WO2021138298A1

WO2021138298A1 - Malt1 modulators and uses thereof

Info

Publication number: WO2021138298A1
Application number: PCT/US2020/067272
Authority: WO
Inventors: Brian Addison DECHRISTOPHER; Guillaume Barbe
Original assignee: Rheos Medicines, Inc.
Priority date: 2019-12-30
Filing date: 2020-12-29
Publication date: 2021-07-08

Abstract

Provided herein are compounds, compositions, and methods useful for modulating MALT1 and for treating related diseases, disorders, and conditions.

Description

MALT1 MODULATORS AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62/954,890, filed on December 30, 2019, the contents of which are incorporated herein by reference in their entirety.

BACKGROUND

[0002] Mucosa associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an intracellular signaling protein, known from innate (e.g., natural killer cells NK, dendritic cells DC, and mast cells) and adaptive immune cells (e.g., T cells and B cells). MALT1 plays an essential role in influencing immune responses. For example, in T cell receptor signaling, MALT1 mediates nuclear factor KB (NFKB) signaling, leading to T cell activation and proliferation. Accordingly, MALT1 is of interest in the mechanism of autoimmune and inflammatory pathologies. In addition, constitutive (dysregulated) MALT1 activity is associated with cancers such as MALT lymphoma and activated B cell-like diffuse large B Cell lymphoma (ABC-DLBCL). Modulators of MALT1 activity may be useful as potential therapeutics.

SUMMARY

[0003] Provided herein are compounds designed to act as MALT1 modulators. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders, or conditions or cancers.

[0004] In one aspect, provided herein is a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; and wherein, if the 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with Ci-6alkyl; B is selected from the group consisting of phenylene, 5-6 membered heterocyclylene, 6-

wherein B may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g;

C is phenyl or 5-10 membered heteroaryl, wherein C may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; and wherein, if the 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Ci-6alkyl;

R^la and Rl^b are independently hydrogen or Ci-6alkyl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents; or

R^la and R^lb together with the carbon to which they are atached form C=O, C=S, C3- 6cycloalkylene, or 3-6 membered heterocyclylene;

R^A is each independently hydrogen or Ci-6alkyl;

R^B is hydrogen or Ci-6alkyl; and

R^g is selected from the group consisting of cyano, halogen, hydroxyl, oxo, Ci-6alkyl, - C(0)OR^b, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 5-6 membered heteroaryl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents; wherein the compound is not a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein:

A is phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; and wherein, if the 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with Ci-6alkyl;

B is selected from the group consisting of phenylene, 5-6 membered heterocyclylene, 6-

, wherein * denotes the point of

R^A is each independently hydrogen or Ci-6alkyl;

R^B is hydrogen or Ci-6alkyl; and

R^g is selected from the group consisting of cyano, halogen, hydroxyl, oxo, Ci-6alkyl, - C(0)0R^b, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 5-6 membered heteroaryl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents; wherein when

phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from cyano, halogen, hydroxyl, oxo, Ci-6alkyl, -C(0)OR^B, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 6 membered heteroaryl. [0006] In another aspect, provided herein is a compound represented by Formula (la):

or a pharmaceutically acceptable salt, wherein:

B is selected from the group consisting of phenylene, 5-10 membered heteroarylene having one heteroatom, and 5-6 membered heterocyclylene, wherein B may be optionally substituted on one or more available carbons with Cmalkyl; and

C is 5-10 membered heteroaryl, wherein C may be optionally substituted on one or more available carbons with oxo; wherein when

substituted on one or more available carbons with Cmalkyl, wherein * denotes the point of attachment to

[0007] In another aspect, provided herein is a compound represented by Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: A is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; C is phenyl or -(Ci-6alkylene)-phenyl, wherein the phenyl and -(Ci-6alkylene)-phenyl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; and

R^g is halogen or Ci-6alkyl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents.

[0008] In some embodiments, a compound provided herein is selected from a compound set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0010] In another aspect, provided herein is a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein.

[0011] In another aspect, provided herein is a method of treating an autoimmune or inflammatory disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein.

[0012] In some embodiments, the autoimmune or inflammatory disorder or disease is selected from the group consisting of acute graft-versus-host disease, chronic graft-versus-host disease, lupus, scleroderma, psoriatic arthritis, primary sclerosing cholangitis and an inflammatory bowel disease.

DETAILED DESCRIPTION

[0013] As generally described herein, the present invention provides compounds designed, for example, to act as MALT1 modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating autoimmune and inflammatory diseases, disorders, or conditions or cancers.

Definitions

Chemical definitions

[0014] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the

Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987.

[0015] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al, Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0016] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0017] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S- compound in such compositions can, for example, comprise, at least about 95% by weight S- compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0018] Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 'H. ²H (D or deuterium), and ³H (T or tritium); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶0 and ¹⁸0; F may be in any isotopic form, including ¹⁸F and ¹⁹F; and the like.

[0019] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0020] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, Ci-

6, Ci-5, Ci-4, Ci-3, Ci-2, C2-6, C2-5, C2- , C2-3, C3-6, C3-5, C -i, C4-6, C4-5, and C5-6 alkyl.

[0021] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“Ci-20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“Ci-io alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“Ci-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of Ci-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0022] As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ( C2 4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2 4 alkenyl groups as well as pentenyl (Cs), pentadienyl (Cs), hexenyl (G,). and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.

[0023] As used herein, “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (Cs), hexynyl (G,). and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like.

[0024] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “cycloalkylene,” “heterocyclylene,” “heteroarylene,” and “phenylene” refer to a divalent radical of an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl (e.g., saturated and partially saturated), heteroaryl, and phenyl group respectively.

