.44 (t, J = 6.0 Hz, 2H), 2.74 (s, 3H), 0.89 (s, 9H).

LCMS-ESI* (m/z): [MHlf calcd for C30H29N4O4:509.21; found: 509.07.

Example 79 : (S)-2-tert-butoxy-2-(5 -(4-chlorophenyl)-7-methyl-2-(pyridin-2yl)quinolin-6-yl)acetic acid (79).

254

(S)-2-tert-butoxy-2-(5-(4chtorophenyi)-7-methyl-2(trifuoromethylsulfonyloxy)quinolin-6y Ijethyl pivalate

(S)-2-terf-butoxy-2-(5-(4chlorcphenyl)-7-metfiyl-2-(pyr>din-2yl)quinofin-6-yl)ethyl pivalate

(S)-2-terf-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-(pyfidîn2-yl)quinotin-6-yl)ethanol

(S)-2-fBrt-butoxy-2-{5-(4chlorophenyl)-7-mettiyl-2-{pyridin2-y()quinolin-6-yi)acet!C acid

Préparation of (S)-2-tert-butoxy-2-(5-(4-chIorophenyl)-7-methyl-2-(pyridin-2yl)quinoIln-6-yl)ethyl pivalate: To a solution of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26; 50 mg, 0.08 mmol) in l,2 -dimethoxyethane (l mL) was added 2-(tributylstannyl)pyridine (0.040 mL, 0.125 mmol) and Pd(PPh₃)₄ and the reaction mixture was degassed with argon for 5 minutes. The reaction was heated to 110 °C în a micro wave reactor for 20 minutes. The crude reaction mixture was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a clear oil (45.2 mg). LCMS-ESI* (m/z): [M+H]⁺calcd for

C32H36CIN2O3:531.23; found: 531.68.

Préparation of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyndin-2yl)quinolin-6-yl)ethanol: To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7methyl-2-(pyridin-2-yl)quinoIin-6-yl)ethyl pivalate (45.2 mg, 0.085 mmol) in tetrahydrofuran and méthanol (5:1,1 mL) was added 1M sodium hydroxidc (2 mL) and the reaction was heated to 45 °C overnight. The reaction was cooled to room

255 température, diluted with water and extracted with ethyl acetate. The organic layer was washed with brinc, dried over sodium sulfaté and concentrated. The crude extract was co-evaporated two times with acetonitrile to give a clear oil (33.S mg). LCMS-ESf (m/z): [M-t-H] calcd for C₂7H2_gClN₂O₂: 447.18; found:447.72.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chloroplienyl)-7-niethy[-2-(pyridin-2yl)quinoiin-6-yl)acetic acid (79): To a solution of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-(pyridin-2-yl)quino]in-6-y])ethanol (33.8 mg, Û.076 mmol) in wet acetonitrile at 0°C was added 0.4 M CrCh/TLlO^l .13 mL, 0.454 mmol) and the reaction was stirred at 0 °C for 2 hours. The reaction was quenched with 1 M NaH₂PO₄2H₂O and extracted with ethyl acetate. The organic layer was concentrated and purified by reverse phase HPLC (Gemini, 10-70% ACN/H₂O +0.1% TFA) and the desired product was lyophilized to give a white amorphous powder (5.1 mg). ’HNMR: 400 MHz, (CD₃CN) δ: 8.77 (d, J - 4.4 Hz, IH),8.62 (d, J = 8.0 Hz, IH), 8.31 (d, J = 8.8 Hz, IH), 8.15 (t, J 7.0 Hz, IH), 8.01 (s, IH), 7.86 (d, J = 8.8 Hz, IH), 7.59 (m, 4H), 7.36 (d, J = 8.4 Hz, IH), 5.26 (s, IH), 2.65 (s,ÎH),0.98 (s,9H). LCMS-ESr (m/z): [M+H]‘ calcd for C^HmCINîOj: 461.16; found: 461.91.

Example 80:(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yI)-7methyI-2-(pyridin-2-yl)quinolin-6-yl)acetic acid (80).

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de] quinolin-7-yl)-7-methyl-2(pyridin-2-yl)quinolin-6*yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyI-2-(pyridin-2-yl)quinolin-6-yl)acetic acid (80) was prepared following the procedure for (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-

i 256 yl)quînolin-6-yI)acetic acid of Example 79 except that (S)-2-tert-butoxy-2-((R)-5-(2,3dihydropyrano [4,3,2-de]qumolin-7-yl)-7-methyl-2(trifiuoromethy!sulfonyloxy)qmnolin-6-yl)ethyl pivalate was used instead of (S)-2-tertbutoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-65 yl)ethyl pivalate, a catalytic amount of lithium chloride was used during the first step and the final step was stirred for 1 hour. ‘H-NMR: 400 MHz, (CD₃CN) S: 8.72 (d, J =

4.4 Hz, IH), 8.63 (m, 2H), 8.23 (d, J = 8.8 Hz, IH), 8.11 (s, IH), 8.07 (t, J = 7.6Hz, IH), 7.70 (d, H = 8.0 Hz, IH), 7.54 (t, J = 4.8 Hz, IH), 7.50 (d, J = 4.8 Hz, IH), 7.47 (d, J = 9.2 Hz, IH), 7.28 (d, J = 8 Hz, IH), 5.22 (s, 1 H),4.62 (m, 2H), 3.47 (t, J = 6.0,

2H), 2.75 (s, 3H), 0.92 (s,'9H). LCMS-ESI* (m/z): [M+H]⁺calcd for C₃₂H_3CNA:

520.22; found: 520.23.

Example 81: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4_i3,2-de]quinolin-7-yl)-7methyl-2-(pyridin-3-yl)quinolin-6-yl)acetic acid (81).

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-niethyl-2· (pyridin-3-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-(pyridin-3-yI)quinotin-6-y])acetic acid (81) was prepared following the procedure use for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2“de]quinolin-7· yl)-7-methyl-2-(lH-pyrazol'5-yl)quinolin-6-yl)acetic acid of Example 71 except that pyridin-3-ylboronic acid was used instead of lH-pyrazol-5-ylboronic acid. ¹ H-NMR:

400 MHz, (CD₃CN)5: 8.73 (d, J = 7.4 Hz, IH), 8.60 (d, J = 5.2 Hz, IH), 8.58 (m, IH),

8.38 (br s, IH), 7.68 (m, 3H), 7.51 (m, 2H), 7.40 (d, J =8.8 Hz, IH), 7.25 (d, J = 8.0 îX

C

Hz, IH), 5.05 (s, IH),4.55 (m, 2H), 3.43 (t, J - 6.0 Hz, 2H), 2.62 (s, 3H), 0.88 (s, 9H). LCMS-ESI* (wi): [M+H]* calcd for C_BH»N₃Ô_t: 520.22; found: 520.22.

Example 82: (S)-2-tert Butoxy-2-(5-(4 -chiorophcnyl)-7 nicthyi-2-(l-methyl-1H5 imidazol-5-yl)quinolin-6-yI)acetic acid (82)

(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(l -methyl-1 H-ïmidazol-5yi)quinolin-6-yl)acetic acid (S)-2-tert-Buîoxy-2-(5-(4-ch]oropheny])-7-methyl-2-(]-methyl-lH-jmidazol-5yl)quinoIin-6-yl)acetic acid (82) was prepared following the procedure for (S)~2-tertbutoxy-2-(5-(4-chiorophenyl)-7-inethy l-2-(pyridin-2-yl)quinolin-6-yl)acetic acid of Example 79 except that l-methyI-5-(tributylstannyl)-lH-imidazole was used instead of 15 2-(tributylstannyl)pyridine, a catalytic amount of lithium chloride was used in the first step and the final réaction was stirred for 3 hours.¹ H-NMR; 400 MHz, (CD₃CN) δ:

8.47 (s, IH), 7.91 (s, IH), 7.85 (s, IH), 7.66 (d, J = 8.8 Hz, IH), 7.58 (s, 2H), 7.54 (t,J = 8.0 Hz, 2H), 7.31 (d, J - 8.4 Hz, IH), 5.22 (s, IH), 4.27 (s, 3H), 2.61 (s, 3H), 0.96 (s, 9H). LCMS-ESf (m/z): [M+H]* calcd for C_2ÉH₂7C1N₃O₃: 464.17; found: 464.51.

Example 83: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3_i2-de]quinolin-7-yl)-7methyI-2-( 1 -methyl-I H-imidazol-5-yl)quinolin-6-yl)acetic acid (83)

258

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4₎3,2-de]quinolin-7-yl)-7-metliyl-2-(l· methyl-l H-imidazol-5-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7mcthy l-2-( l-methyl-lH-imidazol-5-y !)quiriolin-6-y])acetic acid (83) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-mcthyl-2-(pyridin-2-yi)quinolin-6-yl)acetic acid of Example 80 except that l -methyl-5-(tributylstannyl)-lH-imidazole was used instead of 210 (tributylstannyl)pyridine, the first reaction was run for 25 minutes and using a catalytîc amount of lithium chloride, and the second step was stirred atroom température over the weekend instead of overnight at 45 °C. ‘H-NMR: 400 MHz, (CDjCN) Ô: 8.66 (d, J = 4.8 Hz, IH), 8.34 (s, IH), 8.02 (s, IH), 7.62 (d, J - 8.0 Hz, IH), 7.53 (s, IH), 7.47 (d, J = 5.2 Hz, IH), 7.38 (s, 2H), 7.24 (d, J = 7.6 Hz, IH), 5.14 (s, IH), 4.59 (m, 2H), 4.27 <s, 3H), 3.45 (t, J = 5.6 Hz, 2H), 2.74 (s, 3H), 0.92 (s, 9H). LCMS-ESI* (m/z); [M+H]* calcd forC₃iH_3IN₄O4: 523.23; found: 523.28.

Example 84: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-(l-methyl-lH-imidazol-2-yl)quinolin-6-yl)acetic acid (84).

259

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)7-methyl-2-( l -methyl-l H-imidazol-2-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-(l-methyl-lH-imidazol-2-yl)quinolin-6-yI)acetic acid (84) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-methyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid of Example 80 except using l-methyl-2-(tributylstannyl)-lH-imidazole instead of2(tributylstannyl)pyridine, using a catalytic amount of lithium chloride in the first step, and the second step was run at room température over the weekend instead of at 45 ^DC overnight. H-NMR: 400 MHz, (CD3CN)δ: 8.63 (d, J = 4.8 Hz, IH), 8.12 (s, IH), 7.92 (d, J = 8.8 Hz, IH), 7.64 (d, J = 7.6 Hz, IH), 7.47 (m, 4H), 7.25 (d, J = 8.0 Hz, IH), 5.25 (s, IH), 4.60 (m, 2H), 4.30 (s, 3H), 3.45 (t, J = 5.6 Hz, 2H),2.75 (s, 3H), 0.92 (s, 9H). LCMS-ESf (m/z): [M+H]⁺ calcd for C3iH_3lN₄O₄:523.23; found: 523.12.

Example 85: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-(l-methyl-l H-imidazol-4-yl)quinolin-6-yl)a«tic acid (85)

- 260 (S)-2-tert-butoxy-2-((R)-5-(2,3 -dihydropyrano[4.3,2-de]quinolin-7-yl)7-πlethyl-2-( l -methyl-l H-imidazol-4-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-75 methyl-2-(l-methyt-lH-imidazol-4-yl)quinolin-6-yl)acetic acid (85) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(23-dihydropyrano[4,3,2de]qumolin-7-yl)-7-methyl-2-(pyridm-2-yl)quinolin-6-yl)acetic acid of Example 80 except that l-methyl-4-(tributylstannyl)-lH-îmidazok was used instead of2(tributylstannyl)pyridine, and a catalytîc amount of lithium chloride was used in the first step as well as being heated for 25 minutes. The second step was run at room température over the weekend, followed by at 45 °C for four hours. *H-NMR: 400 MHz, (CDjCN) δ; 8.64 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.9C (s, 1H),

7.58 (d, J = 8.0 Hz, 1H), 7.47 (m, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.0 Hz,

H), 5.17 (s, 1H), 4.61 (m, 2H), 3.85 (s, 3H), 3.46 (t, J = 6.0 Hz, 2H), 2.67 (s, 3H), 0.88 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for C₅₁II-, MO*: 523.23; found: 523.28.

Example 8 6: (S)-2-tert-butoxy-2-(5-(4-chlorophenyI)-7-methyî-2-(l -methyl-1Himidazol-4’yl)quinolin-6-y])acetic acid (86)

(S)-2-tert-butoxy-2-(5-(4-chloropheny])-7-methyl-2( 1 -methyl-l H-imidazol-4-yi)quinolin-6-y!)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-( 1 -meûyl-1 H-îmidazol-425 yl)quinolin-6-yl)acetic acid (86) was prepared following the procedure for (S)-2-tertbutoxy-2-(5-(4-chloropheny])-7-methyl-2-(pyridin-2-yl)quinolin-6-yI)aceticacid of t J “

Example 79 except that l-methyi-4-(tributylstannyi)-lH-iinidazole was used instead of 2-(tributyistannyl)pyridine, a catalytic amount of lithium chloride was used in the first step, as well as being heated for 25 minutes instead of 20 minutes, in the final step the reaction was stirred for 4 hours.

*H-NMR: 400 MHz, (CD₃CN) δ: 8.34 (s, IH), 8.04 (s, EH), 7.74 (s, lH), 7.55 (m, 5H),

7.25 (d, J = 8.0 Hz, 1H), 5.16 (s, 1H), 3.87 (s, 3H), 2.52 (s, 3H), 0.93 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C26H27CIN3O3: 464.17; found: 464.48.

Example 87: (S)-2-tert*Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyrimidÎn-5yl)quinolin-6-yI)acetic acid: (87)

(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-niethyl -2-(pyrimîdin-5-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)~7-meΐhyl·2-(pyrimidin-5-yl)quinolin6-yl)acetic acid (87) was prepared following the procedure used for (S)-2-teit-butoxy2-(5-(4-chlorophenyl)-7-methyl-2-(l H-pyrazol-5-yl)quiuolin-6-yl)acetic acid of Example 70 except that pyrimidin-5-yiboronic acid was used instead of 1 H-pyrazol-5ylboronic acid. ’il-NMR: 400 MHz, (CD3CN) S: 9.52 (br s, 2H), 9.26 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.8 Hz, 1 H), 7.83 (d, J = 9.2 Hz, 1H), 7.60 (m, 3H), 7.37 (d, J - 7.6 Hz, 1H), 5.27 (s, I H), 2.65 9s, 3H), 0.99 (s, 9H). LCMS-ESI’ (m/z): [M+H]* calcd for CieHzsClNjOj: 462.15; found: 462.45.

Example 88: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methyl-2-(pyridazin-4-yl)quinolin-6-yl)acetÎc acid (88).

262

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4₎3,2-de]quinolin-7-yl)-7-niethyl-2(pyridazin-4-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2_I3-dihydropyrano[4_J3,2-de]quinolin-7-yl)-7methyl-2-(pyridazin-4-yl)quinolin-6-yl)acetic acid (88) was prepared following the procedure for (S)-2-tert-butoxy’2-((R)-5-(2,3-dihydropyrano(4,3,2-de]quinolin-7-yl)-7methyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid of Example 80 except that 410 (tributylstannyl)pyridazine was used instead of 2-(tributylstannyl)pyridine. The first step was run with a catalytic amount of lithium chloride, and the last step required an additional l mL of 0.4 M CrOj/HdOf, and three drops of water for completion. ^!HNMR: 400 MHz, (CD₃CN) δ: 9.80 (brs, IH), 9.24 (brs, IH), 8.67 (d, J = 4.8 Hz, IH),

8.25 (s, IH), 8.05 (s, IH), 7.83 (d, J = 8.8 Hz, IH), 7.75 (d, J = 8.0 Hz, IH), 7.58 (d, J =

4.4 Hz, IH), 7.48 (d, J = 8.8 Hz, IH), 7.33 (d, J = 8.4 Hz, IH), 5.22 (s, IH), 4.64 {m,

2H), 3.52 (t, J = 5.6 Hz, 2H), 2.76 (s, 3H), 0.94 (s, 9H).

LCMS-ESr (m/z): [M+H]⁺calcd for CjilbçN^: 52L21; found: 52L18.

Example 89: (S)-2-tert-Butoxy-2-((R)-5-(5-chloro-3,4-dihydro-2H20 benzo[b][l,4]oxazin-6-yl)-2,7-dimethylquinolin-6-yl)acetic acid (89)

263

(S)-ethyt 2-(5'bromo2,7-dimettiylquinolin-6yl)-2-fert-butoxyacetate

O'%

Pd (PPh₃)₄

K₂CO₃

NM P

5-chloro-6-(4,4,5,5-tetramethyl1,3,2-dtoxaborolan-2-yl)-3,4dihydro-2H-benzo[b][1,4]oxazine

3,4-dthydro-2H-benzo[b)[1,4]oxazsn-6-yl)2,7-dimethyiquinolin-6-yl)acetate (S)-2-tert-butoxy-2-((R>S-(5chloro-3,4-dihydro-2Hbenzo[b][1,4]oxazin-6-yl}-2,7dimethylquinoltn-6-yl)acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-5-(5-chloro-3,4-dihydro-2Hbenzo|b][l,4]oxaz.in-6-yl)-2,7-dimethylquinolin-6-yl)acetate: Toa solution of (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate(5H) (50 mg, 0.126 mmol) and 5-chloro-6-(4,4₎5₁5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydro-2Hbenzo[b][I,4]oxazine(74 mg, 0.252 mmol) in l-methyl-2-pynOlidinone was added 2 M potassium carbonate (0.252 mL, 0.504 mmol) and Pd(PPh₃)₄ (15 mg, 0.013 mmol) and the reaction was degassed with argon for 5 minutes. The reaction was heated to 110 °C for 30 minutes in a microwave reactor. The crude reaction was absorbed onto silica and purified by flash column chromatography (silica gel, ethyl acctatc/hexanes) to give a yellow oil (44 mg). LCMS-ESI⁺ (m/z): [M+H]*calcd for CïT^CibLA: 483.20; found: 483.93.

Préparation of (S)-2-tert-butoxy-2-((R)-5-(5-chloro-3_î4-dihydro-2H15 benzo[b][l,4]oxazin-6-yl)'2,7-dimethylquinolin-6-yl)acetic acid (89): Toa solution of (S)-ethyl 2-tert-butoxy-2-((R)-5-(5-chloro-3,4-dihydro-2H-benzo[b][l,4]oxa2in-6-yl)-

2,7-dimethylquinolin-6-yl)acetate (44 mg, 0.092 mmol) in

C 264 te trahydrofuranæthanol: water (2:2:1, 3 mL) was added lithium hydroxide (11 mg,

0.459 mmol) and the reaction was heated to 45 °C overnight. The crude material was purified by reverse phase HPLC (Gemini, 10-48% ACN/H₂O +0.1% TFA) and the desired product was Iyophilized to give a yellow powder (3.8 mg). ’H-NMR: 400

MHz, (CD₃CN) S: 8.22 (s, IH), 7.99 (d, J - 8.8 Hz, IH), 7.50 (d, J = 8.8 Hz, IH), 6.81 (d, J = 8.0 Hz, IH), 6.40 (d, J = 8.0 Hz, IH), 5.35 (s, IH), 4.27 (m, 2H), 3.50 (t, J = 4.2

Hz, 2H), 2.87 (s, 3H), 2.80 (s, 3H), 1.10 (s, 9H). LCMSÆSf (m/z): [M+H]* calcd for C_2SH₂₈C1N₂O₄:455.17; found: 455.5 L

Example 90: (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinûlin-6yl)acetic acid (90)

(S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2(trifluoromethylsuifanytoxy) quino(in-ô-yl)ethy I pivalate (SJ-2-fert-butoxy-2-{5-(4chlorophenyl)-2-isopropyl-7methylquinolrn-6-yl)ethyl pivalate

(S)-2-fert-butoxy-2-(5-(4chlorophenyl)-2-isopropyl-7methylquinolin-6-yl)ethanol

(S)-2’tef/-tnJtoxy-2-(5-{4chlorophenyl)-2-isopropyl-7methylquinofin-S-ylJacetic acid

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-715 methylquînolin-6-yl)ethyI pivalate: To a solution of (S)-2-tert-butoxy-2-(5-(4chlorophenyl^-methyl^-ttrifluoromethylsulfonyloxyJquinolin-ô-yOethyl pivalate (compound of Example 26) (200 mg, 0.33 mmol) and iron (III) acetylacetonate (6 mg, 0.017 mmol) in anhydrous tetrahydrofuran ! l-methyl-2-pyrrolidinone (5 mL/ 0.5 mL)

C

265 at 0 °C was added 2.9 M m tetrahydrofuran isopropylmagnesium bromide (0.149-mL, 0.431 mmol) drop wise. The reaction was let warin'to room température over three hours, quenched with water and extracted with ethyl acetate and concentrated. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (77 mg). LCMS-ESI¹ (m/z): [M+H]¹ calcd for C30H39CINO3: 496.25; found: 496.83.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7methylquinolin-6-yi)ethanol: To a solution of (S)-2-tert-butoxy-2-(5-(4-chIorophenyl)2-isopropyl-7-methylquinolin-6-yl)ethyl pivalate (77 mg, 0.156 mmol) in tetrahydrofuran/methanol (2:1, 1 mL) was added ΓΜ sodium hydroxide (2 mL) and the reaction was heated to 45 °C overnight. The reaction mixture was cooled to room température and diluted with water, extracted with ethyl acetate and washed withbrine. The organic layer was then dried over sodium sulfate and concentrated, followed by coevaporation with acetonitrile to give a clear oil (62 mg). LCMS-ESI¹ (m/z): [M+H]¹calcd for C₂₅H₃iC1NO₂: 412.20; found: 412.96.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7methylquinoIin-6-yI)acetic acid (90): To a solution of (S)-2-tcrt-butoxy-2-(5-(4chlorophcnyl)-2-îsopropyl-7-methylquînolin-6-yl)ethanol (62 mg, 0.149 mmol) in wet acetonitrile at O °C was added 0.4 M CrOj/HsIOe (2.24 mL, 0.897 nunol) drop wise and stirred at 0 °C for 3 hours. Reaction was quenched with 2 M NaH₂PO< 2H₂O and purified by reverse phase HPLC (Gemini, 15-56% ACN/H₂O +0.1% TFA) and the desired product lyophilized to give a white powdcr (38 mg).