[0025] When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.

[0026] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 □ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2, 4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0027] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0028] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0029] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.

Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6- membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bi cyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0030] Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ is independently hydrogen, Ci-8 alkyl, C3-10 carbocyclyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl.

[0031] As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocycyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (C5), cyclohexyl (G,). cyclohexenyl (G,). cyclohexadienyl (G,). and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (Cs>), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 /-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicycbc carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0032] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicycbc, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C4-8cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

[0033] As used herein, “C3-6 monocyclic cycloalkyl” or “monocyclic C3-6 cycloalkyl” refers to a 3- to 7-membered monocyclic hydrocarbon ring system that is saturated. 3- to 7-membered monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Where specified as being optionally substituted or substituted, substituents on a cycloalkyl (e.g., in the case of an optionally substituted cycloalkyl) may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached.

[0034] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,”

“heterocyclic moiety,” and “heterocyclic radical,” may be used interchangeably.

[0035] In some embodiments, a heterocyclyl group is a 4-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [0036] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0037] Examples of saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. Where specified as being optionally substituted or substituted, substituents on a heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl group is attached.

[0038] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0039] As used herein, “cyano” refers to -CN.

[0040] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, the halo group is either fluoro or chloro.

[0041] The term “alkoxy,” as used herein, refers to an alkyl group which is attached to another moiety via an oxygen atom (-O(alkyl)). Non-limiting examples include e.g., methoxy, ethoxy, propoxy, and butoxy.

[0042] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., but are not limited to -OCHCF2 or -OCF3.

[0043] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. For the group C_1-4haloalkyl-O- C_1-4alkyl, the point of attachment occurs on the alkyl moiety which is halogenated.

[0044] As used herein, “oxo” refers to -C=O.

[0045] In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0046] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quartemary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR^aa, -N(R^cc)2, -CN, -C(=O)R^aa, -C(=O)N(R^cc)₂, -C0₂R^aa, -SO₂R^aa, -C(=NR^bb)R^aa, -C(=NR^cc)OR^aa, -C(=NR^cc)N(R^cc)₂, - SO₂N(R^cc)₂, -SO₂R^cc, -SO₂OR^cc, -SOR^aa, -C(=S)N(R^cc)₂, -C(=O)SR^cc, -C(=S)SR^cc, - P(=O)₂R^aa, -P(=O)(R^aa)₂, -P(=O)₂N(R^cc)₂, -P(=O)(NR^cc)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc and R^dd are as defined above.

[0047] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

[0048] As used herein, “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0049] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al, describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C_1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0050] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0051] Disease, disorder, and condition are used interchangeably herein.

[0052] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

[0053] As used herein, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0054] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

Compounds

[0055] In one aspect, provided herein are compounds represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

wherein B may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; C is phenyl or 5-10 membered heteroaryl, wherein C may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; and wherein, if the 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted by Ci-6alkyl;

R^A is each independently hydrogen or Ci-6alkyl;

R^B is hydrogen or Ci-6alkyl; and

R^g is selected from the group consisting of cyano, halogen, hydroxyl, oxo, Ci-6alkyl, - C(0)0R^b, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 5-6 membered heteroaryl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents; wherein the compound is not a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein: A is phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; and wherein, if the 5-10 membered heteroaryl contains a substitutable ring nitrogen atom, that ring nitrogen atom may optionally be substituted with Ci-6alkyl;

R^la and R^lb together with the carbon to which they are attached form C=O, C=S, C3- 6cycloalkylene, or 3-6 membered heterocyclylene;

R^A is each independently hydrogen or Ci-6alkyl;

R^B is hydrogen or Ci-6alkyl; and

R^g is selected from the group consisting of cyano, halogen, hydroxyl, oxo, Ci-6alkyl, - C(0)OR^b, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 5-6 membered heteroaryl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents;

wherein when B is , A is phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from cyano, halogen, hydroxyl, oxo, Ci-6alkyl, -C(0)0R^B, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 6 membered heteroaryl.

[0057] In some embodiments, R¹ and R² together with the carbon to which they are attached form C=O.

[0058] In some embodiments, A is selected from the group consisting of phenyl, or

, , wherein A may be optionally substituted with one or two substituents independently, for each occurrence, selected from the group consisting of halogen, Ci-6alkyl, -0-Ci-6alkyl, and 5-6 membered heteroaryl, wherein the Ci-6alkyl may be optionally substituted with one, two, three, or more fluorine.

[0059] In some embodiments, A is phenyl, wherein A may be optionally substituted with halogen, Ci-6alkyl, or -0-Ci-6alkyl. In some embodiments, A is selected from the group

[0060] In some embodiments, A is

[0061] In some embodiments, A is , wherein A may be

optionally substituted with CH₃ or CF₃. In some embodiments, A is

5 [0062] In some embodiments, A is

wherein A may be optionally substituted with two substituents independently, for each occurrence, selected from the group consisting of chlorine, -O-CH₃, and

In some embodiments, A is

or

. [0063] In some embodiments, B is selected from the group consisting of phenylene, 10

wherein B may be optionally substituted with Ci-6alkyl.

[0064] In some embodiments, B is selected from the group consisting

, wherein B may be optionally substituted with CH3.