’H-NMR: 400 MHz, (CD₃CN) S: 8.21 (s, IH), 8.12 (d, J = 9.2 Hz, 1H), 7.60 (m, 4H),

7.33 (d, J = 7.6 Hz, IH), 5.25 (s, IH), 3.57 (dq, J = 6.8,6.4 Hz, IH), 2.68 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H), 1.41 (d, J = 6.4 Hz, 3H), 0.97 (s, 9H).

LCMS-ESI¹ (m/z): [M+H]¹ calcd for C^ClNCh; 426.18; found: 426.78.

Example 91 : (S)-2-tert-Butoxy-2-(5-(4-cblorophenyl)-2-(lH-imidazol-l -yl)-7methylquinolin-6-yl)acetic acid (91)

266

(S)-2-fert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2(trifluoromethylsulfony(oxy) quino(in-6-y IJethyl pivalate

DME

95°C imidazole

(S)-2-fert-butoxy-2-(5-(4chlorophenyl)-2-{1H-imidazol-1-yl)-7methylquinolin-6-yl)ethyl pivalate

CrOg/ HglOç wet ACN

0°C (S)-2-tert-butoxy-2-(5-(4chloropheny!)-2-( 1 H-imidazd-1 yl)-7-methylquino!in-6-yl)ethano!

(S)-2-tert-butoxy-2-{5-(4' dik>rophenyl}-2-{1 H-imidazol1 -yi)-7-methylquinolin-6y l)acetic acid

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-( 1 H-imidazol-1 -yl)-7methylquinolin-6-yl)ethyi pivalate: To a solution of (S)-2-tert-butoxy-2-(5-(4chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (200 mg, 0.332 mmol) in 1,2-dimethoxyethane was added imidazole (226 mg, 3.32 mmol) and the reaction was sealed and heated to 95 °C ovemight. The crude reaction mixture was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (33.2 mg). LCMS-ESf (m/z): [M+H]⁺calcd for C3oH_3îC1N₃O₃: 520.23; found:520.35.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(lH-imidazol-l-yl)-7methylquinolin-6-yl)ethanol: To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)2-(l H-imidazol-1-y l)-7-methylquinolin-6-yl)ethyl pivalate (39.2 mg, 0.075 mmol) in tetrahydrofuran and methanol (5:1, i mL) was added 1 M sodium hydroxide (2mL) and the reaction was heated to 45 °C ovemight. The reaction was cooled to room température, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude extract was

267 co-evaporated two times with acetonitrile to give a clear white oil (32.1 mg). LCMSESr (m/z): [M+H]⁺ calcd for CîsHïtCIN^: 436.17; found:436.86.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chloropheriyl)-z-(Î H-iraidazoi-!-y]'!-7methylquinolin-6-yl)acetic acid (91): To a solution of (S)-2-tert-butoxy-2-(5-(45 chlorophenyl)-2-( 1 H-imidazol-1 -yl)-7-methyiquinolin-6-yl)ethanol (32.1 mg, 0.074 mmol) in wet acetonitrile at 0 °C was added 0.4 M Cr0₃/H₅I06 ( 1.1 mL, 0.442 mmol) and the reaction was stirred at 0 °C for three hours. The reaction was quenched with 1 M NaHîPO^HjO and extracted with ethyl acetate. The organic layer was concentrated and purified by reverse phase HPLC (Gemini, 10-55% ACN/H₂O + 0.1%

TFA) and the desired product lyophilized to give a white amorphous powder ( 1L l mg). ^lH-NMR: 400 MHz, (CD3CN) δ: 9.15 (s, IH), 8.13 (s, IH), 7.87 (m, 2H), 7.58 (m, 4H), 7.51 (s, IH), 7.33 (d, J = 8 Hz, IH), 5.24 (s, 1 H),2.62 (s, 3H), 0.97 (s, 9H). LCMS-ESI* (m/z): [M+H]*calcd for C₂5H₂₅CIN₃0j: 450.15; found: 450.59.

Example 92: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4_J3,2-de]quinolin-7-yl)-2(isobutyl(methyl)amino)-7-methylquinoIin-6-yl)acetic acid (92).

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)2-(isobutyl(methyl)amino)-7-methylquinolin-6-yI)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydTopyrano[4,3₎2-de]quinoliii-7-yl)-2(isobutyl(methyl)amino)-7-methylquinolin-6-yl)acetic acid (92) was prepared following the procedure for (S)-2-tert-butoxy-2-(5-(4-chJoTophenyl)-2-(lH-imidazol-lyl)-7-methylquinolin-6-yl)acetic acid of Example 91 except that (S)-2-tert-butoxy-225 ((R)-5-(2,3-dihydropyrano[4,3,2-de]quinoIin-7-yl)-7-raethyL2(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate was used instead of (S)-2-tert·

t - 268 butoxy-2-( 5-(4-chloropheny l)-7-methyl-2-(tri fl uoromethylsulfonyloxy)quinolia-6—b yl)ethy I pivalate and N,2-dimethyIpropan-1 -amine was used instead of imidazole.

¹ H-NMR: 400 MHz, (CD₃CN) 5: 8.65 (d, J = 4.8 Hz, IH), 7.96 (s, IH), 7.52 (d, J = 7.6 Hz, IH), 7.41 (d, J = 4.8 Hz, IH), 7.26 (d, J = 10.0 Hz, IH), 7.18 (d, J = 7.6 Hz, IH),

6.89 (d, J = 9.6 Hz, 1H),5.12 (s, IH), 4.57 (m, 2H), 3.48 (m, 2H), 3.40 (t, J = 5.2 Hz,

2H), 3.34 (s, 3H), 2.68 (s, 3H), 2.09 (m, IH), 0.93 (m, 6H), 0.86 (s, 9H).

LCMS-ESf (m/z): [M+H]⁺ calcd for CîîHisNjO^ 528.28; found: 528.34.

Example 93 : (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2'10 (ethyl(methyl)amino)-7-methylquinolin-6-yl)aceticacid (93).

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,32-de]quinolin-7-yl)-215 (ethyl(methyl)amino)-7-methylquinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2(ethyI(methyl)amino)-7-methylquinolin-6-yl)acetic acid (93) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihyàopyrano[4₁3,2-de]quinolin-720 yl)-2-(isobutyl(methyI)amino)-7-methylquinolin-6-yl)acetic acid of Example 92 except that N-ethyl-N-methylamine was used instead of N,2-dimethylpropan-l-amine. ^lHNMR: 400 MHz, (CDjCN) δ: 8.64 (d, J - 4.4 Hz, IH), 7.96 (s, IH), 7.51 (d, J = 7.6 Hz, IH), 7.39 (d, J =4.8 Hz, 1 H), 7.25 (d, J = 9.6 Hz, 1H),7.17 (d, J = 8.0 Hz, IH),

6.84 (d, J = 9.6 Hz, IH), 5.11 (s, IH), 4.57 (m, 2H), 3.71 (m, 2H), 3.40 (t, J = 5.6 Hz, 25 2H), 3.31 (s, 3H), 2.66 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.85 (s, 9H). LCMS-ESf (m/z): [M+H]⁺calcd for C30H34N3O4·. 500.25; found: 500.32.

269

Exampïe 94: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4_J3,2-de]quiiioiin-7-yl)-7methyl-2-(pyrrolidin-l-yl)quînolin-6-yI)acetic acid (94).

(S)-2-tert-butoxy-2'((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2(pyrrolidin-l-yl)quinolin-6-yl)aceticacid (S)-2-tert-Butoxy-2-((R)-5-(2_t3-dihydropyrano[4,3,2-de]quinolÎn-7-yl)-7methyl-2-(pyrrolidin-l-yl)quinolin-6-yl)acetic acid (94) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2(isobutyl(methyl)amino)-7~methylquinolin-6-y])acetic acid in of Example 92 except that pyrrolidine was used instead of N,2-dimethylpropan-l -amine. ’H-NMR: 400 MHz, (CD₃CN) δ: 8.64 (d, 4.8 Hz, IH), 7.91 (s, IH), 7.52(d, J = 7.2 Hz, IH), 7.39 (d, J = 4.4 Hz, IH), 7.24 (d, J = 10.0 Hz, IH), 7.17 (d, J “ 8.0 Hz, IH)»6.71 (d, J = 10.0 Hz, IH),

5.11 (s, 1 H), 4.57 (m, 2H), 3.74 (m, 2H), 3.60 (m, 2H), 1.40(t, J = 6.0 Hz, 2H), 2.66 (s, 3H), 2.09 (m, 4H), 0.85 (s, 9H). LCMS-ESI* (m/z): [M-H]* calcd forC₃₁H₃4N₃O₄: 512.25; found; 512.18.

Example 95: (S)-2-((R)-2-(azetidin-l-yl)-5-(2,3-dihydrcpyrano[4,3,2-de]quinolin-7-yl)7-methylquinoIin-6-yl)-2-tert-butoxyacetic acid (95).

270 (S)-2-((R)-2-(azetidin-l-yl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methylquinolin-6-yl)-2-tert-butoxyacctic acid (S)-2-((R)-2-(Azetidin-l-yl )-5-(2,3 -dihydropyrano [4,3,2-de]quinolin*7-yl)-75 methylquinolin-6-yl)-2-tert-butoxyacetic acid (95) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyTano[4,3,2-dc]c]iiinoliii-7-yl)-2(isobutyl(methyl)amino)-7-methylquinolin-6-y!)acetic acid ofExample 92 except that azetidine was used instead of N,2-dimethylpropan-l -amine.

^lH-NMR; 400 MHz, (CD₃CN) Ô: 8.63 (d, (J = 4.4 Hz, IH), 7.77 (s, IH), 7.50 (m, l H),

7.38 (d, 4.4 Hz, IH), 7.19 (d, J = Î0.4 Hz, IH), 7.16 (d, 8.0 Hz, IH), 6.41 (d, 10.0 Hz,

IH), 5.10 (s, IH), 4.56 (m, 2H), 4.40 (m, 4H), 3.39 (t, J = 6.4 Hz, 2H), 2.65 (s, 3H),

2.51 (p, J = 7.6 Hz, 2H), 0.85 (s, 9H). LCMS-ESI* (m/z): [M+Hf calcd for C30H32N3O4:498.23; found: 498.14.

Example 96: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2(dimethylamino)-7-methylquinolin-6-yi)acetic acid (96)

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-dc]quinolin-7-yl)-2(dirnethylannno)-7-methylquinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinoIin-7-yl)-2(dimethylamino)-7-methylquinolin-6-yl)acetic acid (96) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydiopyTano[4,3,2-de]quinoliii~7-yl)-2(isobutyl(methyl)amino)-7-methylquinolin-6-yl)acetic acid of Example 92 except that dimethylamîne was used instead of N,2-dimethylpropan-l-amine.

¹H-NMR: 400 MHz, (CD3CN) δ: 8.63 (d, J = 4.8 Hz, IH), 7.96 (s, IH), 7.52 (d, J = 7.6

Hz, IH), 7.39 (d, J = 4.4 Hz, IH), 7.26 (d, J = 9.6 Hz, IH), 7.17 (d, J = 7.6 Hz, IH),

L

T

271

6.83 (d, J = 10.4 Hz, IH), 5.12 (s, 1 H), 4.57 (m, 2H), 3.39 (ζ J = 6.8 Hz, 2H), 3.32 (s, 6H), 2.66 (s, 3H), 0.86 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for CaHajNjOc 486.23; found: 486.25.

Example 97: (S)-2-tert-Butoxy-2-((R.)-5-(2,3-dihydTopyrano[4,3,2-de]qumolm-7-yl)-7methyl-2-oxo-l,2-dihydroquinolin-6-yl)acetic acid (97)

,OH

O N H (S)-2-tcrt-butoxy-2-((R)-5 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)7-methyl-2-oxo-l ,2-dihydroquinolin-6-yI)acetic acid

Préparation of (S)-2-tert-butoxy-2“((R)-5-(2,3-dihydropyrano[4,3^-de]quinolin“ 7-yl)-7-methyl-2-oxo-l,2-dihydroquinolin-6-yl)acetic acid (97): Compound 97 was isolated as a side product of the synthesis of (S)-2-tert-butoxy-2-((R)-5-(2,3dihydropyrano [4,3,2-de]quinolin-7-yl)-2-( 1 H-imidazol- 1-y i)-7-methylquinolin-6yl)acetic acid (compound 98 of Example 98). ¹ H-NMR: 400 MHz, (CDjCN) δ: 8.69 (d, J = 5.2 Hz, IH), 7.63 (d, J = 8.0 Hz, IH),7.54 (d, J = 4.8 Hz, IH),7.26 (d, J = 4.0 Hz, IH), 7.24 (s, IH), 6.87 (d, J - 9.6 Hz, IH), 6.19 (J = 9.6 Hz, IH), 5.03 (s, IH), 4.59 (m, 2H), 3.47 (t, J = 5.6 Hz, 2H), 2.59 (s, 3H), 0.87 (s, 9H). LCMS-ESf (m/z): [M+H]⁺calcd for C₂₇H₂₇N₂O₅:459.51; found: 459.20.

Example 98: (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolîn-7-yl)-2(lH-îmidazo!-l-yl)-7-methylquinolin-6-yl)acetic acid (98).

272

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinoIin-7-yl)-2-(lH-imidazoll-y])-7-methylquino!in-6 v!)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolîn-7-yl)-2-(lH5 imidazol-l-yl)-7-methylquinolin-6-yl)aceticacid(98)was prepared followingthe procedure for CS)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2(is<)butyl(methyl)amino)-7-methylquinolin-6-yI)acetic acid of Example 92 except that imidazole was used instead of N,2-dimethylpropan-l-aniine and the last step had an additional 6 équivalents of 0.4 CrOj/HsIOs added 2 hours into the reaction and was then stirred an additional 3 hours. ‘H-NMR: 400 MHz, (CDjCN) δ: 9.16 (s, IH), 8.63 (d, J = 4.4 Hz, IH), 8.12 (s, IH), 7.98 (s, IH), 7.59 (d, J = 14.8 Hz, IH), 7.53 (m, 3H),

7.42 (d, J = 4.8 Hz, IH), 5.22 (s, IH),4.59 (m, 2H), 3.43 (t, J = 6.0 Hz, 2H), 2.74 (s, 3H), 0.91 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for C₃₀H₂^O<: 509.21; found: 509.14.

273

Example 99: (S)-2-tert-butoxy-2-((R)-2-(dif]uoromethyl )-5-(2,3-dihydropyrano [4,3,2de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (99).

(S)-5-bromo-6-( 1 -ferf-butoxy(S)-ethyl 2-(5-bromo-2,7-dimethytquinolin- 2-ethoxy-2-oxoethyl}-2,7-

6-yl)-2-teri-butoxyacetate	Br A	dimethylquinoline 1-oxide Λ '
1. aceticacid acetic anhydride
	Des s-Martin
2. 6M KOH	s	M	\ 0	DCM
THF	l N
	OH

(S)-ethyl 2-(5bromc-2-

(S)-ethyl 2-(5-bramo-2-formyl-7methylquinolin-6-yl)-2-terfbutoxyacetate (S)-ethyl 2-(5-bromo-2(difluoranri9thyl}-7-methylquinolin-6yl)-2-tert-butoxyacetate

2,3-dihydropyrano[4,3,2de]quinolin-7-ylboronic acid, HCl sait

Pd (PPh₃)₄K₂CO₃DME

(S)-ethyl 2-terf-bUoxy-2-((R)-2(d ifluoromethy 1)-5-(2,3-dhy d rop y ra n o[4,3,2de]quÎnolin-7-yl)-7-roethylquinolÎn-6’ yl)acetate

274

LiOH

THF/EtOH, water

(S)-2-fert-butoxy-2-((/?)-2-(difluoromethyl)5-(2,3-dihydropyrano[4,3,2-de]quinolin-7yl)-7-methylquinolin-6-yl)acetic acid

Préparation of (S)-5-bromo-6-( l -tert-butoxy-2-cthoxy-2-oxoethyl)-2,7dimethylquinoline 1-oxide: To a solution of (S)-ethyl 2-(5-bromo-2,7dimethylquinolin-6-yl)-2-tert-butoxyacelate (5H) (500 mg, 1.27 mmol) in dichloromethane (13 mL) at 0 °C was added 3-chloroperoxybenzoic acid (269 mg, 77%, L21 mmol) and the réaction mixture was allowed to slowly wann to room température over 3 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes andmethanol/ethyl acetate) to give a 10 yellow oil (497 mg, 95%). LCMS-ESI* (m/z): [M]* calcd for C₁₉H₂₄BrXO₄: 410.3;

found: 410.8.

Préparation of (S)-ethy 12-(5-bromo-2-(hydroxymethyl)-7-methylquînolin-6-yl)-

2-tert-butoxyacetate: A solution of S)-5-bromo-6-( 1 -tert-butoxy-2-ethoxy-2-oxoethyl)-

2,7-dimethylquinoline 1-oxide (497 mg, 1.21 mmol) inacetic acid (12 mL) was heated 15 at 80 °C for 15 minutes. To the solution was added acetic anhydride (1.37 mL, 14.5 mmol) and the resulting solution was heated at 110 °C for 2 hours. The reaction mixture was cooled to 50 °C and méthanol (6 mL) was added and stirred for 1 hour. The reaction was cooled to room température and concentrated. The. résultant oil was taken up in tetrahydrofuran (20 mL) to which was added 6 M potassium hydroxide (20 20 mL) and stirred for 1 hour. The product was extracted with ethyl acetate and the organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (366 mg, 74%). LCMS-ESI* (m/z): [M+H]⁺calcd for C_I9H₂₅BrNO₄: 411.3; found: 410.7.

275

Préparation of (S)-ethyl 2-(5-bromo-2-formyl-7-nethyiquinolin-5-yi/-2-tertbutoxyacetate: To a solution of (S)-ethyl 2-(5-bromo-2-(hydroxyrnethyl)-7methylquinolin-6-yl)-2-tert-butoxyacetate (200 mg, 0.49 mmol) in anhydrous dichloromethane (13 mL) at 0 °C was added Dess-Martîn periodinane (248 mg, 0.58 mmol) and the reaction mixture was stirred for 1 hour. Réaction mixture was partitioned between dichloromethane and water and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a white solid (160 mg, 80%). LCMS-ESI⁺ (m/z): [M+H]‘calcd for CjsHjjBrNOq 408.07; found: 408.88, 410.14

Préparation of (S)-ethyl 2-(5-bromo-2-(difluoromethyl)-7-methylquinolin-6-yl)-

2-tert-butoxyacetate: To a solution of Fluolead (392 mg, 1.57 mmol) in anhydrous dichloromethane (2 mL) at 0 C was added (S)-ethyl 2-(5-bromo-2-formyl-7methylquinolin-6-yl)-2-tert-butoxyacetate (160 mg, 0.39 mmol) as a solution in anhydrous dichloromethane (2 mL) and the reaction mixture was allowed to slowly warm to room température ovemight. The rcaction mixture was quenched with 0.5 M sodium hydroxide (10 mL), stirred ! hour, and then partitioned between dichloromethane and 0.5 M sodium hydroxide and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a white solid (137 mg, 81%). LCMS-ESf (m/z): [M+H]⁺calcd for C^HjjBrNCL:

430.08; found: 430.61,431.85.

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-2-(difluoromethyl)-5-(2,3dihydropyrano[4,3,2-de]quinolîn-7-yI)-7-methylquinolin-6-yl)acetate: To a solution of (S)-ethyl 2-(5-bromo-2-(difluoromethyl)-7-methyIquinolin-6-yl)-2-tert-butoxyacetate (70 mg, 0.16 mmol) in 1,2-dimethoxyethanc (2 mL) was added 2,325 dihydropyrano[4,3,2-de]quinolin-7-yIboronîc acid, HCl sait (82 mg, 0.325 mmol), 2 M potassium carbonate (0.326 mL, 0.65 mmol) and Pd(PPh₃)₄ (19 mg, 0.016 mmol). The reaction mixture was sparged with argon for 5 minutes and then heated in microwave at 100 °C for 40 minutes. The reaction mixture was absorbed onto silica and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a brown film (35 mg, 41%). LCMS-ES1⁺ (m/z): [M+H]⁺ calcd for C^FzNA: 521.22; found:

521.20.

276

Préparation of (S)-2-tert-butoxy-2-((R)-2-(difluoroinethyl)-5-(2,3dihydropyrano[4,3,2-de]quinolîn-7-yl)-7-methylquinolin-6-yl)acetic acid (99): To a solution of (S)-ethyl 2-tert-butoxy-2-((R)-2-(diflu0ron)ethyl)-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yI)-7-methylquinoIin-6-yl)acetate (35 mg, 0.07 mmol) in l : l tetrahydrofuran and éthanol (2.4 mL) was added lithium hydroxide (8 mg, 0.34 mmol) in 0.6 mL of water. The reaction was heated to 45 °C overnight. The reaction mixture was purified by reverse phase HPLC (Gemini, 15 to 55% ACN/H₂0 + 0.1% TFA) and the desired product was lyophilized togive a yellowpowder (15.9 mg). ’H-NMR: 400 MHz, (CDjCN) 5: 8.63 (d, J = 4.8 Hz, lH),8.10(s, IH),7.71 (d,J=8 ' Hz, IH), 7.54 (d, J = 5.2 Hz, IH), 7.48 (s, 2H), 7.30 (d,3 = 8 Hz, IH), 6.83 (t, J_H._F =

55.2 Hz, IH), 5.22 (s, IH), 4.61 (m, 2H), 3.49 (t, J = 6Hz, 2H),2.75 (s, 3H), 0.91 (s, 9H). LCMS-ESf (m/z): [M+Hf calcd for N₂0y 493.19; found: 493.12.

Example 100: (S)-2-tert-butoxy-2-(5-(4Hchlorophenyl)-2-(difluofomethyl)-715 methylquinolin-6-yl)acetic acid (100)

277

(S)-ethyi 2-(5-bromo-2,7dimethylquinolin-6-yl)-2-tertbutoxy acetate (S)-ethyl 2-tert-butoxy-2-{5(4-chloropheny 1)-2,7dimethy Iq uinolin-6-yÎ)acetate

(S)-ethyi 2-fert-butoxy-2-(5-(4chlorophenyl)-2-formyl-7methylquinclin-6-yl)acetate

LiOH

THF/EtOH, water

100 (S) ethyl 2-terf-butoxy-2-(5-(4chlorophenyi)-2-(difluoromethyl)-7methy Iq uinolin6-yl)acetate (S)-2-tert-butoxy-2-(5-{4chbropbenyl)-2-(difluoromethy!)7-fnethylqu inol in-6-y I )acetic acid

Préparation of (S)-ethyl 2-tert-buloxy-2-(5-(4-cMorophcny 1)-2,7dimethylquinolin-6-yl)acetate: To a solution of (S)-ethyl 2-(5-bromo-2,7

C

278 dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (500 mg,. 1.27 mmol) and 4’chlorophenylboronic acid (238 mg, 1.52 mmol) in 1,2-dimethoxyetha.ne (8 mL) was added Pd(PPh₃)4 (147 mg, 0.13 mmol) and 2 M potassium carbonate (1.91 mL). The reaction was degassed for 15 minutes with argon and then heated to 110 °C for 20 minutes in a microwave reactor. The crade reaction was absorbed onto silica and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a pink foam (489 mg). LCMS-ESI' (m/z): [M+H]* calcd for C^H^ClNOj: 426.18; found: 426.75.

Préparation of (S )-6-( 1 -tert-butoxy-2-ethoxy-2-oxoethy I)-5-(4-chloropheuy l)-

2,7-dimethylquinoline I-oxide: To a solution of (S)-ethyl 2-tert-butoxy-2-(5-(4chlorophenyl)-2,7-dimethylquinolin-6-yl)acetate (489 mg, 1.15 mmol) in anhydrous dichloromethane at 0 °C was added 3-chloroperoxybenzoic acid (243 mg, 77%, 1.09 mmol) and the reaction was stirred for 3 h. The crade reaction was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes, methanol/ethyl acetate) to give a white foam (261 mg). LCMS-ESI* (m/z): [M+H]* calcd for C2SH29CINO4: 442.17; found: 442.88.

Préparation of (S)-ethyi 2-tert-butoxy-2-(5-(4-chlorophenyI)-2(hydroxymethyI)-7-methyIquinolin-6-yl)acetate: A solution of (S)-6-(l-tert-butoxy-2ethoxy-2-oxoethyI)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide (261 mg, 0.59 mmol) in acetic acid (6 mL) was heated to 80 °C for 15 minutes. To the solution was added acetic anhydride (0.67 mL, 7.09 mmol) and the resulting solution was heated at 110 °C for 2 hours. The reaction mixture was cooled to 50 °C and 3 mL of methanol was added and stirred for 1 hour. The reaction was cooled to room température and concentrated. The résultant oil was taken up in tetrahydrofuran and 6 M potassium hydroxide was added to adjust to pH 12 and stirred for 3 hours. The mixture was then diluted with water and extracted with ethyl acetate and concentrated. The product was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a clear oil (213 mg).

LCMS-ESI* (m/z): [M+H]* calcd for ^ΙΚΤΙΝΟ.,: 442.17; found: 442.69.

Préparation of (S)-ethy 1 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-fonnyl-7methylquinolin-6-yl)acetate: To a solution of (S)-ethyl 2-tert-butoxy-2-(5-(4chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6-y])acetate (160 mg, 0.36 mmol)

- 279 in anhydrous dichloromethane at 0 °C was added Dess-Martin periodinane ( 184 mg, 0.43 mmol) and the reaction was stirred for l hour at 0 °C. The reaction was quenched with water, extracted with dichloromethane and concentrated. The crude product was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a clear oil (139 mg). LCMS-ESf (m/z): [M <Iif calcd for C25H27CINO4: 440.16; found: 440.55.

Préparation of (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2(difluorornethyl)-7-methylquinolin-6-yl)acetate: To a solution of (S)-ethyl 2-tertbutoxy-2-(5-(4-chlorophenyl)-2-formyl-7-methylquinolin-6-yl)acetate (139 mg, 0.32 10 mmol) in anhydrous dichloromethane (3 mL) at 0 °C was added Fluolead(174mg, 0.695 mmol) and the réaction was stirred for % hour at 0 °C and then allowed to warm to room température ovemîght. The reaction was quenched with 0.5 M sodium hydroxîde and stirred for 1 hour. The crude product was extracted with dichloromethane, concentrated and purified by flash cclumn chromatography (silica 15 gel, ethyl acetate/hexanes) to give a clear oil (111 mg). LCMS-ESf (m/z): [M+HJ* calcd forC2sH27ClF2NO₃: 462.16; found; 462.54.

Préparation of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(difluoromethyl)-7methyiquinoIin-6-yl)acetic acid (100): To a solution of (S)-ethyl 2-tert-butoxy-2-(5-(4chlorophenyl)-2-(difluoromethyl)-7-methylquinorm-6-yl)acetate (111 mg, 0.24 mmol) 20 in tetrahydrofuran:ethanol: water (2:2; 1,3 mL) was added lithium hydroxîde (29 mg,

1.2 mmol) and the reaction was heated to 45 °C ovemîght. The crude product was purified by reverse phase HPLC (Gemini, 20-29% ACN/H2O + 0.1% TFA) and the desired product was lyophilized to give a white powder (77.5 mg).

‘H-NMR: 400 MHz, (CDjCN) δ: 7.97 (s, IH), 7.87 (d, J = 8.8 Hz, IH), 7.59 (m, 4H), 25 7.35 (d, J = 7.6 Hz, IH), 6.84 (t, J_H-f = 55.2 Hz, IH), 5.26 (s, IH), 2.64 (s, 3H), 0.97 (s,

9H). ¹⁹F-NMR: 377 MHz, (CD3CN) δ: -116.71 (dd, J = 62.02, 55.42 Hz). LCMS-ESI* (m/z): [M+H]⁺ calcd for C2ÎH2₃C1F2NO₃: 434.88; found: 434.47.

Example 101 : (S)-2-( 1-(2-(( (9H-Fluoren-9-yl)methoxy)carbonylamino)ethyl)-5-(430 chlorophenyI)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic acid (101).

280

( S)-6-( 1 -terf-butoxy-2hydroxy ethy 1)-5-(4 -ch loropheny l)7-methy Iquinoli n-2( 1 H)-one 8K (S}~6-(1 -tert-txjtoxy-2-(fwfbuty l dimethy I sily loxy)ethyi)-5(4-chk>rophenyÔ-7methylquinolin-2(lH)-one

k^,NHFmoc (S)-2-(trifnethylsilyl)ethyl 2-(6-( t-tertbutoxy-2-(ferfbutyldimethyfsilytoxy)ethyl)-5-(4chlorophenylj-ï-mettiyt^üxoqu ino lin-1 (2H)-y IJethylcarbamate (S)-(9H-fluoren-9-yl)methyl 2-(6-(1tert-butaxy-2-hy draxy ethy 1)-5-(4chtarophenyl)-7-(nethjrt-2-oxoquinolin1(2H)-yl}etbytcarbamate

k^NHFmoc

101 (S)-2-(1-(2-(((9H-fluoren-9yl)methoxy)carbonylamino)ethyl)-5-(4-chtorophenyl)-7met hyi-2-oxo-1,2-dihy drequinolin-6-yl)-2-ter tbutoxyacetic acid

2-bromoethanam ine hydrobromide

H

Br'^'^Ny°^x^TMS O

2-(1rimethylsilyi)ethyf2 -bromoethy Icarba mate

Préparation of (S)-6-( l -tert-butoxy-2-(tert-butyldi methylsilyloxy )ethy 1)-5-(4chIorophenyl)-7-methyIquinolin-2( 1 H)-one: To a solution of (S)-6-( 1 -tert-butoxy-25 hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(IH)-one (8K) (0.5175 g, 1.34

mmol) in DMF (5.0 mL), was added imîdazole (0.204 g, 4.02 mmol), followed by îertbutyldimethylsilyl chloride (0.243 g, 1.61 mmol) at 0 °C. The réaction mixture was warmed to room température overnight. Additional imîdazole (0.2 g) and tertbutyldimethylsîlyl chloride (0.30 g) were added and the mixture stirred for another 2 hours. The reaction mixture was the diluted with ethyl acetate, washed with 5% lithium chloride solution (2x), brine, dried (MgSOi), filtered, concentrated and purified by flash column chromatography (silica gel, 20 to 60% ethyl acetate/hexanes) to give a yellow foam (0.500 g). LCMS-ESI⁺ (m/z): [M+H]⁴ calcd for CaH3jClNO₃Si: 501.1; found: 500.3, 502.2.

Préparation of (S)-2-(trimethyIsilyl)ethyl 2-(6-( l -teit-butoxy-2-(tertbutyldimethy lsilyloxy)ethyi)-5 -(4-chlorophenyl)-7-methy l-2-oxoquinoliii-1 (2H)yl)ethylcarbamate: To a solution of (S)-6-(l-tert-butoxy-2-(tert· butyldimethylsilyIoxy)cthyl)-5-(4-chlorophenyl)-7-methylquinolin-2( 1 H)-one (0.4061 g, 0.812 mmol) in DMF (8.0 mL) was added potassium (wt-butoxide (0.137 g, 1.22 mmol) and the mixture stirred for 30 minutes. A solution of2-(trimethylsilyl)ethyl 2bromoethylcarbamate (0.327 g, 1.22 mmol) in DMF (1 mL) was added and the reaction mixture was allowed to slowly warm to room température overnight. The reaction mixture was cooled to 0 °C, potassium tert-buloxide (0.200 g) was added and the resulting reaction mixture was stirred for 30 minutes. A solution of 220 (trimethylsilyl)ethyl 2-bromoethylcarbamate (0.5 g) in DMF ( 1 mL) was added and the reaction mixture was warmed to room température overnight. Reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2x), brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexanes) to give desiredproduct a yellow foam (0.2725 g). Some O-alkylation side-product was also observed.

LCMS-ESf (m/z): [M+Hf calcd for C_J6H56ClN₂O_sSi₂:688.5; found: 687.1,689.1.

Préparation of (S)-(9H-fluoren-9-yl)methyl 2-(6-(1 -tert-butoxy-2hydroxyethyI)-5-(4-chlorophenyl)-7-methyl-2-oxoquiiKjlin-l(2H)-yl)ethylcarbamate:

To a solution of (S)-2-(trimethylsilyl)ethyl 2-(6-( 1 -tert-butoxy-2-(tertbutyldimethytsiiyloxy)ethyl)-5-(4-chlorophenyl)-7-methyl-2-oxoquinoIin-l(2H)yl)ethylcarbamate (0.456 g, 0.663 mmol) in THF (6.6 mL) at 0 °C was added 1 M

C

282

TB AF in THF (l .99 mL, l .99 mmol) and réaction mixture was warmed to room température overnight. Reaction mixture was cooled to 0 C, additional l M TBAF in THF (l .0 mL, LO mmol) was added and warmed to room température over 8 hours. Reaction mixture was cooled to 0 °C, saturated sodium bicarbonate solution (l .0 mL) and 9-fluorenyImethoxycarbonyl chloride (0.257 g, 0.995 mmol) were added. Reaction mixture was vigorously stined overnight at room température, diluted with ethyl acetate, washed with brine, dried (MgSCL), filtered, concentrated and purifîed by flash column chromatography (silica gel, 30 to 70% ethyl acetate/hexanes) to give a white foam (0.389 g). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for CwHwCINîQs: 652.2; found: 65L2, 652.2, 653.2.

Préparation of (S)-2-(l -(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-5(4-chlorophenyl)-7-methy l-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxy acetic acid (101): To a solution of (S)-(9H-fluoren-9-yl)methyl 2-(6-(1 -tert-butoxy-2hydroxyethyl)-5-(4-chlorophenyl)-7-methyl-2-oxoquinolin-l(2H)-yl)ethylcarbamate (0.3443 g, 0.529 mmol) in dichloromethane (5.0 mL) was added Dess-Martin periodînane (0.449 g, 1.06 mmol). Reaction mixture was allowed to wann to room température over 1.5 hours, quenched with sodium thiosulfate solution and extracted with ethyl acetate. Organic layer was washed with brine, dried (MgSOf. filtered, concentrated and used in next step without further purification. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C39H38CIN2O5: 650.2; found: 649.1,650.1.

To a solution of the above residue in acetonitriie (5.0 mL) and 1 M NalfPOi buffer (5.0 mL) was added 80% sodium chlorite (0.44 g, 1.587 mmol). Reaction mixture was stirred for 1.5 hours, diluted with water and ethyl acetate. The pH was adjusted to ~pH 5 with 1 N MCI solution and organic layer was washed with brine, dried (MgSO4), filtered, concentrated and purifîed by flash column chromatography (silica gel, 0 to 10% methanol/dichloromethane) to give a yellow powder (0.1943 g). *H NMR (400 MHz, CD₃OD) δ 7.78 (d, J = 7.6 Hz, 2H), 7.71 (s, IH), 7.63 (dd, J = 6.4,

6.4 Hz, 2H), 7.57-7.51 (m, 3H), 7.41-7.28 (m, 5H), 7.22 (d, J = 7.2 Hz, IH), 6.47 (d, J = 10 Hz, 1 H), 5.02 (s, 1 H), 4.49 (dd, J = 8.4, 8.4 Hz, 2H), 4.36-4.28 (m, 2 H), 4.15 (dd, J = 7.2, 7.2 Hz, IH), 3.51-3.48 (m, 2H), 2.64 (s, 3H), 0.92 (s, 9H).

LCMS-ES1' (m/z): [M+H]⁺calcd for 666.2; found: 665.1,666.1.

- 283

Préparation of 2-(trimethylsilyl)ethyl 2-bromoeihylcarbanÎate:

„ “t .h' ' X

Trimethylsilylethyl chioroformate was prepared according to Sekine et aï, Lut. Org Chem. 2004,1,179-182. To a mixture of 2-bromoethylamine hydrobromide(1.0g, 4.88 mmol) in THF (20 mL) was added saturated sodium bicarbonate solution, followed by crude trimethylsilylethyl chioroformate (8.8 g, 14.64 mmol). Reaction mixture was stirred ovemight at room température, concentrated and portioned between ethyl acetate and saturated sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate (2x) and combined organic layer was dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give a colorless oil (1.321 g). ^lH-NMR: 400 MHz, (CD₃C1) S: 4.14 (dd, J = 8.4, 8.4 Hz, 2H), 3.74-3.69 (m, 2H), 3.55 (dd, J = 5.6, 5.6 Hz,2H), 3.44 (dd, J = 5.6, 5.6 Hz, 2H), 0.99-0.92 (m, 2H), -0.008 (s, 9H).

Example 102: (S)-2-tert-butoxy-2-((R)-5-(2₎3-dihydrobenzo[de]chromen-7-yl)-2,7dimethylquinolin-6-yl)acetic acid (102A)and (S)-2-tert-butoxy-2-((S)-5-(2,3dihydrobenzo [de] chromen-7 -yl)-2,7-dimethylquinolin-6-yl)acetic acid (102 B).

284

(S)-ethyl 2-(5-broma-2,7-dimethytqufnolin6-yl)-2-ter t-butoxy acetate

(S)-2-tert-butoxy-2((Rl-5-(2_?3dfhydrabenzo[de]chromen-7-yl)2,7-dimethytquinoln-6-yl)acetic acid (2S>ethyl 2-tert-butoxy-2-(5-(2,3dihy(irobenzc[de)chrofnen-7-yl)2,7-dimethy Iquinol i n-6-y I Jacetate

(S)-2-terf-biitoxy-2-((S}-5-(2,3dihydrobenzo[tie]chromen-7-y))-2,7· dimethyiquinolir>-6-yl) acetic acid

Préparation of (2S)-ethyl 2-tert-butoxy-2-(5-(2,3-dihydrobenzo[de]chromen-7yl)-2,7-dimethylquinolin-6-yI)acetate: In a 54 0 mL microwave vial, (S)-ethyl 2-(5bromo-2,7-dirnethylquinolin-6-yî)-2-tert-butoxyacetate (5H) (82.4 mg, 0.21 mmol) was dissolved in 4.0 mL of DMA. To this was added 2-(2,3-dihydrobenzo[de]chromen-7yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (110 mg, 0.37 mmol), Pd(PPh₃)₄ (24.2 mg, 0.021 mmol) and 225 pL of 2 M K2CO3, the reaction vessel sealed and heated thermally at 80 °C for 4 hours. The mixture was diluted 400 % with EtOAc, washed with 5% LiCl (4x8 mL), saturated NH4CI and brine. After drying with sodium sulfate, the extracts were concentrated in vacuo and chromatographed on silica gel using EtOAc in Heptane to give rise to desired product (42.4 mg, 0.088 mmol). LCMS-ES1' (m/z): [M+H]⁺ calcd for C_3!H₃₄NO₄: 483.6; Found: 484.47, 485.49.

Préparation of (S)-2-tert-butoxy-2-((R.)-5-(2,3-dihydrobenzo[de]chronien-7-yl)-

2,7-dimethylquinolin-6-yl)acetic acid (102A) and (S)-2-fert-butoxy- 2-((8)-5-(2,3-

t 285 dihydrobenzo[de]chromen-7-yl)-2,7-dimethylquinolm-6-yl)aceticacid (102B): To a 3:1:1 (v/v/v) THE-MeOH-IfO solution (10 mL) of (2S)-ethyl 2-tert-butoxy-2-(5-(2,3dihydrobenzo[de]chromen-7-yl)-2,7-dimethylquinolin-6-yl)acetate (42.4 mg, 0.088 mmol) was added LiOH (170 mg, 4.05 mmol) and the reaction allowed to stir overnight at 23 °C. Hydrolysis was incomplète, so NaOH (~200 mg) was added and the mixture stirred an additional 90 min at 23 °C. The reaction was diluted 400% with EtOAc, washed with brine and dried with sodium sulfate. Concentration in vacuo followed by PREP HPLC purification gave rise to two atropisomer mixtures.

The first eluting atropisomer mixture was found to be 95:5 (ratio determined by 10 NMR) mixture of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydroben2o[de]chromen-7-yl)-2,7dimethylquinolin-6-yI)acetîc acid (102A) as the major constituent and (S)-2-tertbutoxy-2-((S)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2₎7-diniethylquinolin-6-yl)acetic acid as the impurity. IH-NMR: 400 MHz, (CD₃OD): δ; 8.02 (s, IH); 7.94 (d, J=9.2 Hz, IH); 7.56 (d, J=8.8 Hz, IH); 7.31 (d, >7.6 Hz, IH); 7.26-7.20(m, 2H); 70.07 (d,

J= 8.0 Hz, IH); 7.02 (d, >7.6 Hz, IH); 5.20 (s, IH); 4.554.48 (m,2H); 2.92 (s, 3H); 2.86 (s, 3H); 1.04 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for C»H3oN0₄:456.5; Found: 456.44.

The other atropisomer, (S)-2-tert-butoxy-2-((S)-5-(2,3dihydrobenzo[de]chromen-7-yI)-2,7-dimethylquinoiin-6-yl)acetic acid (102B), eluted 20 later and was obtained as a 2.61:1 (ratio determined by NMR) mixture as the major constituent with (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7dimethyIquinolîn-6-yl)acetic acid as the impurity. 1H-NMR: 400 MHz, (CD3OD): 5: 7.99 (s, IH); 7.89 (d, >8.4 Hz, tH); 7.66 (d,>8.0 Hz, IH); 7.52 (d, >8.8Hz, LH); 7.24-7.20 (m, 2H); 7.13 (d, J=8.0 Hz, IH); 6.81 (d, >8.0 Hz, IH); 5.32 (s, IH); 4.5325 4.51 (m, 2H); 2.91 (2, 3H); 2.82 (s, 3H); 0.73 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for C29H30NO4: 456.5; Found: 456.44.

Example 103 : (2S)-2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H- [l,4]oxazino[2,3,4-ij]quinolin-8-yl)quinolin-6-yl)acetic acid (103)

286

Cl

Br

5-bromoqulnolin-8-ol 3-chloropropanoic acid

Br

8-bromo-3,5,6,7tetrahydro-2/7[1,4]oxazino[2,3,4flquinoline

5-bromo-1-(2chbroethy 1)-1,2,3,4tebahydroquinolin-8-cl

(S)-ethyl 2-(5-bromo2,7-dimethylquinolin-6yl)-2-terf-butoxyacetate

8-(4,4,5,5-tetramethyl-1,3,2dioxaboro!an-2-yl)-3,5,6,7-tetrahydro2H-(1_<4]oxazinoÎ2,3,4-flquînoline

(2S) ethyl 2 fcrf-butoxy-2-(2,7dimethyl-5-(3,5,6,7-tetrahydro-2H[1,4]oxazino[2,3,4-ÿ]quînolin-8yt)quinolin-6-yi)acetate

(2S)-2-tert-biitoxy-2-(2,7-d imethyl·

5-(3.5,6,7-tetrahydro-2H[ 1,4]oxazino[2,3,4-ÿ]quînolin-8yl)quinolin-6-yî)acetic acid

Préparation of 5-bromo-l-(2-chloroethyl)-l,2,3,4-tetrahydroquinolin-8-ok In a round bottom flask, 3-chloropropanoic acid (8.44 g, 89.3 mmol, 20 eq.) was added to 55 bromoquinolin-8-ol (1 g, 4.46 mmol, 1 eq.) în 15 mL THFat 0°C. NaBHL; (759 mg, 20 mmol, 4.5 cq.) was added portionwise in 50 minutes at 0 °C. The reaction was stirred at 0 °C for 30 minutes then heated to 80 °C for 2 hours. The réaction was cooled down.