[0065] In some embodiments, B is selected from the group consisting

[0066] In some embodiments, B is selected from the group consisting

[0067] In some embodiments, C is selected from the group consisting of phenyl

wherein C may be optionally substituted with chlorine, fluorine, oxo, or NH2. [0068] In some embodiments, C is phenyl

[0069] In some embodiments, C is selected from the group consisting of phenyl

wherein C may be optionally substituted with chlorine, fluorine, oxo, or NH2. In some embodiments, C is selected from the group consisting of

[0070] In some embodiments, R^la and R^lb together with the carbon to which they are attached form C3-6cycloalkylene. In some embodiments, R^la and R^lb together with the carbon to which they are attached form

[0071] In some embodiments, A is

wherein A may be optionally substituted with two substituents independently, for each occurrence, selected from halogen and -0-Ci-6alkyl. In some embodiments,

wherein A may be optionally substituted with two substituents independently, for each occurrence, selected from chlorine and -O-CH3. In some embodiments,

[0073] In some embodiments, C is

wherein C may be optionally substituted with halogen. In some embodiments,

wherein C may be optionally substituted with chlorine. In some embodiments,

[0074] In another aspect, provided herein are compounds represented by Formula (la):

or a pharmaceutically acceptable salt, wherein:

3 and wherein * denotes the point of attachment

denotes the point of attachment t

[0076] In some embodiments, B is selected from the group consisting

, wherein B may be optionally substituted with CH3 and wherein * denotes the point of attachment to

denotes the point of attachment t

[0077] In some embodiments, B is selected from the group consisting of wherein *

denotes the point of attachment to and ** denotes the point of attachment

[0078] In some embodiments, B is

substituted with CH₃. In some embodiments, B is

[0079] In some embodiments, C is In some embodiments, C is

[0080] In some embodiments, C is

, wherein

may be optionally substituted with oxo. In some embodiments,

[0081] In another aspect, provided herein are compounds represented by Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

A is 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g;

C is phenyl or -(Ci-6alkylene)-phenyl, wherein the phenyl and -(Ci-6alkylene)-phenyl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from R^g; and

[0082] In some embodiments, A is

. wherein A may be optionally substituted with Ci-6alkyl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more fluorine. [0083] In some embodiments,

, wherein A may be optionally substituted with CF3. In some embodiments,

[0084] In some embodiments, C is phenyl or

. wherein C may be optionally substituted with one or two substituents independently, form each occurrence, selected from Ctb and chlorine.

[0085] In some embodiments, C is phenyl.

[0086] In some embodiments, C is phenyl or

, wherein C may be optionally substituted with Ctb or chlorine. In some embodiments, C is selected from the group consisting

[0087] In some embodiments, C is phenyl optionally substituted with two substituents independently, for each occurrence, selected from Ctb and chlorine. In some embodiments, C is

[0088] In some embodiments, the compound is selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. [0089] In some embodiments, the compound is selected from the group consisting of 2- methyl-3-(l -oxo-1, 2-dihydroisoquinolin-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)benzamide; N- (5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-5-(l-oxo-l,2-dihydroisoquinolin-5- yl)picolinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)-4,5-dihydropyridin-3-yl)-6-(2,8- dihydroquinolin-5-yl)-5-methyl-5,6-dihydropyrimidine-4-carboxamide; N-(5-chloro-6-(2H- l,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-5-(quinolin-5-yl)picolinamide; 3-methyl-2-(quinolin-5- yl)-N-(2-(trifluoromethyl)pyridin-4-yl)isonicotinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl)-3-methyl-4-(quinolin-5-yl)picolinamide; 5-methyl-6-(quinolin-5-yl)-N-(2- (trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide; 6-methyl-5-(l -oxo-1 ,2- dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrazine-2-carboxamide; 5-methyl- 6-(quinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)nicotinamide; N-(5-chloro-6-(2H-l,2,3- triazol-2-yl)pyridin-3-yl)-5-methyl-6-(quinobn-5-yl)nicotinamide; 4-methyl-5-(quinobn-5-yl)-N- (2-(trifluoromethyl)pyridin-4-yl)picobnamide; 4-methyl-5-(l-oxo-l,2-dihydroisoquinobn-5-yl)- N-(2-(trifluoromethyl)pyridin-4-yl)picobnamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-

3-yl)-5-methyl-6-(l -oxo-1, 2-dihydroisoquinobn-5-yl)pyrimidine-4-carboxamide; 5-methyl-6-(l- oxo-l,2-dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-4-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-6-(l-oxo-l,2-dihydroisoquinobn-5- yl)nicotinamide; N-(5-chloro-6-(l,3-dihydro-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-6-methyl-5-(l- oxo-l,2-dihydroisoquinobn-5-yl)pyrazine-2-carboxamide; l-methyl-2-(quinobn-5-yl)-N-(2- (trifluoromethyl)pyridin-4-yl)-lH-imidazole-5-carboxamide; 3-methyl-4-(quinobn-5-yl)-N-(2- (trifluoromethyl)pyridin-4-yl)picobnamide; N-(5-chloro-6-(112,214,3-triazol-2-yl)pyridin-3-yl)-

1-methyl-2-(quinobn-5-yl)-2,5-dihydro-lH-imidazole-5-carboxamide; N-(5-chloro-6-(2H-l,2,3- triazol-2-yl)pyridin-3-yl)-3-methyl-2-(quinobn-5-yl)isonicotinamide; 2-methyl-3-(quinobn-5- yl)-N-(2-(trifluoromethyl)-2,3-dihydropyridin-4-yl)benzamide; N-(5-chloro-6-(2H-l,2,3-triazol-