- 287

Reaction mixture was diluted with ethyl acetate and. washed with brine, dried (AigSCE), fîltered, concentrated to give 5-bromo-l-(2-chloroethyl)-l,2,3,4-tetrahydroquinolin-8-ol crude. LCMS-ESI* (m/z): [M+H]⁺calcd for ChHmBiCINO: 291.58; found: 292.0.

Préparation of 8-bromo-3,5,6,7-tetrahydro-2H-[l ,4]oxazino[2,3,4-ij]quinoline:

The above réaction crude was dissolved in 20 mL MeOH. 50 mL 2 N NaOH aqueous solution was added. The reaction was stirred at room température for 2 days. The reaction mixture was fîltered. The filtrate was concentrated and diluted with ethyl acetate and washed with brine, purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to 8-bromo-3,5,6,7-tetrahydro-2H-[l,4]oxazino[2,3,410 ijjquinoline as a pale solid (374 mg, 33%). LCMS-ESI* (m/z): [M+H]* calcd for CijHjjBrNO: 255.12; found: 255.41.

Préparation of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5,6,7tetrahydro-2H-[ 1,4]oxazino[2,3,4-ij]quinoline: In a round bottom flask was charged with 8-broino-3,5,6,7-tetrahydro-2H-[l,4Joxazino[2,3₅4-ij]quLnoline (104 mg, 0,409 mmol, 1 eq.), 4,4,4',4’,5,5,5',5'-octamethyl-2,2^,-bi(l₎3,2-dioxaboroIane) (208 mg, 0.818 mmol, 2 eq.), Pd(dppf)Cl₂ (33 mg, 10%) and KOAc (201 mg, 5 eq.) in 3 mL dioxane. The reaction was heated at 80 °C under Ar overnight. The reaction was cooled down and diluted with ethyl acetate and washed with brine, purified by flash column chromatography (silîca gel, 0 to 20% ethyl acetate/hexanes) to 8-(4,4,5,5-tetramethyl 20 l ,3,2-dioxaborolan-2-yl)-3,5,6,7-tetrahydro-2H-[l,4]oxazino[2,3,4-Îj]quinoline as a pale solid (146 mg, 100%). LCMS-ESI* (m/z): [M+Hf calcd for C 7H25BNO3: 302.19; found: 302.2.

Préparation of (2S)-ethyl 2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro2H-[l,4]oxazÎno[2,3,4-ij]quinolin-8-yl)quinoliii-6-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-(5-bromo-2,7-diniethylquinolin-6-yl)-2-teit-butoxyacetate (52 mg, 0.133 mmol, 1 eq.), 8-(4,4,SjS-tetramethyl-LS^-dîoxaborolan^-ylj-S,5,6,7tetrahydro-2H-[l,4]oxazino[2,3,4-ij]quinoline(48mg,0.159 mmol.), Pd(PPh₃)₄ (15 mg, 10%) and flushed with nitrogen. Dimethoxyethane (1.6 mL) and 2 M K₂CO₃ (0.24 mL, 0.48 mmol) was added. The reaction was heated în oil bath at 80°C for 5 hours.

The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO-i), fîltered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (2S)-ethy 12-tert-butoxy-2-(2,7-dimethyl-5(X

288 (3,5,6,7-tetrahydro-2H-[l,4]oxazino[2,3,4-ij]quinolin-î-yl)quinolin-6-yl)acetate as atropisomer mixture (39 mg, 60%). LCMS-ESI*: calcd for C30H37N2O4:489,52 (M+H*); Found: 489.3.

Préparation of (2S)-2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H5 [l,4]oxazino[2,3,4-ij]quinolin-8-yl)quino]in-6-yl)aceticacid (163): A solution of(2S)ethyl 2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[l,4]oxazino [2,3,4ij]quinolin-8-yl)quinolin-6-yl)acetate (39 mg) and 2 Msodium hydroxide (0,8 mL) in tetrahydrofuran (0.5 mL) and éthanol (2 mL) was heated at 60 °C for 8 hours. Reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSO₄). filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product Iyophîlîzed to give an orange color powder (18 mg). *H-NMR: 400 MHz, (CDjOD): δ 8.31,8.20 (d,d, 1H),7.92> 7.88 (s, s, IH), 7.70-7.67 (m, IH), 6.74 (m, IH), 6.42 (m, IH), 5.42, 5.37 (s, s, IH), 4.37 (m, 2H), 3.33 (m, 2H),

3.14 (m, 2H), 2.96 (s, 3H), 2.81,2.78 (s, s, 3H), 2.40 (m, IH), 1.96-1.78 (m, 3H), 1.17,

1.04 (s, s, 9H). LCMS-ESI*: calcd for 461.56 (M+H*); Found: 461.3.

Example 104: Compounds 104 and 105

Compounds 104 and 105 were prepared by similar methods as shown in the above Examples.

Compound Number	Compound	Parent MW	Measured mass
104	Cl Cmï^oh JL 0	432.35	432.1/434.1

289

Example 105: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-

7-rncthyl-2-(3-rnethyIpyridin-2-yl)qiiinolin-6~yl)acelic acid (106)

(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-dc]quir.oliii-7y[)-7-melhyl-2(3methylpyridin-2-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-710 methy 1-2-(3 -methylpyridin-2-yl)quÎnolin-6-yl)acetic acid (106) was prepared following the procedure for (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7yl)-7-methyl-2-(pyridm-2-yl)quinolin-6-yl)acetic acid of Example 80 except that 2(dibutyl(pentyl)stannyl)-3-methylpyridine and a catalytic amount of copper iodide was added to the first reaction. ^lH-NMR: 400 MHz, (CD3CN) δ: 8.63 (d, J = 4.8 Hz, IH),

8.57 (d, J = 4.8 Hz, IH), 8.08 (s, JH), 7.90 (d, J = 7.6 Hz, IH), 7.76 (d, J = 8.8 Hz, IH),

7.67 (d, J = 8.0 Hz, 1 H), 7.48-7.43 (m, 311), 5.25 (s, IH), 4.62-4.56 (m, 2H), 3.44 (t, J =

6.2 Hz, 2H), 2.74 (s, 3H), 2.64 (s, 3H), 0.93 (s, 9H). LCMS-ESI* (m/z): [M+H]*calcd for C33H32N3O4: 534.23; found: 534.27.

Example 106: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyTano[4,3₎2-de]quinolin-7-yl)-

7-methyl-2-(4-methylpyridîn-3-yl)quinolin-6-yl)acetic acid (107)

290

(S)-2-tert-butoxy-2-((R)-5-(2_t3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2-(4methylpyridin-3-yl)quinolin-6-yl)acetic acid (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methy[-2-(4-methyIpyridin-3-yl)quinolin-6-yl)acetic acid (107) was prepared similarly to (S)-2-tert-butoxy-2-((R)-5-(2,3-d!hydropyrano[4,3,2-de]quinolin-7-yl)-7“îTiethyl-2(3-methylpyridin-2-yl)quinolin-6-yI)acetic acid of Example 105 using 310 (dibutyl(penty l)stannyl)-4-methy lpyridine instead of 2 -(dibuty I (pentyl)stannyl)-3 methylpyridine. ’H-NMR: 400 MHz, (CDjCN) S: 8.71 (s, IH), 8.64-8.60 (m, 2H), 8.05 (s, IH), 7.78 (d, J =6.0 Hz, IH), 7.68 (d, J = 8.0 Hz, 1 H), 7.49-7.42 (m, 3H),7.27 (d, J = 8.0 Hz, I H), 5.25 (s, 1 H), 4.63-4.59 (m, 2H), 3.46 (t, J - 6.0 Hz, 2H), 2.74 (s, 3H), 2.63 (s, 3H), 0.94 (s, 9H). LCMS-ESI* (m/z): [M+H]*calcd for 534.23;

found: 534.34.

Example 107: (S)-2-tcrt-Butoxy-2-(2-(difluoromcthy!)-7-methyi-5-(spiro[2.5]oct-5-en-

6-yl)quinolin-6-yl)acetic acid (108)

291

(S)-2-(5-bromo-2(hydroxymethyl)-7methylquinolin-6-ylj-2-tertbutoxyacetic acid (S)-methyl 2-(5-bromo-2(hydroxymethyl)-7methylqu inol i n-6-y l)-2-tertbu toxy acetate

(S)-mettiy 12-(5-bromo-2(dîffuoromethyl)-7methy lquinolin-6-y l)-2-feributoxy acetate (S)-methyl 2-tert-butoxy2-(2-{dif I uoroniethyî)-7methy l-5-(spiro(2.5]oct-5en-6-yl)quinolin-6yljacetate

(S)-2-tert-butoxy-2-(2(d)fliJoromethyl)-7-methyl-5(spiio[2 5]oct-5-en-6yt)quinolin-6-yl)acetic acid

Préparation of(S)-2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2tert-butoxyacetic acid: (S)-2-(5-Bromo-2-(hydroxyniethyl)-7-methylquinolin-6-yl)-25 tert-butoxyacetic acid was isolated as a side product of the reaction forming (S)-ethyl 2(5-bromo-2-(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-butoxy acetate front Example 99. LCMS-ESI* (m/z): [M+HJ*calcd Cr/li-JirNCb: 382.06; found: 382.72.

O{

292

Préparation of (S)-methyl 2-(5-bromo-2-(hydroxymethyl)-7’methylquinolm-6yl)-2-tcrt-butoxyacetate: To a solution of (S)-2-(5-bromo-2-(hydroxymethyl)-7methylquinolin-6-yI)-2-tert-butoxyaceiic acid (3.6 g, 9.4 mmol) in anhydrous dichloromethane and methanol ( 1 ; 1, 20 mL) was added (trimethylsilyi)diazomethane (2 5 M in hexanes, 5.17 mL, 10.34 mmol) and the reaction was stirred at room température for three hours. An additionaî 2 mL of (trimethylsilyl)diazoroethane was added and stirred for 2 hours, followed by an additionaî lmL of (trime thylsiiyl)dÎazomethane for 1 hour, then 1 mL of (trimethylsilyl)diazomethane added and tet go overnight. An additionaî 3.5 mL of (trimethylsilyl)diazomethane were added and stirred for 1 hour.

The reaction was quenched with 30 mL of acetic acid and then stirred 15 minutes. The reaction was concentrated under reduced pressure and then absorbed onto silica. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow foam (2.37 g). LCMS-ESf (m/z): [M+H]⁺ calcd CjsHaBrNOj: 396.07; found: 396.71.

Préparation of (S)-methyl 2-(5-broino-2-(difluoromethyl)-7-methy]quinolin-6yl)-2-tert-butoxyacetate: Prepared similarly to (S)-ethyl 2-(5-brorao-2(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetateof Example 99 using (S)methyl 2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate instead of (S)-ethyl 2-(5-bromo-2-(hydroxymelhyl)-7-me1hylquinolin-6-yl)-2-tert20 butoxyacetate. LCMS-ESf (m/z): [M+H]⁺ calcd CjdLifWùMO;,: 416.06; found: 416.75.

Préparation of (S)-methyl 2-tert-butoxy-2-(2-(difluoromethyl)-7-methyl-5(spiro[2.5]oct-5-en-6-yl)quinolm-6-yl)aceîate: To a solution of (S)-methyl 2-(5-bromo-

2-(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate (50 mg, 0.12 mmol) în 25 tetrahydrofuran and water (l mL and 0.1 mL) was added 4,4,5,5-tctramethyl-2(spiro[2.5}oeÎ'5'en-6-yl)-1,3,2 dioxaborolane (42 mg, 0.18 mmol), potassium phosphate (84 mg, 0.36 mmol) and (2-dicyclohexylphospbino-2',6'-dimethoxy-l,l'biphenyl)[2-(2-ammoethylphenyl)]palladÎum(]I) chloride methyl-f-butyl ether adduct, (SPhos) palladîum(n) phenethylamine chloride (8.1 mg, 0.012 mmol). The reaction 30 was heated in a microwave reactor at 110 °C for 30 minutes and then absorbed onto silica. The crude reaction was purified by flash column chromatography (silica gel,

293 ethyl acetate/hexanes) to give a clear white oil (44.7 mg). LCMS-ESf (m/z): [M+H]⁺calcd CjdfzfNOj: 444.23; found: 444.54.

Préparation of (S)-2-tert-butoxy-2-(2-(diflüoromethyl)-7-methyl-5(spiro[2.5]oct-5-en-6-yl)quinolin-6-yl)acetîc acid (108): To a solution of (S)-methyl 25 tert-butoxy-2-(2-(difluoromethyl)-7-methyl-5-(spiro[2.5]oct-5-en-6-yl)quinolii)-6yi)acetate (44.7 mg, 0.101 mmol) in tetrahydrofuran:methanol:water (2:2:1,2 mL) was added lithium hydroxide (12 mg, 0.504 mmol) and the reaction was heated to 50 °C ovemight. The réaction was diluted with acetonitrile and purified by reverse phase HPLC (Gemini, 15 to 95 ACN/H2O +0.1% TFA) and the desired product was lyophilized to give a white powder (29.2 mg). ’H-N.MR.: 400 MHz, (CD₃CN) δ: 8.49 (d, J = 8.8 Hz, IH), 7.85 (s, IH), 7.69 (d, J “ 8.4 Hz, lH),6.84(t, Jn__F = 55.2 Hz, IH), 5.93 (s, 1 H), 5.68 (s, IH), 2.67 (m, lH),2.62(s, 3H),2.46(m, 1H)„ 2.28-2.24 (m, 2H), 1.66 (m, 2H), 1.23 (s, 9H), 0.54-0.40 (m, 4H). LCMS-ESf (m/z): [M+H]⁺calcd for CîjHjoFîNOj: 430.21; found: 430.32.

Example 108: (S)-2-tert-butoxy-2-((R)-2-(cydopropylmethoxy)-5'(2,3dihydropyrano[4,3,2-de jquinolm-7-yl)-7-mcthylquinolin-6-yl)acetic acid (109).

C

294

(S)-24erf-butoxy-2-((R)-5-(2,3dihydropyrano[4,3,2-de)quinolin-7-yl)7-methyl-2-oxo-1,2-<iihydroquinolîn-6yljethyl pivalate

(S)-2-ter(-butoxy-2-((R)-2(cyclopropyfrnethoxy )-5-(2,3dihydropyrano[4,3,2-dejquinolin-7· yl)-7-methylquino!in-6-yl)ethanol

S?

<S)-2-terf-butoxy-2-((R>-2(cyclopropylmethoxy )-5-(2,3dihydropyrano(4,3,2-de]quinolin-7-yl)-7methytqijinolin-6-yl)ethy1 pivalate

(S)-2-tert-butoxy-2-{(R)-2(cyclopropylmethoxy )-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yi)7-methylquinolin-6-yl)acetic acid

Préparation of(S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)ethyl pivalate: To a solution of(S)-2-tert-butoxy-2-((R)-5-(23-dihydropyrano[4,3,2-de]quinolin-7-yl)-75 methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (100 mg, 0.189 mmol) and silver carbonate (156 mg, 0.567 mmol) in benzene:dichloroethane (1:1, 1 mL) wasadded (bromomethyl)cyclopropane (0.037 mL, 0.38 mmol) and the reaction was heated at 45 °C ovemight. The crude reaction was purified by flashcolumn chromatography (silica gel, ethyl acetate/hexanes) to give a brown oil (65.8 mg). LCMS-ESI* (m/z): [M+H]⁺ calcd for CîJLbN^Oî: 583.31 ; found: 583.67.

Préparation of (S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-nicthylquÎnolîn-6-yi)ethanol: To a solution of (S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2₁î-dihydropyTano[4,3₁216294

C 295 de]quinoIÎn-7-yI)-7-methylquinoiin-6-yl)ethyl pivalate (65.8 mg,0.ll3 mmol) in tetrahydrofùran:methanol (5:1,3 mL) was added 1 M sodium hydroxîde (3 mL) and the reaction was heated at 45 °C ovemîght. The reaction was diluted with water, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The solution was concentrated and then co-evaporated 2 times with acetonitrile to give a brown oil (55 mg). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C_3!H₃sN₂O₄:499.25; found: 499.54.

Préparation of (S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy )-5-(2,3 dihydropyrano[4,3^-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (109): To a solution of (S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,310 dihydropyrano[4,3,2-de]qumolin-7-yl)-7-methylquinolin-6-yl)ethanol (55 mg, 0.11 mmol) in wet acetonitrile (2 mL) was added CrCMLIOf, (0.4 Μ, 1.65 mL, 0.662 mmol) at 0 °C. The reaction was stirred for 3 hours and then diluted with methanol. The crude material was purified by reverse phase HPLC (Gemini, 15 to 65% ACN/H₂O = 0.1% TFA) and the desired product was lyophilized to give a yellow powder (18.1 mg).

'H-NMR: 400 MHz, (CD₃CN) δ: 8.58 (d, J = 5.2 Hz, 1 H), 7.76 (s, 1 H), 7.71 (d, J = 8.0

Hz, IH), 7.55 (d, J = 5.2 Hz, IH), 7.30 (d, J « 8.0 Hz, IH), 7.13 (d, J = 92 Hz, IH),

6.67 (d, J = 8.8 Hz, IH), 5.14 (s, IH), 4.64-4.58 (m,2H),4.28 (d, J = 6.8Hz, 2H), 3.49 (t, J = 5.6 Hz, 2H), 2.67 (s, 3H), 1.33-1.28 (m, IH), 0.91 (s, 9H), 0.60-0.57 (m, 2H), 0.40-0.37 (m, 2H). LCMS-ESf (m/z): [M+H]⁺calcd for CaiH^NA: 513.23; found:

513.31.

Example 109: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de] quinolin-7-yl)-

7-methyl-2-(trifluoromethyl)quinolin-6-yl)acetic acid (110)

296

(trifluoromethyl)quinolin-6-yl)-2-tertbutoxyethyl pivalate

(S)-2-tert-butaty-2-((F?)-5-(2,3~ dihydropyrano [4,3,2-de]quinolin-7-yl[-7-methyl-2(trifluofonnethyl)quinolin-6-yl)etriyl pivalate

NaOH/50 °C

MeOH/THF/H₂q

CrC>3

H₅IO₆ch₃cn O’C (S)-2-tert-butoxy-2-((i?)-5-(2_>3-(!thy(iropyrano [4,3,2-de]qurolirv-7-y1)-7-methyi-2(tfifluorarnethyl)quinolin-6-yl)etîianol

(S)-2-tert-butoxy-2-((ff)-5-(2,3-dihydropyrano [4,3,2-</θ1ηυΐηοΙίη-7-γ1)-7-πιβίΚγΙ~2(trifluoroniethyt)quinotin-6-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-cie]quinolin-

7-yl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)ethyl pivalate: (S)-2-tert-Butoxy-2- ((R)-5'(2_J3-dihydropyrano[4,3,2-de]quïnolin-7-yl)-7-inethyl-2(trifluoromethyI)quinolin-6-yl)ethyi pivalate (72 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(trifluoromethyl)quinoIin-6-yl)ethyl pivalate (7H) of example 7J except using2,3dihydropyrano[4_ï3,2-de]quinolin-7-ylboronic acid hydrochloride instead of 4-

C 297 chlorophenylboronic acid. LCMS-ESI* (m/z): [M+H]*calc’d forC33H36F3N2O4:581.2; Found: 581.L

Préparation of (SJ^-tert-butoxy-Z-ffRXb-^.B-dihydropyranof^V-dejquinolmT-yli-ï-niethyl^-ttrifliioromethyljquïnolin-é-ytyethanol: (S)-2-tert-Butoxy-2-((R)-55 (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2-(trifluoromelhyl)quinoIin-6yl)ethanol (60 mg) was prepared in a similar manner ascornpound (S)-2-tert-butoxy-2(5-(4-chlorophenyI)-7-niethyl-2-(trifluoromethyl)quinoiin-6-yl)ethanol (71) of example 7J except using (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[43,2-de]quinolin-7-yl)~

7-methyi-2-(trifluoromethyI)quinolin-6-yi)ethyl pivalate instead of (S)-2-tert-butoxy-2- (5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)ethyl pivalate (7H). LCMS-ESI* (m/z); [M+H]*calc’d for CaHaFMOj: 497.2; Found: 497.0.

Préparation of (S)-2-tert-butoxy-2-((R)-5-(23-dihydropyrano[4,3,2-de]quinolin-

7-yl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)acetic acid (110): (S)-2-tert-Butoxy-2((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-2- (trifluoromethyl)quinolin-6-yl)acetic acid was prepared in a similar manner as cornpound (S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2(trifluoromethyl)quinolin-6-yl)acetic acid (7J) of example 7J except using (S)-2-tertbutoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinoIin-7-yl)-7-niethyl-2(trifiuoromethyl)quinolîn-6-yl)ethanoI instead of (S)-2-tert-butoxy-2-(5-(420 chlorophenyl)-7-methyl-2-(trifluoromethyl)quinoIin-6-yl)ethanol(7I). *H-NMR 400 MHz, (CD3OD) 5 8.70 (d, J = 5.5 Hz, 1 H), 8.26 (s, 1 H), 7.87 (d, J = 8.2 Hz, 1 H), 7.80 (d, J = 5.5 Hz, I H), 7.70 (d, J = 9.0 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 1 H), 7.46 (d, J = 7.8 Hz, l H), 5.28 (s, I H), 4.74 (m, 2 H), 3.66 (t, J = 5.5 Hz, 2 H), 2.88 (s, 3 H), 0.95 (s, 9 H); LCMS-ESI* (m/z); [M+H]*calc’d for C₂₈H₂₆F3N₂O₄: 511.20; Found: 511.10.

298

Example HO: (S)-2-((R)-2-Acety 1-5-(-2,3-dihydropyrano[4,3,2-de]quinoi in-7-yl)-7methylquinoIin-6-yl)-2-tert-butoxyacetic acid (111)

PdCWPPhsh

LiCI/DMF

(S)-2-terf-butoxy-2-((R)-5-(2_r3-dihydro pyrano[4,3,2-de]quinolin-7-yl)-7methyl-^trifluoronnetiiylsulfonyloxy) quinolin-6-yt)ethyl pivalate (S)-2-tert-butoxy-2-({R)-5-(2,3-ditiydro -pyrano[4,3,2-de]quinolin-7-yf)-2 -(1-eltioxyvinyl}-7-methylquinolir)-6-yl) ethyl pivalate

(S)-2-twÎ-butoxy-2-((R)-5-{2,3-dihydro pyrano[4_[3,2-de]quinolirb7-yl)-2( 1 -ethoxy vinyl)-7-methylqiiinolin-6-yl)etfianol

CrOa h₅io₆ch₃cn o°c

-({R)-6-((S)-1-tert-butoxy-2hydroxyethyl)-5-(2,3dihydropyrano[4,3,2-Îfe]quinotin-7-yl) -7-methylquinolin-2-y1)ethanone

(S)-2-((R)-2-acety 1-5-(2,3-dihydro pyrano[4,3,2-de]quinolin-7-yi)-7methylquinolin-6-yl)-2-fertbutoxyacetic acid

Préparation of (S)-2-tert-butoxy-2-((R)-5-(2,3-dîhydropyrano[4,3,2-de]quinolin7-yl)-2-( 1 -ethoxyvinyl)-7-methy]quinolin-6-yl)ethyl pivalate; (S)-2-tert-Buloxy-2-((R)-

5-(2,3-dihydropyrano[43,2-de]quÎnolin-7-y])-2-(l-ethoxyvinyl)-7-methylquinolin-6- yl)ethyl pivalate (46 mg) was prepared in a similar manner as 5-bromo-7-methyl-6

C 299 vinylquinoline (8E) of example 8L except using (S)-2-tert-butoxy-2-((R)-5-(2,3dîhydropyrano [4,3,2 -de]quino]in-7-yl)-7-methyl-2-(trifluoromethylsulfonyloxy) quinolin-6-yl)ethyI pivalate and tributyl(l-ethoxyvinyl)stannane instead of5-bromo-7methylquinolîn-6-yl trifluoromethanesulfonate (8D) and tributyl(vinyl)stannane.

LCMS-ESI* (m/z): [M+H]* calc’d for C₃₆H₄₃N₂O₅: 583.30; Found: 583.30.

Préparation of(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-2-(I -ethoxyvinyl)-7-methylquinolin-6-yl)ethancl: (S)-2-tert-Butoxy-2-((R)-5(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(l-ethoxyvinyl)-7-niethylquinoIin-6yl)ethanol (16 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-210 (5-(4-chlorophenyl)-7-methyi-2-(trifluoromethyl)quinolin-6-yl)ethanol (71) of example 7J except using (S)-2-tert-butoxy~2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-

2-(l-ethoxyvinyl)-7-methylquinolin-6-yl)ethyl pivalate instead of(S)-2-tert-butoxy-2(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quinolin-6-yl)ethyl pivalate (7H). LCMS-ESI* (m/z): [M+H]* calc’d for C₃iH35N₂()₄:499.31; Found: 499.30.

Préparation of 1 -((R)-6-((S )-1 -tert-butoxy-2-hydroxyethy 1)-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methylquinolin-2-yl)ethanone: (S)-2-tertButoxy-2-((R)-5-(2,3 -dihydropyrano[4,3,2-de]quinolin- 7-yI)-2-( I -ethoxyvinyl)-7methylquinolin-6-yl)ethanol (16 mg) was dissolved in acetone (1.6 ml), and aqueous hydrochloric acid (2 N, 0.16 ml) was added. The mixture was stirred for 12 hours, and diluted with dichloromethane. The organic solution was wshed with water and brine, and dried over sodium sulfate. Concentration and purification with flash cloumn chromatography (silica gel, hexane/EtOAc) gave 1 -((R)-6-((S+1 -tert-butoxy-2hydroxyethyI)-5-(2,3-dîhydropyrano[4,3,2-de]quinolin-7-yl)-7-methylquinolin-2yl)ethanone (15 mg). LCMS-ESI* (m/z): [M+H]*calc’d for C29H31N2O4: 471.2; Found: 25 471.1.

Préparation of (S )-2-((R)-2-acety 1-5-(2,3-dihydropyrano [4,3,2-de]quïnolin-7y1)-7-methylquinolin-6-y1)-2-tert-butoxyacetic acid (111): (S)-2-((R)-2-Acetyl-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyIquinolin-6-yl)-2-tert-butoxyacetic acid (7.2 mg) was prepared in a similar manner as compound (S)-2-tert-Butoxy-2-(5-(430 chlorophenyl)-7-methyI-2-(trifluoromethyl)quinolin-6-yl)acetic acid (7J) of example 7J except using l-((R)-6-((S)-l-tert-butoxy-2-hydroxyethyl)-5-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methylquinolin-2-yl)ethanone instead of (S)y

300

2₇tert-butoxy-2-(5-(4-chlorophenyi)-7-methy 1-2-( trifluoroniethyl)qumolin-6-yl)ethanol (71). ’H-NMR '400 MHz (CD₃OD) δ 8.69 (d, J = 6.3 Hz, 1 H), 8.29 (s, 1 H), 7.89-7.79 (m, 3 H), 7.53 (d, J = 9.0 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 1 H), 5.28 (s, 1 H), 4.70 (m, 2 H), 3.66 (t, J = 5.5 Hz, 2 H), 2.86 (s, 3 H), 2.82 (s, 3 H), 0.95 (s, 9 H); LCMS-ESI* (m/z): [M+Hfcalc’d for C»H₂₉N₂O₅:485.2;'Found: 485.1 ; LCMS-ESI⁺ (m/z): [MH]*calc’d for C₂9H₂₇N₂O₅:483.2; Found: 483.2.

Example 111: (2S)-2-tert-Butoxy-2-((5R)-5-(2,3-dihydropyrano[4,3,2-de]qumolin-7 yl)-2-(l-hydroxyethyl)-7-methylquinolin-6-y])acelic acid (112)

(S)-2-((/?)-2-acetyi-5-(2,3-dihydro pyrano[4,3,2-de]qutnolin-7-yl)-7methylquinolin-6-yl)-2-terfbutoxyacetic acid

NaBH₄MeOH

(2S)-2-ferf-butoxy-2-((5R)-5(2,3-dihydro pyrano[4,3,2-de)quinolin-7-yl)-2(1-hydroxyethyl)-7methylquinolin-6-yl)acetic acid

Préparation of (2S)-2-tert-Butoxy-2-((5R)-5-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-2-(I-hydroxyethyl)-7-methylqumolin-6-yl)acetic acid (112): To the solution of(S)-2-((R)-2-acetyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7methylquinolin-6-yl)-2-tert-butoxyacetîc acid (4.4 mg) im methanol (0.2 ml) at 0 °C was added sodium borohydride (1 mg). The mixture was warmed to 25 °C and stirred for one hour. The mixture was quenched with water, and methanol was removed under reduced pressure. Filtration and purification by reverse phase HPLC (0.1%TFA/CH₃CN-0.1%TFA/H20) gave (2S)-2-tert-butoxy-2-((5R)-5-(2,3dihydropyrano[4.3,2-de]qiiinolin-7-yI)-2-(l-hydroxyethyi)-7-melhy!quino!in-6 yl)acetic acid (112) (0.5 mg). ’H-NMR 400 MHz (CD₃0D) Ô 8.64 (d, J - 5.2 Hz, 1 H),

8.25 (s, 1 H), 7.90-7.87 (m, 1 H), 7.74 (m, I H), 7.66-7.60 (m, 2 H), 7.36-7.34 (m, 1 H),

C

301

5.26 (s, 1 H), 5.20 (m, 1 H), 4.66 (m, 2 H), 3.55 (m, 2 H), 2.89 (s, 3 H), 1.60 (m, 3 H), 0.92 (s, 9 H); LCMS-ESI* (m/z); [M+H]*calc’d for C₂₉H3jN₂O₅: 487.2; Found: 487.2.

Example 112. The following illustrate représentative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prcphylactic use in humans.

(i) Tablet 1 Compound XLactose Povidone Croscaimellose sodium Microcrystalline cellulose Magnésium stéarate	mg/tah!et 100.0 77.5 15.0 12.0 92.5 10 300.0
(iî) Tablet 2 Compound X= Microcrystalline cellulose Starch Sodium starch glycolate Magnésium stéarate	mg/tablet 20.0 410.0 50.0 15.0 10 500.0
(îii) Capsule Compound X= Colloïdal silicon dioxide Lactose Pregelatinized starch Magnésium stéarate	mg/capsule 10.0 1.5 465.5 120.0 3.0 600.0

(iv) Injection 1 ( I mg/mL)mg/mL

Compound X- (free acid form)1.0

Dibasic sodium phosphate12.0

Monobasic sodium phosphate0.7

Sodium chloride4.5

1.0 N Sodium hydroxide solution

(pH adjustment to 7.0-7.5) Water for injection

q.s. q.s. ad 1 mL

302

	(v) Injection 2 (10 mg/mL)	mg/mL
	Compound X= {free acid form)	10.0
	Monobasic sodium phosphate	0.3
	Dibasic sodium phosphate	1.1
5	Polyethylene glycol 400 01 N Sodium hydroxide solution	200.0
	(pH adjustment to 7.0-7.5)	q.s.
	Water for injection	q.s, ad 1 mL
10	(vi) Aérosol	mg/can
	Compound X--	20.0
	Oleic acid	10.0
	Trichloromonofluoromethane	5,000.0
	Dichlorodîfluoromethane	10,000.0
15	Dichlorotetrafluoroethane	5,000.0

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

AU publications, patents, and patent documents are incorporated by référencé herein, as though individually incorporated by référencé. The invention has been described with référencé to various spécifie and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made

Claims

What is claimed is:

l. A compound of formula I:

wherein:

G^l is N, G² is CR⁸, and the dashed bond is a double bond; or

G^l is CR⁵, G² is N, and the dashed bond is a double bond; or

G¹ is CR⁵, G² is NR¹³, the dashed bond is a single bond, and R⁷ is an oxo (=0) group; or

G¹ is CR⁵, G² is NR¹³, the dashed bond is a single bond, and R⁷ and Rⁿ together with the atoms to which they are attached form a heteroaryl, wherein the heteroaryl is optionally substituted with one or more Z¹ groups;

R¹ isR^Iaor R^lb;

R² is R^2a or R^2b;

R³ isR^îaor R^îb;

R³’ is R³¹’ orR^îb ;

R⁴ is R^4a or R^4b;

R⁵ is R^5aor R^Sb;

R⁶ is R^6a or R^6b;

R⁷ is R^7a or R^7b;

R⁸ is R^8a or R^8b;

R^t3 is R¹³* orR^l3b;

R^ta is selected from:

a) H, halo, (Cj -Ce)alkyl and (C i-C₆)haloalkyl;

304

b) (C₂-Ce)alkenyl, (C₂-Ci)alkynyl, (C₃-C₇)cyclo alkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R' -C(=O)-O-R, -O-R'¹. -S-R¹¹, -S(O)R”, -SQ-R¹¹, -(CrCgjalkyl-R¹¹, -(Ct-Cô)alky]-C(=O)-R^l1, -(Ci-C6)alkyl-C(=O)-0-R, -(C _t-C_e)alky]-ORⁿ, -(Ci-Céjalkyl-S-R¹¹, -(CrC6)alkyl-S(O)-R^!1 and -(C;-C₆)alkyl-SO_:-R^!'. wherein each R^!1 is independently selected from H, (Cj-Cgjalkyl, (C₂'C_t)alkenyl, (C₂-C₆)alkynyl, (CjC6)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R^!0, -C(=O)-N(R⁹)R¹⁰, -0-C(=0)-N(R⁹)R^1ü, -SO--N(R⁹)R¹⁰, -(CrC6)alkyl-N(R⁹)R^lo,-(Ci-Cfi)alkyl-C(=0)-N(R⁹)R^,0,-(C|-C6)alkyl-0-q=0)-N(R⁹)R¹⁰and -(Ci-C6)alkyl-SO2'N(R⁹)R^1tJ, wherein each R⁹ is independently selected from H, (Cr C6)alkyl and (CrC7)cycloalkyl, and each R^l0is independently selected from Rⁿ,-(CiCfi)alkyl-R' *, -SO₂-R_s -C(=O)-R' -C(-O)OR'¹ and -C(=O)N(R⁹)R, wherein each R¹¹is independently selected from H, (C]-C_s)alkyl, (C₂-C₆)alkenyl, (Ci-Qjalkynyl, (C,Cg)haloalkyl, (C₃-C₇)cycloaikyl, aryl, heterocycle and heteroaryl;

and wherein any aryl, heterocycle or heteroaryl of R^la is optionally substituted with one or more Z¹⁰ groups;

R^Ib is selected from:

a) -(C]-C6)alkyl-0-(CrCé)alkyl-(Cî-C₇)carbocycle, -(C|-C6)alkyl-S-(C₍Cejalky 1-(Cj-C₇)carbocycle, -(C i-C₆)alkyl-S(O)-(C i -C₆)alky 1-(C₃-C₇)carbocycle, -(C i C₆)alkyI-S02-(C_rC6)aIkyl-(C_}-C₇)carbocycle, -(CrCeialkyl-SOz-tCi-C^aikyl-Z’^-CfO)(Ci-Ce)alkyl-Zⁿ, -O-CCi-Cejalkyl-Z¹³, -S<CrC6)alkyl-Z¹³, -S(O)-(CrC_s)aIkyl-Z¹³,-S0r (Ci-CùJalkyl-Z¹³, -(CrC6)alkyl-Z¹⁴, -(C,-C6)aiky 1-0(0)-(Cj-Cjalky 1- Z^:\ -(C^^alkylC(0)-0(Ci-C6)aikyl-Z¹³,-(Cl-C6)alkyl-0-(CrC6)alkyl-Z^,1,-(Cl-C6)alkyl-S-(CrC_É)alkylZ¹³, -(C₂-C6)aIkenyl-(C_rC6)haloalkyI, -(Cî-CfiJalkynyHQ-Cgihaloalkyl, - (C_rC₇)halocarbocycle, -NRaSChNRcRj, -NR_aS0₂0(C3-C₇)cart>ocycle, -NR_aSOjC)ayl, -(C₂-C6)alkenyI-(CrC₇)carbocycle, -(Cz-Côjalkenyl-ary!,-((T-C₆)a:keny1-beteroaryl, -(C2-Ci)alkenyi-heterocycle, -(C₂-C₆)alkyny]-(CyC₇)carbccyc!e, -(C2-C₆)a]kynyl-aryl, -(C₂-C6)alkynyl-heteroaryl -(C₂-C6)alkynyl-heterocycle, -ÎC₃-C₇)carbocyck-Z' and -ha!o(C!-C₆)alkyl-Z’, wherein any (C_rC₆)alkyl, (Cj-Cejhaloalkyl, (C₃-C₇)carbocycle, (C₃C₇)halocarbocycle, (C₂-Ce)alkenyl, (C₂-Cfi)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

C

305

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicycl ic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more Z^! groups, wherein two 2¹groups together with the atom or atoms to which they are attached optionally form a (C_rC-r)carbocyc!e or heterocycle, wherein the (Cj-OJcarbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

c) (C[-Ci)alkyl, wherein (Ci-Cé)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z* groups;

d) -X(C_t-C₆)alkyl, -X(C_rC₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-Q)alkynyl and -X(C₃-C₇)carbocycIe, wherein any -X(C i -C^Jalkyl and -X(Ci-Cf,)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹groups, and wherein any -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)caibocycle,is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as partof a group, is substituted with one or more Z^s groups and optionally substituted with one or more Z¹groups;

f) (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (CvCéjalkenyl, and (C₃-C₆)alkynyl, wherein (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C6)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹groups; and

g) -NR^ -C(O)NR_cR_f, -OC(O)NRJ<_S, -SO₂RR_OR_t, -(C] -C^alkyl-NRA, -(CrCejalkylCtOj-NReRf, -(C_rC₆)alkyI-O-C(O)-NR_eR_fand -(CrCJalkyl-SCbNReRf, wherein each any (Ci-C₆)alkyl, as part of a group, is optionally substituted withone or more Z¹ groups;

R^2î Îs selected from:

a) H, (Ci-Cft)alkyl and -O(C|-C₆)alkyl,

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (CpCfijhaloalkyl, (C_rC₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;

306

c) -C(=O)-R' -C(=O)O-R^!I, -S-R^:i, -S(O>Rⁿ, -S02-R^h, -(Ci-C6)alkyl-R. -(CrCeJalkyl-C^O-R¹¹, -(C,-C6>lkyl-C(=0)-O-R^! -(CrC₆)alkyI-ORⁿ, 4CrC6)alkyl-S-R^H, <C|-C6)alkyl-S(O)-R^,: and -(CrC^alkyl-SO^R¹¹, wherein each R^u is independently selected from H, (C_rC_s)alkyi, (C₂-C₆)alkenyl, (C₂-C«)alkynyl, (C_rCejhaloalkyl, (C₃-C7)cycloalkyl, aryl and heterocycle and heteroaryl, wherein aiyl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups;

d) -OH, -O(C₂-C₆)alkenyl, -O(C₂-C₆)alkynyl, -O(C_rC₆)haloalkyl, -O(C₃C7)cycloalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl; and

e) -N(R⁹)R‘°, -C(=O)-N(R⁹)R‘°, -O-C(-0)-\(R’)R'³, -SOî-NfR^R¹⁰, -(CiCfiJalkyl-NfR^R¹⁰, <Ct-C6)alkyl-C(=O)-N(R’)R‘⁰, -(CrCeJalkylO-Ct^OfNÎR^R¹⁰, and -(Cj-C6)alkyI-SO₂-N(R⁹)R^,°, wherein each R⁹ is independently selected from H, (Cr Cs)alkyl and (Cj-Cjkycloalkyl, and each R^,ois independently selected from R¹¹, -(CiC6)alkyl-R”, -SCb-R¹¹, -C(=O)-R¹¹, -C(=O)OR'^! and -C^OMR’jR¹¹, wherein each R¹’ is independently selected from H, (Ci-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (CiC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^2b is selected from:

a) -(Ci -Cs)alky]-O-(C _rC6)alkyl-(C₃-C₇)carbocyc]e, -(C ] -C₆)alkyl-S-(C j -

C_fi)alkyl-(CrC₇)carbocycle, -(Ci -C₆)alkyi-S(OXCi-C6)a]kyl-(C₃-C7)carbocycle, -(Ci C6)alkyl-SOr(Ci-C₆)alkyl-(C₃-C₇)carbocycle, -(C₂-C₆)alkenyl-(C_rC6)haloalkyl, -(C₂C₆)alkynyl-(C_t-C₆)haloaIkyi, -(C,-C₆)alky]-SO₂-(C_t-C₆)alkyl-Z^!3, -C(O)-(C,-C6)aIkyl-Z¹³, -O-iC,-C6)alkyl-Z^B, -S-(Ci-C6)alkyl-Z¹³, -SO-fCrC^alkyl-Z¹ \ -SO2-(Ci-C₆)alkyl-Z^t3, -(CrC6)alkyl-Z^!\ -(C^^l-CfOXCi-CeJalkyl-Z¹³, -(CrC₆)alkyl-C(O)-O(CiC₆)alkyl-Z¹³, -(C1-C6)alkyl-O-(C1-C6)alkyI-Z¹³, -ÎCi-C^lkyl-S-tCrQalkyl-Z¹³, -(C3C₇)balocarbocycle, -NR₄SO₂'NR._cR_<j, -NRaS0₂0(C₃-C₇)caibocycle, -NRaS0₂0aryl, -(C₂-C6)alkenyl-(C₃-C₇)carbocycle, -(C₂-C₆)aikenyl-aiyl,-(CzXEkdkenyî-heteroaryl, -(C₂-C₆)alkenyl-heterocycle_s -(C₂-C6)alkynyl-(C₃-C₇)carbocycle, -(Cj-CsXkynyl-aryi, -(C₂-Cfi)alkynyl-heteroaryl, -(C₂-C₆)alkynyl-heterocycle, -(C_rC₇)carbocycle-Z¹ and -halo(CrC6)alkyl-Z³, wherein any (C|-C6)alkyl, (Ci-CeJhaloalkyl, (C₃-C7)carbocycle, (C₃C₇)halocarbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

307

b) spîro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more Z¹ groups, and wherein two Z’ groups together with the atom or atoms to which they are attached optionally form a (C3-C?)carbocycle or heterocycle, wherein the (C3-C7)carbocycle or heterocycle is optionally substituted with one or more Z^! groups;

c) (Ci-Ce)alkyl, wherein (CrC₆)alky! is substituted with one or more Z³groups and optionally substituted with one or more Z¹ groups;

d) -X(C|-C6>alkyl, -X(Ci-C6)haloalkyI, -XfCrC^alkenyl, -X(C2-Câ)alkynyl and -X(C₃-C7)carbocycle, wherein any -XfCi-CiJalkyl, -X(C]-C6)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any -X(C₂-C₆)alkenyl, -X(C₂-C6)alkynyl and -X(C3-C₇)carbacycle is substituted with one or more Z* groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl,-Xhcteroaryl and-Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z^s groups and optionally substituted with one or more Z^!groups;

f) (Ci-C₆)haloalkyl, (Cî-C₇)carbocycle, (QrCcJalkenyl, and (Cï-Cejalkynyl, wherein (Ci-C^Jhaloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkenyi and (C₂-C₆)aikynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹groups; and

g) -NR<R._f, -C(O)NReRf, • OC(O)NR_<Rr. -SG-NIW, -(Ci-Qûalkyl-NReRf, -(Ci-C6)alkylC(O)-NReRf,-(CrCiJalkyl-O-CtOJ-NReRfand-fCi-Cgjalkyl-SOîNReRf, wherein each (Ci-Cyalkyl is optionally substituted with one or more Z¹ groups;