2-yl)pyridin-3-yl)-2-methyl-3-(quinolin-5-yl)benzamide: 6-methyl-5-(quinobn-5-yl)-N-(2- (trifluoromethyl)pyridin-4-yl)pyrazine-2-carboxamide; N-(5-chloro-6-(112,2,3-triazobdin-2- yl)pyridin-3-yl)-6-methyl-5-(quinobn-5-yl)pyrazine-2-carboxamide; 5-methyl-6-(l-oxo-l,2- dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)nicotinamide; N-(5-chloro-6-(l,3- dihy dro-2H- 1 ,2,3-triazol-2-y 1)- 1 ,6-dihy dropy ri din-3 -y 1)- 1 -methyl-2-( 1 -oxo- 1,2- dihydroisoquinobn-5-yl)-4,5-dihydro-lH-imidazole-5-carboxamide; l-methyl-2-(l-oxo-l,2- dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-imidazole-5-carboxamide; N- (5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-3-methyl-4-(l-oxo-l,2-dihydroisoquinobn-5- yl)picobnamide; 3-methyl-4-(l -oxo-1, 2-dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-

4-yl)picobnamide; 3-methyl-2-(l-oxo-l,2-dihydroisoquinobn-5-yl)-N-(2- (trifluoromethyl)pyridin-4-yl)isonicotinamide; 4-methyl-3-(l-oxo-l,2-dihydroisoquinobn-5-yl)- N-(2-(trifluoromethyl)pyridin-4-yl)-2H-114-thiophene-5 -carboxamide; N-(5-chloro-6-(2H-l,2,3- triazol-2-yl)pyridin-3-yl)-3-methyl-2-(l -oxo-1, 2-dihydroisoquinobn-5-yl)isonicotinamide; N-(5- chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-3-methyl-4-(l-oxo-l,2-dihydroisoquinolin-5- yl)thiophene-2-carboxamide; 3-methyl-4-(quinohn-5-yl)-N-(6-(trifluoromethyl)-3,6-dihydro-2H- 112-pyridin-4-yl)thiophene-2-carboxamide; 4-(2H-112-quinolin-5-yl)-N-(5-chloro-6-(l,2,3- triazobdin-2-yl)piperidin-3-yl)-3-methylthiophene-2-carboxamide; 4-methyl-5-(quinobn-5-yl)- N-(2-(trifluoromethyl)pyridin-4-yl)isoxazole-3-carboxamide; 5 -methyl- l-(l-oxo- 1,2- dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-imidazole-4-carboxamide; N- (5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-l-(l-oxo-l,2-dihydroisoquinobn-5- yl)-lH-imidazole-4-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl- 5-(quinobn-5-yl)isoxazole-3-carboxamide; 4-methyl-5-(l-oxo-l,2-dihydroisoquinolin-5-yl)-N- (2-(trifluoromethyl)pyridin-4-yl)isoxazole-3-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl)-4-methyl-5-(l -oxo-1, 2-dihydroisoquinobn-5-yl)isoxazole-3 -carboxamide; 5- methyl-l-(quinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-l,2,3-triazole-4-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-l-(quinobn-5-yl)-lH-l,2,3-triazole- 4-carboxamide; l-methyl-5-(quinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-imidazole-2- carboxamide; l-methyl-5-(l-oxo-l,2-dihydroisoquinohn-5-yl)-N-(2-(trifluoromethyl)pyridin-4- yl)-lH-imidazole-2-carboxamide; 4-methyl-5-(quinohn-5-yl)-N-(2-(trifluoromethyl)pyridin-4- yl)-lH-pyrazole-3-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-5- (quinobn-5-yl)-lH-pyrazole-3-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-

1-methyl-5-(l-oxo-l,2-dihydroisoquinobn-5-yl)-lH-imidazole-2-carboxamide; N-(5-chloro-6- (2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-methyl-5-(quinobn-5-yl)-lH-imidazole-2-carboxamide; 5- methyl- 1 -( 1 -oxo- 1 ,2-dihy droisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 1H- 1,2,3- triazole-4-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl-l-(l-oxo- l,2-dihydroisoquinobn-5-yl)-lH-l,2,3-triazole-4-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-

2-yl)pyridin-3-yl)-6-(quinolin-5-yl)nicotinamide: 5-methyl-6-(quinobn-5-yl)-N-(2- (trifluoromethyl)pyridin-4-yl)picolinamide; 6-methyl-5-(l-oxo-l,2-dihydroisoquinolin-5-yl)-N- (2-(trifluoromethyl)pyridin-4-yl)picobnamide; 6-methyl-5-(quinobn-5-yl)-N-(2- (trifluoromethyl)pyridin-4-yl)-5,6-dihydropyridine-2-carboxamide; N-(5-chloro-6-(2H-l,2,3- triazol-2-yl)pyridin-3-yl)-6-methyl-5-(l-oxo-l,2-dihydroisoquinobn-5-yl)picobnamide; N-(5- chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-6-methyl-5-(quinobn-5-yl)picobnamide; 3-methyl-

4-(qumohn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)benzamide; 4-methyl-5-(l-oxo-l,2- dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)nicotinamide; 4-methyl-5-(quinobn-

5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)nicotinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl)-4-methyl-5-(l-oxo-l,2-dihydroisoquinobn-5-yl)nicotinamide; N-(5-chloro-6- (l,3-dihydro-2H-l,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-5-(quinobn-5-yl)nicotinamide; N-(5- chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-3-methyl-4-(quinolin-5-yl)benzamide; N-(5- chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-3-methyl-4-(l-oxo-l,2-dihydroisoquinolin-5- yl)benzamide; 3-methyl-4-(l -oxo-1 ,2-dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4- yl)benzamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-2-methyl-3-(l-oxo-l,2- dihydroisoquinobn-5-yl)benzamide; 5-methyl-l-(quinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4- yl)-lH-imidazole-4-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-5-methyl- l-(quinobn-5-yl)-lH-imidazole-4-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3- yl)-4-methyl-5-(quinobn-5-yl)pyrimidine-2-carboxamide; 4-methyl-5-(l-oxo-l,2- dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)pyrimidine-2-carboxamide; N-(5- chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-5-(l-oxo-l,2-dihydroisoquinobn-5- yl)pyrimidine-2-carboxamide; 4-methyl-5-(quinolin-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)- 4,5-dihydropyrimidine-2-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-6- methyl-5-(l -oxo-1, 2-dihydroisoquinolin-5-yl)nicotinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl)-6-methyl-5-(quinobn-5-yl)nicotinamide; 6-methyl-5-(l-oxo-l,2- dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)nicotinamide; 6-methyl-5-(quinobn- 5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)nicotinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl)-5-(quinobn-5-yl)nicotinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3- yl)-5-(quinobn-5-yl)thiophene-3-carboxamide formate; N-(5-chloro-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl)-5-(4-fluorophenyl)-4-methylnicotinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl)-4-methyl-5-phenylnicotinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3- yl)-5-(2-fluorophenyl)-4-methylnicotinamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3- yl)-5-(2-chlorophenyl)-4-methylnicotinamide; 5-(2-aminophenyl)-N-(5-chloro-6-(2H-l,2,3- triazol-2-yl)pyridin-3-yl)-4-methylnicotinamide hydrochloride; 4-methyl-5-(l-oxo-l,2- dihydroisoquinobn-5-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)thiophene-3-carboxamide; N-(5- chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-5-(l-oxo-l,2-dihydroisoquinobn-5- yl)thiophene-3-carboxamide; N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-4-methyl-5- (quinobn-5-yl)thiophene-3-carboxamide; 4-methyl-5-(quinobn-5-yl)-N-(2- (trifluoromethyl)pyridin-4-yl)thiophene-3-carboxamide; N-(4-bromophenyl)-4-methyl-5- (quinobn-5-yl)nicotinamide; 4-methyl-N-(5-methylpyridin-3-yl)-5-(quinobn-5-yl)nicotinamide; N-(4-chlorophenyl)-4-methyl-5-(quinobn-5-yl)nicotinamide; N-(2-methoxyphenyl)-4-methyl-5- (quinobn-5-yl)nicotinamide; N-(2-isopropoxyphenyl)-4-methyl-5-(quinobn-5-yl)nicotinamide formate; N-(4-ethylphenyl)-4-methyl-5-(quinolin-5-yl)nicotinamide formate; 4-methyl-N-(l- methyl-lH-pyrazol-4-yl)-5-(quinobn-5-yl)nicotinamide; N-(2-chlorophenyl)-4-methyl-5- (quinobn-5-yl)nicotinamide; N-(2-bromophenyl)-4-methyl-5-(quinobn-5-yl)nicotinamide; N-(4- fluorophenyl)-4-methyl-5-(quinolin-5-yl)nicotinamide; N-(4-methoxyphenyl)-4-methyl-5- (quinolin-5-yl)nicotinamide; N-(2-isopropylphenyl)-4-methyl-5-(quinolin-5-yl)nicotinamide; N- (3-ethylphenyl)-4-methyl-5-(quinolin-5-yl)nicotinamide; l-(2-chlorophenyl)-5-(trifluoromethyl)- N-(2-(trifluoromethyl)pyridin-4-yl)-lH-pyrazole-4-carboxamide; l-(3-chlorophenyl)-5- (trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-pyrazole-4-carboxamide; l-(o-tolyl)-5- (trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-pyrazole-4-carboxamide; l-(2,3- dimethylphenyl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-pyrazole-4- carboxamide; l-(m-tolyl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)-lH-pyrazole- 4-carboxamide; 1 -phenyl-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)- lH-pyrazole- 4-carboxamide; l-(2,3-dichlorophenyl)-5-(trifluoromethyl)-N-(2-(trifluoromethyl)pyridin-4-yl)- lH-pyrazole-4-carboxamide; l-(l-phenylethyl)-5-(trifluoromethyl)-N-(2- (trifluoromethyl)pyridin-4-yl)-lH-pyrazole-4-carboxamide; (3R,4S)-N-(5-chloro-6-(2H-l,2,3- triazol-2-yl)pyridin-3-yl)-l-(3-chloropyridin-2-yl)-3-methylpiperidine-4-carboxamide; (3R,4R)- N-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)-l-(3-chloropyridin-2-yl)-3-methylpiperidine- 4-carboxamide; 5-chloro-N-(l-(l-(3-chloropyridin-2-yl)piperidin-4-yl)cyclopropyl)-6- methoxypyri din-3 -amine; or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions and Routes of Administration

[0090] Compounds provided in accordance with the present invention are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.

S. Banker & C. T. Rhodes, Eds.)

[0091] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery- inserted cylindrical polymer.

[0092] One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0093] Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.

[0094] Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0095] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0096] The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0097] The compositions are preferably formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0098] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0099] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[00100] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[00101] In some embodiments, a pharmaceutical composition comprising a disclosed compound, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Methods of Use

[00102] Compounds and compositions described herein are generally useful for modulating

MALT1 and are useful for in treating diseases or disorders, in particular those susceptible to modulation of proteolytic and/or autoproteolytic activity of MALT1. In some embodiments, the compounds and compositions described herein are useful for inhibiting MALT1. In some embodiments, it is contemplated that the compounds and compositions of the present invention may be useful in the treatment of a disease, a disorder, or a condition characterized by dysregulated NF-kB activation, for example, autoimmune or immunological and inflammatory disorders, allergic disorders, respiratory disorders and oncological disorders.