R^3a is (Ci-Céjalkyl, (Ci-C₆)haloalkyl, (CrC₆)alkenyl, (C_rC₆)alkynyI, -(Ci-C6)alkyl-CC3-C₇)cycloa!kyl, -(CrC^alkyl-aryl, -(Cj-C6)alkyl-heterocycle, -(CrCejalkyl-heteroaryl, -OfCrC^aikyl, -0(CrC₆)haloalkyl, -O(C₂-C6)aIkenyl, -O(C₂-C₆)alkynyl, -O(C3-C₇)cycloaIkyl, -Oaryl, -0(C_rC₆)alkyl-(C3-C₇)cycIoalkyl, -O(Ci-C₆)alkyl-aryl, -O(Ci-C₆)alkyl-heterocycle or -OfCi-QOalkyl-heteroaryl, wherein any (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (CyCJalkenyl or (Cj-C^alkynyl of R³¹, either alone or as a group, is optionally substituted with one or more groups selected from -OfCj-CsJalkyl,

308 halo, oxo and -CN, and wherein any (Cj-C₇)cydoalkyl, aryl, heterocycle or heteroaryl of R^3a, either alone or as a group, is optionally substituted with one or more groups selected from (C_rCe)alkyl, O(C|-C₆)alkyl, halo, oxo and -CN;

and R^3a is H;

R^3b is -(C7-Cj4)alkyi, (C3-C7)carbocyde, aryl, heteroaryl, heterocycle, -(CrC,)alkyIOH,-(C.-CfiJalkyl-O-fCrC^alkyl-Z'², -(CrC^alkyl-O-i^-C^alkenyl-Z¹², -(Cî-Ciialkyl-O-ÎCî-Céjalkynyl-Z’^-ÎCi-CfiJalkyl-S-iCrCsialkyl-Z¹², -(C,-Ci)alkyl-S(C2-C₆)alkcnyl-Z^,2;-(C|-C6)alkyl-S-(C2-C6)alkynyl-Z^l2,-(C|-C6)alkyl-S(Ü)-(CiC₆)alkyl-Z^l2,-(Cl-C6)alkyl-S(O)-(C2-C6)aikenyl-Z’²,-(CrC6}alkyl-S(O)-(C₂C₆)alkynyl-Z¹², -(Cl-C6>lkyl-SO2-(Ci-C6)alkyl-Z^!2> -(CrC^alkyl-SOî-tCiCiialkenyl-Z¹², -(CI-C6)alkyl-SO2-(C2-C6)alkynyl-Z'², -(C i-CbJalkyl-NRRt,, -(CrCôJalkylOQOLNRX. -(Ct-Cfejalkyl-NRa-CCOyORb, -(C\-C6)dkyl-NÏVC(O)-NR_aR_b, -(Ci-C^alkyl-SChiCr C_É)alkyl, -(C|-C₆)alkyl-SO₂NR_<R_d, -(Ci-CeJalkyl-NRaSOjNRJU -(Ci-C_e)alkyl-NRaSO2O(Cî-C₇)carbocycle,-(CrCeJalkyl-NRjSOîOaryl, -(Ci-C₆)alkyl-NR_a-S0₂-(C_l-C₆)atkyl,-(C_l-C₆)alkyl-NR_a-S0₂-halo(C₁-C5}alkyl, -CCi-Cijalkyl-NRa-SOï-CCi-Ceïalkenyl,-(Ci-Cejalkyl-NR^-SOî-fCj-CfiJalkynyl, -(Ci -C<5)alkyl-NR_e-SO₂-(Cj-C₇)carbocycle, -(C ] -Cejalkyl-NRg-S0₂-halo(Cj-C₇)ca!bocycIe, -(Cj-Ci)alkyl-NR_a-SO₂-aryl, -(Ci-CéJalkyl-NRa-SOrheteroaryl, -(C₁-C₆)alkyl-NR_a-SO₂-heterocyde, -O(C₇-Ci₄)alkyl, -O(CrC₆)alkyl-NRaRb, -0(Ci-C6)alkyiOC(0)-NRcRd, -0(C₁-C_fi)alkyl-NR_a-C(0)-OR_b, -O(Ci-C_s)alkyl-NR_e-C(O)-NR_IR₍„ -O(C_rC₆)alkyl-NR,-SO₂-(CrC₆)a:kyl₎-OÎCrCsÎalkyl-NRe-SOrhaloiCrCeialky], -0(C_]-C₆)alkyi-NR_a-S0₂-(C₂-C₆)alkenyl, -O(C_:-C(,)aIkyl-NRa-SO₂-(C₂-C6)alkynyl, -0(C_l-C₆)alkyl-NR.-S0₂-(Cj’C₇Xaibocycle, -O(C j -C_b)alky l-NR_a-S0₂-halo(C₃-C₇)carbocyc le, -O(C ] -CgJalkyl-NK-SOraryl, -OfCrCdalkyl-NRe-SOî-heteroaryl, -OÎCi-Cejalkyl-NRj-SQi-heterocycle, -OfCi-Csjalkyl-NRa-SOrNRJRb, O(C;-C₆)alkY!-N7L-S0₂-(C_rC₇)carbocycle, -O(Ci-C_É)alkyI-NR_a-SO₂-halo(Cî-C₇)carbocycle, -O(C i-C6)alky:-NR_a-SO₂-aryi, -0(CiCeialkyl-NRaSOzNRcRj, -O(C_;-C₆)alkyl-NR_üSO₂O(C₅-C₇)carbocycle₎ -O(Ci-C₆)aîkylNRaSO₂OaryI, -Oheteroaryl, -Oheterocycle, -Sheteroaryl, -Sheterocycle, -S(0)hetcroaryl, -S(O)heterocycle, -S(D₂heteroaryl or -SOïheterocycle, wherein any (Ci-C^Jalkyl, (C₂Cs)alkenyl, -(C₇-C|₄)alkyl, (CrCs)alkynyl, aryl, (C₃-C₇)carbocycle, heteroaryl or

309 heterocycle of R’^h. either alone or as a group, is optionally substituted with one or more Z¹groups;

and R^3b is H, (C,-C6)alkyl or -O(C,-C6)alkyl; orR³” and R^3b'together with the carbon to which they are attached form a heterocycle or (C3-C₇)carbocycle which heterocycle or (Cj-CAcarbocycle of R^3b and R.ⁿ together with the carbon to which they are attached is optionally substituted with one or more Z¹ groups;

R^4a is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R^4a is optionally substituted with one or more groups each independently selected from halo, (Ci-C₆)alkyl, (Cj-C^alkenyl, (C;-C_É)haloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(Ci-Ce)alkyI, -SH, -S(Ci-Ce)alkyl, -NIE, -NH(Cî-Cé)alkyl and -N((Ci-Ce)alkyl)2, wherein (Ci-Câ)alkyl is optionally substituted with hydroxy, -O(C|-C_É)alkyl, cyano and oxo;

R^4b is selected from:

a) (C i -C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (Ci -C_É)alkyl, (C₂-Cs)alkenyl and (C₂A3_â)alkynyl are each optionally substituted with one or more Z^!groups;

b) (C₃-Ci₄)carbocycle, wherein (C₃-Cj₄)carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle;

c) spiro-heterocycle and bridged-heterocycle, wherein spiro-heterocycle and bridged-heterocycle are each optionally substituted with one or more Z¹ groups, and wherein two Z¹ groups together with the atom or atoms lo which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle;

d) aryl, heteroaryl, spiro-heterocyclc, fused-heterocycle and bridgedheterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups; or

R⁴ and R³ together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle ofR⁴ and R³ together with the atoms to which they are attached maybe optionally substituted with one or more Z¹ groups; and R³ is H, (Ci-C₆)alkyI or -G(C _rC₆)alkyl;

310

R⁵* is selected from:

a) halo, nitro and cyano;

b) ' R¹¹, -C(=O)-R, -C( O)-O-R^u, -O-R^h, -S-R, -S(O)-R^h, -SO2-R^h, -(CiC6)alkyl-R¹¹,-(CrCs)alkyl-C(=O)-R^l!, -(C1-C₆)alkyl-C(=OyO-R, -(Cï-QalkyÎ-O-R¹¹, (Cj-CsÎalkyl-S-R¹¹,-(Ci-C6)alkyl-S(O)-R^H and ^Ct-Céjalkvl-SOrR¹^ wherein each R¹¹ is independently selected from H, (C₍-C₆)alkyl, (C_rC₆)alkenyI, (C₂-C_È)alkynyl, (C_: Céjhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups; and

c) -N(R’)R¹⁰, -C(=O)-N(R⁹)R'° -O-C(-O)-NÎR⁹)R^,ü, -SO2-N(R⁹)R'⁰, -(Cr C₆)alkyl-N(R⁹)R^IÛ, -ÎCI-C6)alkyl-C(=O)-N(R⁹)R^lf’, -(C1-C₆)alkylO-C(-O)-\(R⁹)R^::j, and -(Ci-CûJalkyl-SOî-NfR^R¹⁰, whereineach R⁹ is independently selected from H, (CjCs)alkyl and (C3-C7)cycloalkyl, and each R^iOis independently selected from R^::, -(CiC6)alkyl-R^!I, -SO2-R”, -C(=O)-R' -C(=O)OR^{l 1} and -Ct^NCR’iR’¹, wherein each R¹¹is independently selected from H, (Ci-C6)alkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl,(C]Céjhaloalkyl, (Cj-Cvicycloalkyl, aryl, heterocycle and heteroaryl;

R⁵*¹ is selected from:

a) -(C t -C₆)alkyl-O-(C ₍ -C₆)alky |-(C ₃-C₇)carbocycle,

-(C i -C₆)alkyl-S-(C i <é)al ky l-(Ci-C7)carbocycle,

-(C, -C₆)alkylS(O)-(Ci -C₆)alkyl-(C₃-C₆)carbocycle, -(Ci-C6)alkylSOï(Ci-C6)alkyl-(C₃-C7)carbocycle, -(C₂-Gjalkenyl-(C;-C₆)halo;ilkyl,-(C₂C₆)alkynyl-(CrC₆) haloalkyl, -(C₃-C7)halocarbocycle, -NR,SO₂NR_cRj, -NR,SO2O(C₃C₇)carbocycle, -NRaSO₂0aryl, -(C₂-C6)alkenyl-(C₃-C₇)caibocycle, -(Cj-C^alkenyl-ary!. -(C₂-C6)alkenyl-heteFoaryl, -(CrC^alkenyl-heterocycle, -(C₂-C6)alkynyl-(C₃-C₇)carbocycle, -(C₂-C6)alkyny]-aryl,-(C2-Cs)alkynyi-heteroaryL -(C₂-C6)alkynyi-heterocycle, -(C₃-C7)carbocycle-Z’ and -halo(Ci-Cs)alkyl-Z³, whereinany (Ci-Cô)alkyl, (Cf-C^haloalkyl, (C₃-C₇)carbocycle, -(CrCijhalocarbocycle, (C₂-C6)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either aione or as part of a group, is optionally substituted with one or more Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally foim a (Cr C₇)carbocycle or heterocycle, wherein the (Cj-C^carbccyfe or heterocycle is optionally substituted with one or more Z^l groups;

c) (Ci-CéJalkyl, wherein (CrC₆)alkyl is substituted with one ormore Z¹groups and optionally substituted with one or more Z¹ groups;

d) -X(C_rC₆)alkyl, -X(C_rC₆)haloalkyl, -X(C₂-C₆)alkcnyl, -X(C_rC_t)alkyny| and -X(CrC₇)carbocycle, wherein any X(C_rC6)alkyl and -X(Ci-C6)haloalkyl is substituted with one or more Z^J groups and optionally substituted with one or more Z¹groups, and wherein any -X(C₂-C₆)alk.cnyl, -X(C2'Cs)alkynyl and -XfCrCiJcarbocycleis independently substituted with one or more Z⁴ groups and optionally substituted with one ormore Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group are each independently substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups;

f) (Ci-C₆)haloalkyl, (C₃-C7)carbocycle, (C₂-C₆)alkenyl, and (C₂-C_s)alkyny!₎wherein (Ci-C₆)haloalkyl, (Cî-C₇)carbocycie, (Ci-C^alkenyl and (Cz-Csjalkynyl are each independently substituted withone ormore Z⁶groups andoptionally substitutedwithone or more Z¹ groups; and

g) -NR^Rr, -C(O)NI^R_r. -OC(O)NRJ6, -SO₂NR_eR_s -(Cj-Qalkyl-MCRf, -(Ci-C6)alkylC(O)-NReR_f,-(CrC6)alkyI-O-C(O)'NReRfand -(C^Qalkyl-SOjNRJtf, wherein any (Cj-Côjalkyl, as part of a group, is optionally substituted with one or more Z¹groups;

R^6a is selected from:

a) H, halo, (C_rC₆)alkyl, and (C_rC₆)haloalkyl;

b) (Cî-Celalkenyl, (C₂-C6)alkynyl, (Cj-CiJcycIoalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R, -C(=O)-O-R¹¹, -O-R¹', -S-R, -S(O)-R^u, -SOtR,

-(C₁-C₆)alkyl-R^!\-((::rC6)alkyl-C(-O)-R^!‘>-(C₁-C₆)a]kyl-C( -(C_rC_s)alkyl-0R”, -(CrC₆)alkyl-S-R^H, -(C_rC₆)alkyl-S(O)-R and -(C^alkyl-SOj-R, wherein each • 3I2

R^î! is independently selected from H, (Cj-C₆)alkyl, (CrC,;alkenyl, (C₂-Câ)alkynyl, (C_tCe)haloalkyl, (Cj-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) ' -N(R’)R^I0, -C( O)-N(R⁵)R'^î!, -O-C(-O)-M R’)R^ic, -SOi-NfR’jR¹⁰, -(Ci-Ci)alkyl-N(R^<>)R'^ü.-(Cl-C₆)alkyi-C(-0)-N(R⁹)R'^c',-(C|-Cé)a]kyl-0-C('-0)-N(R⁹iR^ICland -(Cj-C6)alkyl-SO2-N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C)C6)alkyl and (Cj-C₇)cycloalkyl, and each R¹⁰is independently selected from R^]l,-(CiC6)alkyl-R^[ -SO,-R'¹, -C(-O)-R'-C(=O)OR^{! 1} and -C(=O)N(R⁹)R'¹, wherein each R¹¹is independently selected from H, (CpCeialkyl, (C2-C₆)alkenyl, (C₂-C₆)alkynyl, (C_rC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

and wherein any aryl, heterocycle or heteroaryl of R^Sa is optionally substituted with one or more Z¹⁰ groups;

R⁶* is selected from:

a) -(Ci-C₆)alkyl-O-(C_i-C₆)alkyl-(C_rC7)cartocycle,-(C|-C6)alkyl-S-(C_rC₆)alkyl-(C₃-C₇)carbocycle, -(C_rC6)alkyl-S(O)-(C ]-Cyalky]-(C_}-C₇)caibocycle, -(CjC6)alkyl-SO₂-(Ci-Cfi)aIkyI-(C3-C₇)carbocycle, -(C^-Céjalkenyl-fCi -Cf,)haloaikyl, -(C₂C₆)alkynyl-(Ct-C₆)haloalkyl_J -halofCj-CvJcarbocycle.-NR^SCfNRJfi, -NRaSO₂O(C₃C₇)carbocycle, -NRaSO₂Oaryl, -(C2-C₆)alkenyl-(C₃-C₇)carbocyclc, -(Ç₂-C₆)alkenyl'aryl, *(C₂-C₆)alkenyI-heteroaiyl,-(C₂-C6)alkenyl-heterocycle,

-(C₂-C_È)alkynyl-(C ₃-C₇>carbocyc le, -(Cî-C^alkynyi-aryl, -(Ca-Qalky nyl-heteroaryl, -(C₂-C6)aIkynyI-hetcrocycle, --(C^-Cvjcarbocycle-Z' and-halofCi-Qalkyl-Z³, wherein any (Ci-C₆)alkyl, (C|-C6)haloaikyl,(C₃-C₇)carbocycle, (C₂-C₆)a!kenyl, (C₂-C₆)alkyny!, aryl, heterocycle and heteroaryl, either alone or as part of a group, îs optionally substituted with one or more Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fùsed-bîcyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle îs optionally substituted with one or more Z¹ groups;

c) (Ci -C₆)alkyl, wherein (Ci-C^alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

C 313

d) -XfCrCôialkyl, -X(C,-C₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycIe, wherein any -X(C_:-C<;)alkyi and -X/Ci-C^hatoalkyl is substituted with one or more Z^J groups and optionally substituted with one or more Z¹groups, and wherein any -X(C₂-C6)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and - Xheterocycle, wherein any aryl, heteroaryl and Heterocycle, either alone or as part of a group, is ' substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹groups;

f) (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-C_s)alkynyl, wherein (Ci-C6>haloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C$)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

g) -NIL.R_f. -C(O)NfoR_f, -OC(O)NR.R_fl -SOjNReRf, -(C.-C^alkyl-N^Rf, -(C_I-C₆)alkylC(0)-NR_ÎR_f,-(C_!-C₆)alkyl-0-C(0)-NR_eR_rand-{C₁-C₆)alkyI-S0₂NR_ïRr wherein any (Ci-Csjalkyl, as part of a group, îs optionally substituted with one or more Z¹groups;

R^7a is selected from:

a) H, halo, (C ) -C₆)alkyl and (C j -Côïhaloalky] ;

b) (C₂-C_e)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R' -C(=O)-O-R'¹, -O-R, -S-R¹¹, -SCOJ-R, -SO2-R^h, -(C1-C₆)alkyl-R^tl,-(C1-C6)alkyl-C(=O)-R^1,,-(Cl-C_t)alkyl-C(=0)-O-R^!1,-(CrCs)alkyl-0R'-(CrCfilalkyl-S-R¹¹, -(CrC6)alkyl-S(O)-R^U and -(Ci-C^alkyl-SOî-R¹¹, wherein cach R¹¹ is independently selected from H, (C i-C(s)alky I, (Cj-C/Jalkcnyl, (Cz-CsJalkynyl, (CiC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R¹⁰, -C^O^Ry⁰, -O-C^N^R, -SO2-bl(R⁹)R^,c, -(CrG>lkyl-N(R⁹)R^]0, -(CpC^alkyl-q^-NiR^R'^Ci-C^Ikyl-O-C^Ol-NCR’lR¹⁰and -(CrC>,)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C|Ce)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R'^l, -(C|16294

314

Cejalkyl-R¹’, -SO2-R¹¹, -C( O)-R' -C(-O)0R'· and -CRO)N(R’)R^U. wherein each R¹¹is independently selected from H, (C|-C6)alkyl, (C₂-C6)alkenyl, (C₂-Ci)alkynyl, (C i Cùjhaloalkyl, (C₅-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

and wherein any aryl, heterocycle or heteroaryl ofR⁷’ is optionally substituted with one or more Z^t0 groups;

R^7b is selected from:

a) -(C_t-C₆)alkyl-SO₂-(C|-C_s)alkyl-Z^!J, -C(Oy(C,-C6;aIkyl-Z^J, -0-(Cr C₆)alkyl-Z¹³, -S-(CrCe)alkyl-Z¹³. -S(OXCrC₆)alkyl-Zⁿ, -SO2-(C1 -C6)alkyl-Z¹³, XCrC₆)alkyl-Z¹⁴, -(Cp^alkyl-CtOkCCrQalkyl-Z¹³, -ÎC1-C6)alkyl-C(0)-O(C1Crjalkyl-Z¹³, -(Ci-C6)alkyl-O-(C_;-C6)alkyl-Z¹³, •<CrC6)a]kyl-S-(Cl-C6)alkyl-Zⁿ, -(Cr C_É)aIkyl-O-(C_!-C₆)aIkyl-(C₃-C₇)carbocycle,-(C]-C6)alkyl-S-(CiC₆)alkyl-(C₃-C₇)carbocycle, -(Ci-Ctlalkyl-SiOXC^Cé^lkyl-fCj-CvXarlwcycle, -(C _rC6)alkyl-SO₂-(Ci-C6)alkyl-(C₃-CT)carbocycle, -(C₂-C_é)a)kenyl-(Ci-C₆)ha!oaIky], -(C₂CôJalkynyl-ÎCi-Cejhaloalkyl, -(Cj-C₇)halocarbocycle, -NRSOjNRRd, -NRaSChCXCsC₇)carbocycle, -NRSO₂Oaryl, -(C₂-C6)alkenyl-(C₃-C₇)caibocycle, -(CrCeJalkenyl-aryl, XC₂-C$)alkenyl-heteroaryl, -(C₂-Cfi)alkenyl-heterocycle, -(C₂-C₆)alkynyl-(C_rC7)carbocycle, -(C_rC₆)alkynyl-aiyl.-(C₂-C6>lkynyl-heteroaryl, -(C₂-Ci,)alkynyl-heterocycle, -(Cj-C^arbocycle-Z¹ and -halo(C)-Câ)alkyl-Z³ .wherein any (Ci-C^alkyl, (Cf-Cgjhaloalkyl, (C;}-C₇)carbocycle, (Cj-C₇)halocarbocycle, (C₂-Ce)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z^! groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclîc carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle, wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z^! groups;

c) (Ct-C₆)alkyl, wherein (CrC^alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) -X(Ci-C₆)alkyl, -XtCrC^haloalkyl, -X(C_rC₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle, wherein any -X(C_rC₆)alkyl and -XiCXXhaloaTyl is

315 substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C7)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z^s groups and optionally substituted with one or more Z¹groups;

f) (C]-Cé)haloalkyl, (C₃-C₇)carbocycle, (Cn-QJalkenyi and (G-C₆)alkynyl, wherein (C_I-C6)haIoalkyl, (C₃-C₇)carbocycle, (CrCsJalkenyl and(C2-C₆)alkynyl are each substituted with one or more Z^s groups and optionally substituted with one or more Z¹groups; and

g) -NR«Rf, -C(O)NR_tR_f, -OC(O)\R_cRf, -SO^Rf, -(C₁-C₆)alkyl-NR_ïR_f, <C₁<₆)alkylC(0)-NR_<R_f,-(Ci-C₆)alkyl-0-C(0)-NR_tR_fand-(C|-C₆)alkyl-S0₂NR_eR_f, wherein each (Ci-CeJalkyl is optionally substituted with one or more Z¹ groups;