[00103] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a solvate (e.g., hydrate) of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein, e.g. a compound of Formula I); such as a compound of Formula named herein.

[00104] In some embodiments, the autoimmune and inflammatory disorders are selected from arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, rheumatic fever, gout, organ or transplant rejection, acute or chronic graft-versus-host disease, chronic allograft rejection, Behcet's disease, uveitis, psoriasis, psoriatic arthritis, BENTA disease, polymyositis, dermatitis, atopic dermatitis, dermatomyositis, acne vulgaris, myasthenia gravis, hidradenitis suppurativa, Grave's disease, Hashimoto thyroiditis, Sjogren's syndrome, and blistering disorders (e.g., pemphigus vulgaris), antibody- mediated vasculitis syndromes, including ANCA-associated vasculitides, Henoch-Schonlein Purpura, and immune-complex vasculitides (either primary or secondary to infection or cancers).

[00105] In some embodiments, the oncological disorders are selected from carcinoma, sarcoma, lymphoma, leukemia and germ cell tumors, adenocarcinoma, bladder cancer, clear cell carcinoma, skin cancer, brain cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, brain tumors, breast cancer, gastric cancer, germ cell tumors, glioblastoma, hepatic adenomas, Hodgkin's lymphoma, liver cancer, kidney cancer, lung cancer, pancreatic cancer, head/neck/throat cancer, ovarian cancer, dermal tumors, prostate cancer, renal cell carcinoma, stomach cancer, hematologic cancer, medulloblastoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), activated B cell-like diffuse large B Cell lymphoma (ABC-DLBCL), mantle cell lymphoma, marginal zone lymphoma, T cell lymphomas, in particular Sezary syndrome, Mycosis fungoides, cutaneous T-cell lymphoma, T-cell acute lymphoblastic leukemia, melanoma, mucosa-associated lymphoid tissue (MALT) lymphoma, multiple myeloma, plasma cell neoplasm, lentigo maligna melanomas, acral lentiginous melanoma, squamous cell carcinoma, chronic myelogenous leukemia, myeloid leukemia, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, amelanotic melanoma, soft-tissue melanoma, melanoma with small nevus-like cells, melanoma with features of a Spitz nevus, uveal melanoma, precursor T-cell, leukemia/lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, follicular lymphoma, chronic lymphocytic leukemia/lymphoma, Burkitt's lymphoma, mycosis fungoides, peripheral T-cell lymphoma, nodular sclerosis form of Hodgkin lymphoma, mixed-cellularity subtype of Hodgkin lymphoma, non-small-cell lung cancer, large-cell carcinoma, and small-cell lung carcinoma.

[00106] In some embodiments, the oncological disorder is a cancer in the form of a tumor or a blood bom cancer. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is malignant and/or metastatic. In some embodiments, the tumor is selected from an adenoma, an adenocarcinoma, a blastoma (e.g., hepatoblastoma, glioblastoma, neuroblastoma and retinoblastoma), a carcinoma (e.g., colorectal carcinoma or heptatocellular carcinoma, pancreatic, prostate, gastric, esophageal, cervical, and head and neck carcinomas, and adenocarcinoma), a desmoid tumor, a desmoplastic small round cell tumor, an endocrine tumor, a germ cell tumor, a lymphoma, a leukemia, a sarcoma (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, or any other soft tissue sarcoma), a Wilms tumor, a lung tumor, a colon tumor, a lymph tumor, a breast tumor or a melanoma.

[00107] In some embodiments, the allergic disorder is selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, and berylliosis.

[00108] In some embodiments, the respiratory disorders is selected from asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension and emphysema.

[00109] In some embodiments, the compounds and compositions of the present invention may be useful in the treatment of rheumatoid arthritis, systemic lupus erythematosus, vasculitic conditions, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), acute or chronic transplant rejection, graft versus host disease, cancers of hematopoietic origin or solid tumors, chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma or other B cell lymphomas.

Combination Therapy

[00110] A compound of composition described herein may be administered in combination with another agent or therapy. A subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy.

[00111] In some embodiments, the compound of composition described herein may be administered either simultaneously with, or before or after, one or more other therapeutic agent. In some embodiments, the compound of composition described herein may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.

[00112] In some embodiments, the compound described herein may be administered as the sole active ingredient or in conjunction with, e.g., as an adjuvant to, other drugs e.g., immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g., for the treatment or prevention of alio- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g., a malignant cell anti-proliferative agent. For example, the compounds of the invention may be used in combination with a calcineurin inhibitor, e.g., cyclosporin A or FK 506; a rmTOR inhibitor, e.g., rapamycin, 40-0- (2-hydroxyethyl)-rapamycin, biolimus-7 or biolimus-9; an ascomycin having immunosuppressive properties, e.g., ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; or IL-1 beta inhibitor.

[00113] In some embodiments, the compound described herein is combined with a co-agent which is a PI3K inhibitor.

[00114] In some embodiments, the compound described herein is combined with co-agent that influence BTK (Bruton's tyrosine kinase).

[00115] For the treatment of oncological diseases, the compound described herein may be used in combination with B-cell modulating agents, e.g., Rituximab, Ofatumumab, BTK or SYK inhibitors, inhibitors of PKC, PI3K, PDK, PIM, JAK and rmTOR and BH3 mimetics. EXAMPLES

[00116] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention.

[00117] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[00118] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[00119] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually or via an automated system. The compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in part per million (ppm) and are generated using methods well known to those of skill in the art.