R^ga îs selected from:

a) halo, nitro and cyano;

b) R¹¹, -C(-O)-R’\ -C( O)-O-R¹¹, -O-R^tl, -S-R¹’, -S(())-R” , -SQ-R'¹, <Csialkyl-R¹¹, -(Cj-Ceialkyl-Ct^-R, -(CrC^alkyl-QO^O-R”, -(G-Qalkyl-O-R¹¹, (CrC^alkyl-S-R¹¹, <C,-C6)alkyl-S/O-R¹' and -(Ct-C₆)alkyl-SO;-R^il, wherein each R¹¹ is independently selected from H, (Ci-Ce)alkyl, (C-C^alkcnyl, (C₂-C₆)alkynyl, (C|Ce)haloalkyl, (C_rC₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups; and

c) -N(R’)R¹⁰, -(-Χ -ΌΤΝ^Χ⁰, -0-C(=0)-N(R⁹)R ^io, -SO2-N(R⁹)Rⁱ⁰, <Cr C₆)alkyi-N(R⁹)R’⁰, -(Ci-Cô)alkyl-C(=O)-N(R⁹)R^1(>, -(C)-C6)alkyl-0--CtOJ-N^R¹⁰ and (Ci-Cfifalkyl-SOi-N/R^R¹⁰, wherein each R⁹ is independently selected from H, (Cr C6)alkyl and (C3-C7)cycloalkyl} and each R^!Ois independently selected from R¹¹,-(CiCeialkyl-R, -SOz-R, -C(=O)-R^1], -C(=OX)R^U and -C(-O)N(R’)R, wherein each R¹’ is independently selected from H, (Ci-Ce)alky 1, (C2-C₆)alkenyl, (C₂-Cfi)alkynyl, (C_;C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z^l! groups;

R^8b is selected from:

a) -(CrC^alkyl-SOi-CCrCéJalkyl-Z¹³, -C(G)-(Q-Q)aJkyl-Z^!3, -O-(Cr C6)alkyl-Z'\-S-(CrC6)alkyi-Z¹³,-S(0)-(Ci-Cfl)alkyi-Z^;\ -S02-(C;-C6>lkyi Z^lî, -ÎCi-C6)alkyl-Z¹⁴,-(CrCe)alkyl-C(OXCi-C6)alkyl-Z¹³, -(Ci-C6\aikyLCiO)-O(C_rC₆)alkyl-Z¹³, -(CrCôfalkyl-O-fCi-Célalkyl-Z¹³, -(Ci-C6)aikyl-S-(Ci-Ci)alkyl-Z’³, <C,Ceïalkyl-O-fCrCsÎalkyl-iCrCvicarbocycle, -(Ci-Ce)alkyl-S-(CiCô)alkyl-(C3-C7)carbocycle,-(C|-C6)alkyl-S(O)-(Ci-Ce)alky]-(C3-C₇)carbocycle, -(C_tC₆)alkyl-SO2-(C_rCô)alkyI-(C3-C7)carbocycle, -(C₂-C₆)alkenyl-(Ci-C6)haloalkyl, -(C₂C₆)alkynyl-(Ci-C6)haloalkyl, -ha!o(C}-C₇)carbocycle,-NR_lSO-NR_cR_<j, NR_aS0₂0(C₃-C₇)carbocycle, -NRaS0₂Oaryl, -(C2-C₆)alkenyl-(CrC₇)carb<x:yclc, -(C₂-C₆)alkenyl-aryl, -(C2-(’6)alkenyl-heteroary], -(C₂-C₆)alkenyl-heterocycle, -(C₂-Ce)alkynyl-(C3-C₇)carbocycle, -(C₂<6)alkynyl-aryl,-(C₂-C₆)alkynyl-heteroaryl, -(C₂-C(>)alkynyl-heterocycle, XC₃-C₇)carbocycle-Z^l and -halo(C , -C^alkybZ³, wherein any (Ci-C₆)alkyl, (Ci-C₆)haloalkyl, (C3-C₇)carbocycle, (Ci-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

b) spîro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spîro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

c) (C)-Cs)alkyl, wherein (C j -C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) -X(C,-C₆)alkyl, -X(C_rC₆)halcalkyl, -X(C,-C₆)alkenyl, -X(C2-C₆)alkynyl and -X(C3-C₇)carbocycle, wherein any -X(Cr(_B,)alkyl and -X(Ci-Cf.)haloalkyl issubstituted with one or more Z³ groups and optionally substituted with one or more Z¹groups, and wherein any -X(C₂-Cô)alkenyl, -X(C2-C6)alkynyl and -X(CrC₇)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group is substituted with one or more Z^s groups and optional ly substituted with one or more Z’ groups;

f) (C|-C₆)haloalkyl, (Cj-Cvjcarbocycle, (Cï-CsJalkenyl and (Ci-Cgjalkynyl, wherein (Ct-C^Jhaloalkyl, (Cj-CvJcarbocycle, (Cz-C^jalkenyl and (C₂-Cs)alkynyl are each independently substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups; and

g) -NR^Rf, -C(O)NR_rR_f, -0C(O)NR_eR_f, -SChNRA, -(CrQalkyl-NR^f, -(C₁-C₆)alkylC(O)-NR_cR_f, -(CrCsJalkyl-O-CtOÏ-NKRf and -(Ci-QOalkyl-SCbNRcRf, wherein each (Ci-C₆)alkyl is optionally substituted with one or more Z¹ groups;

R^13a is selected from:

a) R¹¹, -C(=O)-Rⁿ, -C(=O)-O-R, -0-R, -S-R^-SÎOl-R¹¹, -5Ο2-Κ^Η, -(C,Cé)alkyl-R^! -(Ci-C6)alkyl-C(=O)-R^u, -(CrC6)alkyl-CK))-O-R'^l, -(Ci-C5)alkyl-O-R^1:. (Ci-Ce^alkyUS-R¹¹, -(C^eîelkyi-SCOyR and -(CrCslalkyl-SOi-R¹¹,whereineachR^,:is independently selected from H, (C|-C_e)alkyl, (Cî-C^Jalkenyl, (C₂-Q)alkynyl, (Cr Cfi)haloalkyl, (Cj-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups; and

b) -C(=O)-N(R⁹)R¹⁰, -SOrNfRV⁰, <Cl-C6)alkyl-N(R⁹)R^:', -(C i-C6)alkylC(=O)-N(R⁹)R¹⁰, -(Ci-C^lkyl-O-CWNCR’jR·· and -(CrC6)alkyl-SO2-N(R⁹)R^l°, whereineach R⁹ is independently selected from H, (C;-C6)alkyl and (CrC₇)cycloalkyl, and each R¹⁰is independently selected from R^l!,-(Ci-C/alkyl-R¹ ’.-SOj-R¹¹, -C(=0)-R¹¹, -C(=0)OR^lf and -C(=O)N(R’)R¹¹, wherein each R^li is independently selected from H, (Ci-C_È)alkyl, -(CrC₆)alkylaryl, (C₂-C₆)alkenyl, (Cj-C/jalkynyl, (CrC₆)haloalkyl, (C₃C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups;

R^nb is selected from:

a) -(CrCeJatkyl-SOz-tC^Jalkyl-Z*^J, -C(O)-(C(-C6)alkyl-Z¹³, -O-(Cr

C₆)alkyl-Z¹³, -S-ÎC]-C6)alkyl-Z¹³, -S(O)-(Ct-C₆)alkyl-Z^u, -SOr(C!-C6)alkyl-Z¹³, -(Ci-C6)alkyl-Z¹⁴, -(Ci-C6)alkyl-C(OHC|-C6)aiky]-Z¹³, -(CrC₆)aIkyl-C(0>0(Cr C₆)alkyl-Zⁿ, -(C,-C6)alkyl-O-(C:-C6)alkyl-Z¹³, (C, C^alkyl-S-fCpC^lkyl-Z¹³, -(C;16294

318

C₆)alky 1-O-(C _f -C₆)alky 1-(C₃-C₇)carbocycle, -(C ₍ -C₆)alky l-S-(C_rC₆)alkyl-(C3-C₇)carbocycle, -(Ci-C₆)aIkyl-S(OXC| -C₆)alkyl-(C3-C₇)caibocycle, -(C·C_t,)aikyl-SO2(C_i-C₆)alkyl-(CVC7)carb<)cycle,-(Cd-QUÎkenyl^CrCbJhaloaky:, -(C₃C₆)alkynyl-(C;-Cô)halo?.lkyl, -halo(C₃-C₇)carbocycle, -(CrCejalkenyl-tCrCrjcarbocycle, -(C₂-C₆);ilkeny[-aryL -(C2-C₆)alkenyl-heteroaryl, -(C₂-C6)alkenyl-heterocycle, -(C₂-C_h)alkynyl-(C₃-C₇)carbocyclc, -(C₂-C₆)alkynyl-aryl, -(O--C₆)alkynyl-heteroaryl, -(C₂-C₆)alkynyl-heterocycle, - (C₃-C₇)carbocycle-Z^!, -halofCi-CgJalkyl-Z³, -NRgSOaNRcRd, -NRaSO₂O(Cj-C₇)carbocycle and -NRaSChOaryl, wherein any (Ct-CsJalkyl, (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-Cô)aikenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle are optionally substituted with one or more Z¹ groups, wherein two Z¹groups together with the atom or atoms to which they are attached optionally form a (C3-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

c) (Ci-CeJalkyl, wherein (CrQ)alkyl is substituted with one or more Z¹groups and optionally substituted with one or more Z¹ groups;

d) -X(Ci-C6)alkyl, -X(C_t-C₆)haloalkyl, -X(C₂-C_s)alkenyl, -X(CrC₆)alkynyI and -X(C3-C₇)carbocycle, wherein any X(Ci-C_É)alkyl and -X(C|-Cfi)haloalkyl is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹groups, and wherein any -X(Ci-C₆)aIkenyl, -X(C₂-C₆)alkynyl and -X(Cj-C₇)carbocycle, is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as partof a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹groups;

f) (Ci-C₆)haloalkyl, (CrCjjcarbocyc le, (C₂-C_È)alkeny I and (C₂-C_s)alkynyl, wherein (CpCôjhaloalkyl, (Cj-C₇)carbocyclc, (C₂-C₆)alkenyl and (Cj-CsJalkynyl are each

C

319 independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

g) -C(O)NReRf, -SOzNR^Rf, -(CrQJalkyl-NR^Rf, -(Ci-QalkylCfO-NR.Rf,

-(Ci-Cfi)alkyl-O-C(O)-NReRf and -fCi-C^alkyl-SO^NReRf* wherein eachfCi-C^alkyl is optionally substituted with one or more Z¹ groups;

or any of R³² and R^6a, R⁶¹ and R^7a, R⁷¹ and R⁸’, R¹ and R^s, R¹ and R² or R¹ and R¹³together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5,6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or the 4, 5,6 or 7-membered heterocycle is optionally substituted with one or more substituents each independently selected from halo, (Ci-C₆)alkyl, (C₂-C₆)alkenyl, (Ci-C₆) haloalkyl, (C₃C₇)cycloalkyl, -OH, -O(Ci-C₆)alkyl, -SH, -S(CrC₆)alkyl,-NH₂, -NH(Ci-C₆)alkyl and -N((C_rC₆)alkyl)2;

or any of R³ and R⁶, R⁶ and R⁷ or R⁷ and R^s, together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or the 4, 5,6 or 7-membered heterocycle are each independently substituted with one or more Z⁷ or Z⁸ groups, wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C7)carbocyc!e or 4, 5 or 6-membered heterocycle;

or any of R¹ and R⁸, R¹ and R² or R¹ and R¹³ together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or the 4, 5,6 or7-membered heterocycle are each independently substituted with one or more Z⁷ or Z⁸ groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C₇)carbocycle or 4, 5 or 6-membered heterocycle;

X is independently selected from O, -C(O)-, -C(0)0-, -S-, -S(0)-, -SO2., -(CiC₆)alkylO-, -(C,-C_s)alkylC(O)-, -(Ci-C₆)alkylC(0)O-, -(C₁-C₆)alkylS-, -(CrC^alkylSfO)and -(C_rC6)aIkyISO₂-;

each Z¹ îs independently selected from halo, -ΝΌ-, -OH, =NORa, -SH, -CN, -(C_rC₆)alkyl, -(C₂-C6)alkenyl, -(C₂-C₆)alkynyl, -(Ci-C₆)haloalkyl, (C]-C₇)carbocycle, - (C₃C₇)halocarbocycle, -aryl, -heteroaryl, -heterocycle, -O(Ci-C₆)alkyl, -0(C2-C_fc)alke!iyl, -O(C₂-C6)alkynyl, -O(Cj-C6)haioalkyl, -O(C₃-C₇)carbocyclc. -O(C₃-C₇)halocarbocycle,

320

Oaryl, -Oheteroaryl, -Oheterocycle, -S(C | -C^alkyl, -S(C2-C6)alkenyl, -S(C₂-C6)alkynyl, -S(C_l-C6)haloaIkyl,-S(C_J-C7)carbocycle₎ -S(C-,-C_?)halocarbocyc!e, -Saryl, -Sheteroaryl, -Sheterocycle, -S(O)(C]-C6)alkyl, -S(O)(C₂-C₆)alkenyl, -S(01(C₂-C₆)alkyny1, -S(O)(C_rCsJhaloalkyl, -S(O) (C₃-C₇)carbocycle, -S(0)(C_rC₇)halocaibocycle, -SO2(C|O₆)alkyl, -S(O)aryl, -S(OJcarbocycIe, -S(O)heteroaryl, -S(O)heterocycle, -SO2(C2-C_s)alkenyl, -SO₂(C₂-C₆)alkynyl, -SGhfCt-Qjhaloalkyl, -SOi(CrC₇)carbocycle, -SO₂(C₃Cvjhalocarbocycle, -SOiaryl, -SO₂heteroaryl, -SO2heterocycle, -SChNRjRd, -NR<Kj, -NR.QOjK, -NR_aC(O)OR_a, -NR_aC(O)NR_<R_< -NRaSOA, -NR,SO₂NR_tR_d. -NRaS0₂0(C₃-C₇)carbocycle, -NRjSO₂Oaryl, -OSfO^Rj, -C(O)Ra, -C(O)ORb, -C(0)NRcRd, and -OC(O)NR_cRd, wherein any (C_t-C6)alkyl,(Ci-C₆)haloalkyl, (C₂CJalkenyl, (C₂-C6)alkynyl,-(Cj-C₇)halocarbocycle, (Cj-C₇)carbocycle, (C₃C₇)halocarbocycle, aryl, heteroaryl and heterocycle of Z¹, either alone or as part of a group, is optionally substituted with one or more halogen, -OH, -ORj,, -CN, -NR^CCOJ-R),, heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -SfO^NRcRa;

each Z² is independently selected from -NO2, -CN, spiro- heterocycle, bridgedheterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NR_ÜSO₂(C₃C₇)carbocycle, -NR₄S0₂aryL -NILSOjheteroaryl, -NRaSC^NILRd, -NRaSO2O(C₃C₇)carbocycle and -NRaSO₂Oaryi;

each Z³ is independently selected from -NO₂, -CN, -OH, oxo, =N0Ra, thioxo, -aryl, -heterocycle, -heteroaryl, (C₃-C₇)carbocycle, -(C₃-C₇)habcaTbocycle, -OfCi-C^alkyl, -O(C₃-C₇)carbocycle, -Ohalo(C₃-C₇)carbocycie, -Oaryl,-Oheterocycle, -Oheteroaryl, -S(Ci-Cé)alkyI, -S(C₃-C₇)carbocycle, -S(C₃-C₇)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(O)(Ci-C₆)alkyl, -S(O)(C3-C₇)carbocycle,-S(O) (C₃-C₇)ha!ocarbocycle, -S(O)aryI, -S(O)heterocycle, -S(O)heteroaryl, -SO₂(Ci C_s)alkyl, -S0₂(C₃-C₇)carbocycle, -SOî(C₃-C₇)halocarbocycle, SO₂aryl, -SO₂heterocycle, -SO₂heteroaryl, -NRaRi,, -NRaC(O)Rb, -C(O)NR_cRd, -SO₂NRcR<i, -NR^SO^NILR^, -NRaS0₂0(C₃-C₇)carbocycle and -NRaSO₂Oaryl;

each Z⁴ is independently selected from halogen, -(Ci-Cejalkyl, (Ci-C₇)carbocycle. -haloCCi-CôJalkyl, -NO_2î -CN, -OH, oxo, ‘-NOR_ê, thioxo, aryl, heterocycle, heteroaryl, (C₃C₇)halocarbocycle, -O(C]-C6)alkyl, -O(C₃-C₇)carbocycle, -0(C₃-C7)halocarbocycle,

321

-Oaryl, -Oheterocycle, -Oheteroaryl, -S(Ci-Cs)alkyl, -S(C₃-C₇)carbocycle, -S(C₃C7)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(OXC]-C6)alkyl, -S(O)(C₃C₇)carbocycle, ~S(OXC₃-C₇)halocarbocycle, -S(O)aryl, -S(0)heterocycle, -S(O)heteroaryl, -SO₂(Ci-C₆)alkyl, -SO2(C',-C?)carbocycie, -S02(C₃-C₇)halocarbocycle, SCbaryi, -S0₂heterocycle, -SO₂heteroaryl, -NRaRj,, -NReC(O)Ra, -CfOJNRçRj, -SOîNd^Rj, -NRaSOîNRcRd, -NRaSO₂O(C₃-C₇)carbocycle and -NR_aSO₂Oaryl;

each Z⁵ is independently selected from -NO₂, -CN, -NRaSOîNRcRd, -NR_aS0₇0(C₃C₇)carbocycle, -NRaSO₂Oaryl, -NR^SOjfCrCéÎalkyl, -NR.ySOjiG-C^aikenyl, -NR_iSO₂(C₂-C&)alkynyl, -NR_aSO₂(C₃-C'7karbocycle, -NR*SQ2(Cj-C₇)halocarbocycle, -NRaSO₂aryl, -NR_aSO₂heteroaryl, -NR_aSO₂heteroary], -NR_aSO₂heterocycIe, -NR_eC(O)alkyl, -NRaC(O)alkenyl, -NR_aC(O)alkynyl. -NRaC(O) (C₃-C₇)carbocycle, -NRaC(0)(C₃-C₇)halocarbocycle, -NR_aC(())aryl, -NRXXCOheteroaryl, -NRaC(O)heterocycle, NRaCfOjNRcRd and NR_aC(O)OR_t;

each Z⁶ is independently selected from -NO₂, -CN, -NR^R* NR_aC(0)Ro, -C(O)NR_cRd, -(Cj-C₇)halocarbocycle, aryl, heteroaryl, heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C₃-C₇)halocarbocycle, -OtCrCôJalkyl, -0(0] -C₆)alky 1-O-(C]-C^alkyl, -O(C₃-C₇)carbocycle, -Ohalo(C_rC₆)alkyi, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C₃C₇)halocarbocycle, -S(Ci-C6)aïkyl, -S(C₃-C₇)carbocycle,-S(Ci-C6)haloalkyl, -S(O)aryl, -S(O)heteroaryl, -S(0)heterocycle, -S(0)(C₃-C₇)halocarbocycle, -S(O)(C i-C₆)alkyl, -S(OXC₃-C₇)carbocycle, -S(O)halo(C)-C₆)alkyl, -SO-aryl,-S0₂ heteroaryl, -S0₂heterocycle, -SO₂(C]-C₆)alkyl, -SQïhaioCCi-CéJalky], -S0₂(C₃-C₇)carboeycle, -S02(C₃-C₇)halocarbocycle, -SOjNR^Rj, -NRaS0₂(C₃-C₇)balocarbocycle, -NRiSOjaryl, -NRjSOîheteroaryl, -NR_aSO₂heteroaryl, -NRaSOiNRîRa.-NRaSOjO^-Cjlcajbocycle and -NRaSOjOaryl;

each Z⁷ is independently selected from -N02, =N0Ra, -CN, -(Ci-CâJalkyl-Z¹², -(C2C6)alkenyl-Z¹², -(CrCsJalkenylOH, -(C2-C6)alkynyl-Z¹²,<C2-CÉ)alkynyl-0l·L -(C|C₆)haloalkyl-Z¹², -(C]-C6)haloalkylOH, -(C3-C7)carbocycle-Z¹², -(C3-C₇)carbocycleOH, (C₃-C₇)halocarbocycle, -(C_rC₆)aIkylNR<;Rd> -(CrCelalkylNRjCtO)]^,-(CC6)alkylNRaSO₂Ra, aryl, heteroaryl, heterocycle, -O(Cj -C₆)alkyl-Z¹², -O(Ci-C₆)aIkenyl, -O(C₂-Ce)aIkynyl, -O(Ci-Câ)haloalkyl, -O(C₃-C₇)carbocycie, -0(C₃-C₇)halocarbocyele, -Oaryl, -0(C_l-C₆)alkylNR_cR_<j, -OfCrC^aikylNR/XO)^,-OtCi-i^alkylNR.SO;^,

322

-Oheteroaryl, -Oheterocycle, -S(C;-Q)alkyl-Z^l2, -S(C2-Ct)alkenyl, -S(C2-G)aikynyl. -S(C|-C6)haloalkyl, -S(C3-C7)carbocyde, -S(C3-C7)halocarbocycle, -S(C--C6)alkylM^R^ -SfCi-CeJalkylNRaCiOJRa, -S/Cj-CûJalkylNl^SOîR^-Sajyl, -Sheteroaiyl, -Sheterocycle, -S(OXCt-Cfi)alkyI, -S(O)(C2-C6)alkenyl, -S(O)(C2-C6)alkynyl, -S(O)(Ci-C6)haloalkyl, -S(OXCrC7)carbocyde, -S(0)(C3-C7)haIocarbocycle, -SOXCi-CôJalkyl, -SfOXCiC^alkylNR^Rj, -S(OXCrC6)alkylNRiC(0)Ra, -S(O)(C, -C6)alkylNRaSO2R* -S(O)aryl, -S(0)heteroaryl, -S(0)heterocycle, -SO2(Ci-C6)alkyl, -SO:(C-.-C>,)alkenyl, -SO2(C2C6)alkynyl, -SO2(Ci-C6)halÔaikyls -SO2(C3-C7)carbocycIeI -S02(C3-C7)halocarbocycle, -SO2aryI, -SO2heteroaryl, -SO2heterocycle, -SO2(C!-G,)alkylN!<RJ, -S02(Cr C6)aIkylNR1C(O)Ra,-S02(C1-C6)alkylNRaS0îRil, -SGNRJG, -NRaC(0)ORb, -NRaC(O)NRcRij -NRgSOîRb, -NR^SOiNRcRd, -NRaS020(C3-C7)carbocycIe) NRaS020aryl, -OS(O)2Ra, -C(O)NRcRd, and -OC(O)NRçRt, wherein any (Ci-C)alky 1, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-Cfi)alkynyl, (C3-C7)carbocycle, (C3C7)halocarbocycle, aiyl, heteroaryl and heterocycle of Z⁷, either alone or as part of a group, is optionally substituted with one or more halogen, -OH, -OR.,, -CN, -NR^C/ObRb, heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHhelerocyclc, or -S(O)2NR<Rb;

each Z⁸ is independently selected from-N0₂ and -CN;

each Z⁹ is independently selected from -{Cj-CéJalkyl and -O(Ci-C6)alkyl;

each Z¹⁰ is independently selected from:

i) halo, oxo, thioxo, (C₂-C₆)alkenyl, (Ci-C6)ha)oalkyl, (C₃C₇)cycloalkyl, (C₃-C₇)cycIoallcyl-(Ci-C₆)alkyl-, -OH, -O(Cr C₈)alkyl, -O(Ci-C₆)haloalkyl,-SH, -S(C_rC₆)alkyI,-SO(CiC_s)alkyl, -SO₂(C_rC₆)alkyL -NH₂, -NH(C)-C₆)alkyl and -NtCCrCôJalkylh;

îi) (C] -Cs)alkyl optionally substituted with-OH, -O-(CiC₆)haloalkyl, or -O-(Cr-C_é)alkyl, and iti) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (C|-C6)alkylor COOH;

each Z¹¹ is independently selected from Z’°, -C(-O)-NH₂, -C(=O)-NH(Ci-C4)alkyl, -C(=O)-N((Ci-C₄)alkyl)₂₁ -C(=O)-aryl, -C(=O)-heterocycie and -C(- O)-heteroaryl;

each Z¹² is independently selected from -NO₂, =N0Ra, thioxo, aryl, heterocycle, heteroaryl, (Cs-C^halœarbocycle, (C₃-C₇)carbocycle, -0(C₃-C₇)carbocycle, -OhalofO,C₇)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(Ci-C₆)alkyl, -SiCj-C₇)carbocycle. -Shalo(CrC₇)carbocycle, -Saryl, -Sheterocycle, -Sheteroaiyl, -SfOXCj-Csjalkyl, -S(O)(C3-C₇)carbocycIe, -S(O)halo(CrC7)carbocycle, -S(O)aryl, -S(O)heterocyc]e, -S(O)heteroaryl, -SO₂(Ci-C_e)alkyl, -SO₂(C3-C₇)carbocyclc_> -S0₂(Cy C?)halocarbocyc]e, -SOjaryl, -SOïheterocycle, -SO₂heteroaryl, -NR.,R,. -NRaC(O)Ri>, -C/OiNRJO. -SO₂NRcRd, -NRjSOiNRtRq, -NR_eS020(C₃-C₇)carbocycle and -NR,SO-Oaryl;

each Z¹³ is independently selected from -N02, -OH, =NOR<? - SH, -CN, -{C3C7)halocarbocycle, -O(Ci-C6)alkyl, -O(C2-C6)alkenyl,-O(C2-Ci)alkynyl, -O(CiCJhaloalkyl. -O(C3-C7)carbocycle, -O(Ci-C7)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(Ci-C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkYnyl,-S(C;-C,>)haloalkyl, -S(C3-C7)carbocyc!e, -S(C3-C7)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(OXCt-C6)alkyl, -S(O)(C2-C6)aIkenyl, -S(O)(C2-C6)alkynyl, -S(0)(C|-C6)haloalkyl, -S(0)(C3-C7)carbocycle, -S(OXC3-C7)halocarbocycle, -S(0)aryl, -S(O)beteroaryl, S(0)heterocycle, -SO2(Ci-C6)alkyl, -SO2(C2-C6)aIkenyl, -SO2(C2-Cfi)aIkynyl, -SO2(CiC6)haloalkyl, -SO2(C3-C7)carbocycle, -S02(C3-C7)balocarbocyclc, -SO2aryl, S02heteroaryl, -S02heterocycle, -SOîNRtRd, -NRcRq, -Ν%Ο'(Ο)Κ„ -NRaC(O)ORb, -NRJXOJNRJ·^ -NRaSO2Rb, -NR^SOjNRJO, -NR,SO2O(C3-C7)carbocycle, NROSO2Oaryl, -OS(O)2Ra, -C(O)RO -C(O)0Rt, -C’tOJNR^, and -0C(0)NRcR,, wherein any (Ci-C6)alkyl, (Ci-Cyhaloalkyl, (Ch-CeJalkenyl, (C2-COalkynyl,(C3-C7)carbocycle, (C3-C7)halocarbocycle, aryl, heteroaryl and heterocycle ofZⁿ, either alone or as part ofa group, is optionally substituted with one or more halogen, -OH, -ORb, -CN, -NR2C(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroatyl, -NHheterocycle, or -StOXNR.Raî each Z¹⁴ is independently selected from -NO₂, =NOR_a -CN, -(CjC₇)halocarbocycle, -0(C₃-C₇)halocarbocycîe, -S(C₃-C₇)halocarbocycle₎ -S (0)(0C₇)halocarbocycle, -SO₂(C₃-C₇)halocarbocycle, -NR_aSO :NK R<<_: -NRaSO₂O(C₃C₇)halocarbocycle, -NRaSO₂Oaryl and -OS(O)₂R_a, wherein any -(CrC₇)halocarbocycle of Z¹⁴, either alone or as part of a group, is optionally substituted withone or more halogen,

C • 324

-OH, -ORb, -CN, -NR_aC(O)₂R_b, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, NHheteroaryl, -NHheterocycle, or -S(O)₂NR_<R_d;

each Ra is independently H, (C|-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryl(C_t-C6)aIkyl-, heteroaryl or heteroarylfCiC6)alkyl-, wherein any (Ci-Cô)alkyl, (C₂-Ce)alkenyl, (C₂-C_s)alkynyl, (C₃-C₇)caibocycle, heterocycle, aryl or heteroaryl of Ra, either alone or as partof agroup, is optionally substituted by one or more halogen, OH and cyano;

each Rb is independently (Ci-C^alkyl, (C₂-C₆)alkenyl. (C₂-C6)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryl(C |-C₆)alkvl-, heteroaryl or heteroaryl(Cr C6)alkyl-, wherein any (Ct-Cs)alkyl, (C₂-Cfi)alkenyl, (Cf-CJalkyiiyl, (C3-C₇)carbocycle, heterocycle, aryl or heteroaryl of Rt, either alone or as part ofa group, is optionally substituted by one or more halogen, OH and cyano;

Rc and Rj are each independently selected from H, (C i-Ce)alkyk (CrCeJalkenyl, (C₂-C6)alkynyl, (C₃-C₇)carbocycle, aryl, arylfCi-CsJalkyl-, heterocycle, heteroaryl and hetcroaryl(Ci-C₆)alkyl-, wherein any (Cj-C₆)alkyl, (C₂-Ct.)a]kenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl and heteroaryl of R_c or K, either alone or as part of a group, îs optionally substituted by one or more halogen, OH and cyano; or Rc and R| together with the nitrogen to which they are attached form a heterocycle, wherein any heterocycle ofRcand Rd together with the nitrogen to which they are attached is optionally substituted by one or more halogen, OH or cyano;

each R< is independently selected from -ORa, (C]-Cj)alkyl and (C₃-C₇)carbocycle, wherein (Ci-CsJalkyl and (C₃-C₇)carbocycle is substituted by oite or more Z⁶ and optionally substituted with one ormore Z¹, (CrCiJhaloalkyl, (C₂-C6)alkenyl and (C₂-C6)alkynyl, wherein any (C₂-C6)haloalkyl, (C₂-Cfi)alkenyl and (C₂-Câ)alkynyl is optionally substituted with one or more Z¹ ; and aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl îs substituted by one or more Z^s;

each Rf is independently selected from -R_g. -OR^ -(Ci-C6)alkyl-Z⁶, -SO₂R_B, C(O)R_Ê, C(0)ORg and -C(O)NRcR_g; and each R_g is independently selected from H, -ORa, (C_rC_s)alkyl, (Cj-C₇)carbocycle, (Ci-Cs)haloalkyl, (Cù-C&lalkenyl, (C₂-Cé)alkynyl, aryl, heterocycle and heteroaryl, wherein

325 any (Ci-Cgjalkyl, (Cj-Cîjcarbocycle, (C|-C₆)haloalkyl, (Ci-C₆)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl of R_g is optionally substituted with one or more Z] groups; or a sait thereof.
2. The compound ofclaim l wherein R³ is (Ci-C6)alkyl, (C2-Cs)alkenyl or -O(C;C6)alkyl, wherein any (CrC6)alkyl or (C2-Cé)alkenyl of R³ îs optionally substituted with one or more groups selected from -O(Ci-C6)alkyl, halo, oxo and -CN, and wherein R³ is H.
3. The compound ofclaim l wherein R³ is -O(Ci-C4)alkyl, and wherein R³ is H.
4. The compound of any one of claims l -3 wherein R² is halo, H or -CH₃.
5. The compound of claim l which is a compound of formula Ih

Ih or a sait thereof.
6. The compound of any one of claims 1-5 wherein R¹ is H.
7. The compound of any one of claims 1 -6 wherein R⁶ is H.
8. The compound of any one of claims 1-7 wherein R^s is H or (C j -Cejalkyl.

326
9. The compound of claim l which is a compound of formula lk or a sait thereof.
10. The compound of any one of daims l -9 wherein R⁴ is selected from:

a) aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl is optionally substituted with one or more groups each independently selected from halo, (Ci-C₆)alkyl, (C2-C₆)alkenyl, (C_rC6)haloalkyl, (Cî-C₇)cyc!oalkyl, -OH, -O(C|C<$)alkyl, -SH, -S(Ci-Ce)alkyl, -NH2, -NH(Ci-Cô)alkyl and -N((Ci-€<$)alkyl}2, wherein (CjC₆)alkyl is optionally substituted with hydroxy, -O(C]-C()alkyl, cyano or oxo;

b) (C3-C i4)carbocycle, wherein (C₃-C_l4)carbocycle is optionally substituted with one or more Z* groups, wherein two Z^l groups together with the atom or atoms to which they are attached optionally fonm a (Cî-C7)carbocycle or heterocycle; and

c) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle are each independently substituted with orte or more Z⁷ groups and optionally substituted with one or more Z¹ groups.
11. The compound of any one of daims I -9 wherein R⁴ is selected from:

a) aryl, heterocycle and heteroaryl, wherein anyaryl, heterocycle and heteroaryl is optionally substituted with one or more groups each independently selected from halo, (C]-C₆)alkyl, (C₂-C₆)alkenyl, (Ci -C^haloalkyl, (Cî-CTjcy+oalkyl, -OH, -O(C|Côjalkyl, -SH, -S(C|-C₆)alkyl, -NH₂, -NH(Ci-C6)alkyi and -N((C|-C6)alkyl)_2! wherein (C|C₆)alkyl is optionally substituted with hydroxy, -O(Ci-C₆)alkyl, cyano or oxo; and

327

b) aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.
12. The compound of any one of claims 1-9 wherein R⁴ is selected from:

a) heterocycle, wherein heterocycle is optionally substituted with one or more groups each independently selected from halo, (C j -C^alkyl, (C₂-C₆)a)kenyl, (C_tC₆)haloalkyi, (C_rC₇)cycloalkyl, -OH, -OfCt'-Qalkyl, -SH, -SfCrQalkyl, -NH₂, -NH(C_rCfi)alkyi and -N((Cj-C₆)alkyl)2, wherein (Ci-C(,)alky 1 is optionally substituted with hydroxy, -O(Ci-C₆)alkyl, cyano or oxo; and

b) fused-heterocycle, wherein fused-heterocycle js substituted with one or more Z⁷ groups and optionally substituted with one or more Z^! groups.
14. The compound of any one of claims 1-9 wherein R⁴ is:

328

I5. The compound ofany one of claims M4 wherein R⁷ îs selected from:

a) H, halo, (Ci-C(,)alkyl and (Cj-CgJhaloalkyi;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycleor heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -C(=O)-R^U, -C(=O)-O-R, -O-R¹', -S-R¹¹, -SfCO-R^-SOrR¹¹, -(Ct<6)alkyl-R^1!, -(Cl-C_s)alkyl-C(-O)-R¹¹, -(CrC6)alkyl-C(-O)-0-R, -(Ci-C6)alkyl-OR^lt, -(Cî-Ceialkyl-S-R¹ -(CrC6)alkyLS(O)-Rⁿ and -fCrC^lkyl-SOi-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Cijalkyl, (C₂-C«)alkenyl, (C₂-C₆)alkynyl, (C_;Cs)haloalkyl, (Cî-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z^!0 groups;

d) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R¹⁰, -O-C(=0)-N(R⁹)R¹⁰, -SO2-N(R’)R°, -(CrC6)alkyi-N(R⁹)R¹⁰, /C.-C6)alkyl-C(-O^R^R¹⁰, -(C ,-C6)aIkyl-0-C(=O)-N(R⁹)R^[ûand -(C1-C6)alkyI-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Cr Ce)alkyl and (Cj-CvJcvcloalkyl, and each R^,c'is independently selected from R,-(C]C6)alkyl-R^1!, -SO2-R^i!, -C(=O)-R^b, -C(=O)0R and -CRO'^îR^r’'¹, wherein each R¹¹is independently selected from H, (C|-Ce)alkyl, (C₂-C6)alkenyl, (Cj-C/jalkynyl (C_rC₍,)haloalkyl, (C₃-C₇)cydoalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) -(C.-Côialkyl-SOî-iCrCsïalkyl-Z¹¹, -CfORCrUJalkyl-Z¹¹, -O-(C,C6)alkyl-Z¹³, -S-(C [-Côïalkyl-Z^{1 J}, -S(O)-(C rC₆)alkyl-Z^B, -SOoRCrC^lky'.-Z¹⁵, -(C1-C6)aIkyl-Z^l\-(Ci-C6)aIkyl-C(OXC₁-C₆)alkyI-Z^B,-(Ci-C6)alkyl-C(O)-O(C1C6)alkyl-Z¹³, -(CrQalkyl-O-CCi-C^alkyl-Z¹³, -(Cj-QelkyLS-ÎCi-C^alkyl-Z'³, -(Cr C₆)alkyI-O-(Ci -Cf^alkyl-fC^-C-^aibocycie, -(C_rC₆)alkyl-S-(CiC₆)alkyl-(Cj-C7Xarbocycle,-(C|-C₆)alkyl-S(0)-(Ci-C₆)alkyl-(C3-C7)carbocycle, -(C]16294

329

C₆)alkyl-S02-(C_rC₆)alkyl-(C₃-C7)carbocycle, -(C₂-C₆)alkenyl-(C|-C₆)haloalkyl, -(C₂C_É)alkynyl-(C)-C₆)haloalkyl, -(C₃-C₇)halocarbocyc[e, -NR_aS0₂NR_cR_d, -NRSO-OîCjC₇)carbocycle, -NR_aSO₂Oan.'l, -(C₂-C6)alkenyl-(Cj-C₇)carbocycle, -(Cî-C_s)alkenyl-aiyl, -(Ci-Cô^lkenyl-heteroaryl, -(C₂-C₆)alkenYl-heterocyclc.

-(Cz-CJalkynyI -(CrC₇)carbocycle, -(C2-C₆)alky nyl-aryl, *(C₂-C_s)al kynyl-heteroaryl, -(Cz-QOalkynyl-heterocycle, -(C₃-C₇)carbocycle-Z¹ or -halofCj-C^alkyl-Z¹, wherein any (Cj-Cslalkyl, (Ci-CjJhaloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl, (Cj-CsJalkynyl. aryl, heterocycle and heteroaryl, either alone or as a group, is optionally substituted with one or more Z¹ groups;

f) -X(Ci-C₆)alkyl, X(C^haloalkyl, X(C₂-C₆)alkenyl, -XCCî-C^alkynyl and -X(C₃-C₇)carbocycle, wherein any X(Ci-C₆)alkyi and X(Ci-C6)haloalkyI is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any X(C₂-C₆)alkenyi, -X(C₂-C6)aikynyl and -X(C₃-Ci)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups;

g) (Ci-C₆)alkyl, wherein (C |-Cô)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

h) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z^s groups and optionally substituted with one or more Z¹groups;

î) (Ci -C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkyny 1, wherein (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹groups; and

j) -NReRj, -C(O)NR_ÎR_f, -OQO)NR^r, ’WRA -(C₁-C₆)alkyl-NR_tR_f, -(C_l-C_;,)alkylC(O)-NR_cR_f, -(C_rC₆)alkyl-0-C(O)-NR_{R_fand -(Ci-C₆)alky 1-SO-NfoR,-, wherein each (Ci-C$)alkyl is optionally substituted with one or more Z¹ groups.
16. The compound of any one of claims 1-14 wherein R⁷ is selected from:

a) H, (Ci-C₆)alkyl and (Ci-C^haloalkyl,

330

b) (C'2-C₆)alkenyl, (C₂-C₆)alkynyl. (Cj-CvJcycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -C(O)-O-R^{l l}, -O-R¹¹, -(CL-Oalkyl-R¹¹ and -(CrC6)alkylO-R' \ wherein each Rⁿ îs independently selected from H, (Ci -CjJalkyl, (C2-C₆)alkenyi, (C₂QJalkynyl, (Ci-C₆)haioalkyl, (Cj-C₇)cycloalkyl, aiyl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z^lû groups;

d) -NÎR’JR¹⁰, -C(=O)-N(R^q)R'°, -(C1-C6)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C|-Cg)alkyl and (Cj-Cb/cycloalkyl, and each R¹⁰ îs independently selected from R^ll,-(C|-C6)alkyl-R¹¹, -SO2-R^U, -C(=O)-R^1!, -C(-O)OR^!Iand -6(=0)151^⁹^¹¹, wherein each R¹¹ is independently selected fromH, (Ci-CtOalkyl, (C₂-C₆)alkcnyl, (C₂-C6)alkynyl, (Ci-C₆)haloalkyl, (Cj-C_T)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) -(C₂-C6)alkynyl-(C3-C₇)carbocycle and -(C₂-C₆)alkynyl-aryl₁ wherein any -(C₂-C6)alkynyl-(Cj-C₇)carbocycle and -(C₂-C/)alkynyl-a.ryl is optionally substituted with one or more Z¹ groups;

f) -X(C )-CeJalky 1, wherein -X(CfC6)alkyI is substituted with one or more Z³groups and optionally substituted with one or more Z¹ groups, and wherein X is O;

g) (Cj-Cslalkyl, wherein (Ci -C₆)alkyl is substituted with one or more Z¹groups and optionally substituted with one or more Z^! groups;

h) aryl, heteroaryl and heterocycle, wherein any aryl, heteroaryl and heterocycle is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups;

i) (CÇCôJhaloalkyl, (Cj-CvJcarbocycle, (C₂-C₆)alkenyl and ((E-Cfjalkynyl, wherein any (Ci-Cf.)haloaikyl, (Cj-C₂)carbocycïe, (C₂-C₆)alkenyl and (C;.-C$)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹groups; and

j) -NReRf, -C(O)NReRf and -(C i-CVjalkyi-NR^R.·, wherein -(Ci-C₆)alkylNRt-Rf îs optionally substituted with one or more Z¹ groups.

331
17. The compound of any one of claims 1-14 wherein R⁷ is selected from:

a) H, (Ci-C₆)alkyl and (Cj-C₆)haloalkyl;

b) (C2-C&)aikynyl and aryl, wherein aryl îs optionally substituted with one or more Z¹⁰ groups;

c) (Q-CJalkyi. wherein (C[-Ce)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) aryl, wherein aryl îs substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and

e) (C_rC6)haloalkyl, wherein (C)-C₆)haloalkyl is substituted with one or more Z⁶ groups and optionally substituted with one or more ZI groups.
18. The compound of any one of claims 1-14 whcrcin R⁷ is selected from:

a) (CrCeJhaloalkyl; and

b) (C t -C₆)haloalky 1, wherein (C i -C₆)haloalkyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.
19. The compound of any one of claims 1-14 wherein R⁷ is:

333
20. The compound of claim l selected from;

334

335

ΟΘ

C

336

C 337

338

C!

339

Ο

340

341

C

- 342

343 and salts thereof.

2t. Apharmaceutical composition comprisinga compound of formula ί as described in any one of claims 1-20, or a pharmaceuücaV.y acceptable sait üiereof, in combination with a pharmaceutically acceptable carrier.
22. A compound as described in any of daims 1-20 or a pfermaceuticaüy acceptable sait thereof, for use in medical therapy.
23. A compound as described in any one of claims 1-20 or a pharmaceutically acceptable sait thereof, for use in the prophylaxie or therapedic treatment ofthe prolifération of the HiV virus or AIDS cr for use in the therapeutic treatmentofôdavinj the onset of AIDS or ARC symptoms.