List of Abbreviations:

Pd(dppf)Cl2 [l,r-bis(diphenylphosphino)ferrc>cene]palladiuin(II) di chloride

Pd(OAc)2 palladium(II) acetate

EtOAc ethyl acetate

THF tetrahydrofuran

PE petroleum ether

DMA dimethylacetamide

MeOH methanol EtOH ethanol

ACN acetonitrile

DMF N, N-diimethylformamide

Et₃N triethylamine

DIEA N, N-Diisopropylethylamine

NMP N-methyl-2-pyrrolidone

DMSO dimethyl sulfoxide

Ti(OPr)4 titanium isopropoxide

Et₂O diethyl ether xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

FA formic acid m-CPBA meta-chloroperoxy benzoic acid

AC₂0 acetic anhydride

KOAc potassium acetate

AcOH acetic acid

DABCO l,4-diazabicyclo[2.2.2]octane n-BuLi n-butyllithium

LDA lithium diisopropylamide

Example 1. Preparation of the compounds

[00120] Methods for preparing compounds described herein are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating the invention and should not be regarded in any manner as limiting the scope or the spirit of the invention. Starting materials shown in the schemes may be obtained from commercial sources or can be prepared from commercially available sources based on procedures described in the literature. General Scheme 1:

[00121] An ester with a halogenated B ring was reacted with a boronate ester with a C ring and then hydrolyzed to provide a carboxylic acid intermediate. Then the acid intermediate was treated with an amine with an A ring to provide a compound of formula I.

Synthesis of 1-c:

[00122] A mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,4-dihydroisoquinolin- 1-one (400 mg, 1.47 mmol), methyl 3-bromo-2-methylbenzoate (304 mg, 1.33 mmol), Pd(dppl)Cl2.CH2Cl2 (108 mg, 133 pmol) and K2CO3 (461 mg, 3.34 mmol) in dioxane (5 mL) and H2O (1 mL ) was stirred at 100 °C for 16 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to afford the crude product, which was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 0/1 to 1/1) to give methyl 2-methyl-3- (l-oxo-l,2-dihydroisoquinolin-5-yl)benzoate (200 mg, 51.2% yield) as a solid m/z: [M+H]⁺ Calcd for CisHieNCb 294.1; Found 294.1. ¾ NMR (400 MHz, CDCb) d = 10.97 - 10.84 (m, 1H), 8.49 (d, =7.6 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.60 - 7.53 (m, 2H), 7.35 (d, J= 4.0 Hz, 2H), 7.08 (br d, J= 6.4 Hz, 1H), 6.11 (d, J= 7.2 Hz, 1H), 3.94 (s, 3H), 2.24 (s, 3H)

Synthesis of 1-d:

[00123] To a mixture of methyl 2-methyl-3-(l-oxo-l,2-dihydroisoquinolin-5-yl)benzoate (220 mg, 750 pmol) in THF (3 mL) and H2O (1 mL) was added lithium hydroxide monohydrate (94.4 mg, 2.25 mmol), and then the mixture was stirred at 50 °C for 16 hours. IN HC1 was added to adjust the pH to 2-3 and the mixture was extracted with EtOAc (10 mL ^c 2). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give 2-methyl-3-(l-oxo-l,2-dihydroisoquinolin-5-yl)benzoic acid (180 mg, 86.1% yield) as a solid m/z: [M+H]⁺ Calcd for C17H14NO3280.1; Found 280.1.

Synthesis of Example 1 (Compound 1):

[00124] To a mixture of 2-methyl-3-(l-oxo-l,2-dihydroisoquinolin-5-yl)benzoic acid (70 mg, 250 pmol) and 2-(trifluoromethyl)pyridine-4-amine (48.6 mg, 300 pmol) in pyridine (3 mL ) was added POCh (57.4 mg, 375 pmol) at 0 °C under N2 atmosphere and the mixture was stirred at 0 °C for 1 hour. Saturated NaHCCh aqueous solution (10 mL) was added and the mixture was extracted with EtOAc (20 mL ^c 2). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude product which was purified by prep-HPLC (column: Xtimate C18 100*30mm*3pm, condition: 32-72% B (A = water

(0.05% ammonia hydroxide v/v)), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220 nm) to afford 2-methyl-3-(l-oxo-l,2-dihydroisoquinolin-5-yl)-/V-[2-(trifluoromethyl)pyridine-4- yl]benzamide (4.1 mg, 3.9% yield) as a dry powder m/z: [M+H]+ Calcd for C23H17F3N3O2 424.1; Found 424.1. ¾ NMR (400 MHz, MeOD) d = 8.61 (d, J= 5.6 Hz, 1H), 8.42 - 8.38 (m, 1H), 8.25 (d, J= 2.0 Hz, 1H), 7.97 - 7.94 (m, 1H), 7.65 - 7.63 (m, 1H), 7.63 - 7.61 (m, 1H), 7.60 - 7.57 (m, 1H), 7.47 (t, .7= 7.6 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.13 (d, J= 7.6 Hz, 1H), 6.19 (d, J = 7.2 Hz, 1H), 2.10 (s, 3H).

General Scheme 2:

[00125] An acid with a halogenated B ring was treated with an amine with an A ring to yield an amide intermediate, which was reacted with a boronate ester with a C ring in the presence of a Pd catalyst to provide a compound of formula I.

Exemplary procedure of scheme 2:

Synthesis of 2-c:

[00126] A solution of 5-bromo-4-methylpyridine-3-carboxylic acid (500 mg, 2.31 mmol) and 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine (541 mg, 2.77 mmol) in pyridine (5 mL ) was cooled to 0°C. Phosphoroyl trichloride (530 mg, 3.46 mmol) was added at 0 °C and the mixture was stirred at 0°C for 1 hour. The reaction was quenched by adding saturated sodium bicarbonate (30 mL) and then extracted with EtOAc (20 mL ^c 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtO Ac/PE = 1/10 to 1/0) to give 5-bromo-N-[5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl]-4-methylpyridine-3- carboxamide (400 mg, 44.0% yield) as a solid m/z: [M + H]+ Calcd for CwHioBrClNeO 395.0; Found 394.8. ¾NMR (400MHz, CDCb) d = 8.78 (br s, 1H), 8.76 (s, 1H), 8.76 (br s, 1H), 8.63 (s, 1H), 8.54 (d, J= 2.4 Hz, 1H), 7.93 (s, 2H), 2.59 (s, 3H). Synthesis of Example 2 (Compound 61):

[00127] To a solution of 5-bromo-N-[5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl]-4- methylpyridine-3-carboxamide (200 mg, 508 pmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-l,2-dihydroisoquinobn-l-one (165 mg, 609 pmol), dipotassium carbonate (139 mg, 1.01 mmol) in H2O (0.4 mL ) and dioxane (4 mL ) was added palladium(II) bis(2- (diphenylphosphanyl)cyclopenta-2,4-dien-l-yl) dichloromethane iron dichloride (41.4 mg, 50.8 pmol) under N2 and the reaction mixture was stirred at 100 °C for 16 hours. The reaction was quenched by adding water (30 mL) and was extracted with EtOAc (3 x 20mL). The combined organic layers was dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give the reaction mixture. The reaction mixture was purified by prep-HPLC (column: Phenomenex Gemini NX-C18(75*30mm*3pm), condition: 14%-54% CTLCN in water (0.225%FA), flow rate: 25mL/min) to give N-[5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl]-4- methyl-5-(l-oxo-l,2-dihydroisoquinolin-5-yl)pyridine-3-carboxamide (22.3 mg, 9.6%) as a dry powder m/z: [M + H]+ Calcd for C23H16CIN7O2458.1; Found 458.1. ¾ NMR (400MHz, DMSO-d6) d = 11.44 (br s, 1H), 11.38 (br s, 1H), 8.86 (s, 1H), 8.85 (d, J= 2.0 Hz, 1H), 8.70 (d, J= 2.0 Hz, 1H), 8.53 (s, 1H), 8.34 (dd, J= 3.0, 6.4 Hz, 1H), 8.19 (s, 2H), 7.67 - 7.59 (m, 2H), 7.20 (br s, 1H), 5.89 (d, J= 7.2 Hz, 1H), 2.13 (s, 3H).

General Scheme 3:

[00128] A halide with a B ring was treated with an alcohol in the presence of CO and a Pd catalyst to form an ester intermediate, which was reacted with 4,4,5,5-tetramethyl-l,3,2- dioxaborolane to provide a boronate ester intermediate. The intermediate was treated with a halide with a C ring in the presence of Pd catalyst to give a coupling intermediate, and then hydrolyzed to form an acid intermediate. The acid intermediate was reacted with an amine with an A ring to provide a compound of formula I. Exemplary procedure of scheme 3:

Synthesis of 3-b:

[00129] A mixture of 3-bromo-4-methylthiophene (3 g, 16.9 mmol) , palladium(2+) bis(2- (diphenylphosphanyl)cyclopenta-2,4-dien-l-yl) dichloromethane iron dichloride (1.38 g, 1.69 mmol) and triethylamine (5.12 g, 50.6 mmol) in MeOH (18mL ) and DMA (36 mL ) was stirred at 80 °C under CO (50 psi) for 24 hours. The reaction mixture was concentrated under reduced pressure to remove CH3OH. The mixture was filtered and the filtrate was diluted with water (40 mL) and extracted with EtOAc (30 mL ^c 3). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude product which was purified by flash chromatography on silica gel (EtO Ac/PE = 0/1 to 1/20) to give methyl 4-methylthiophene-3-carboxylate (2.30 g, 87.4% yield) as a liquid m/z: [M + H]⁺ Calcd for CrHsChS 157.0; Found 156.8. ¾ NMR (400MHz, CDCb) d = 8.07 (d, J= 3.2 Hz, 1H), 6.94 - 6.88 (m, 1H), 3.84 (s, 3H), 2.46 (d, J = 0.9 Hz, 3H).

Synthesis of 3-d:

[00130] A suspension of (l,5-cyclooctadiene)(methoxy)iridium(I) dimer (120 mg, 166 pmol) in n-hexane (10 mL ) was cooled to 0 °C under N2. 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.80 g, 14.1 mmol) , 4,4-di-tert-butyl-2,2-dipyridyl (66.8 mg, 249 pmol) was added at 0 °C and the mixture was stirred for 1 min. Methyl 4-methylthiophene-3-carboxylate (1.3 g, 8.32 mmol) was added and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtO Ac/PE = 0/1 to 1/20) to give methyl 4-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-3-carboxylate (1.22 g, 52.1% yield) as an oil. m/z: [M + H]⁺ Calcd for C13H19B04S 283.1; Found 282.9. ¾ NMR (400 MHz, CDCb) d = 8.29 (s, 1H), 3.84 (s, 3H), 2.67 (s, 3H), 1.34 (s, 12H).

Synthesis of 3-f:

[00131] A mixture of methyl 4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)thiophene-3-carboxylate (850 mg, 3.01 mmol) , 5-bromoquinoline (567 mg, 2.73 mmol) , Pd(dppl)Cl2.CH2Cl2 (222 mg, 273 pmol) and K2CO3 (945 mg, 6.84 mmol) in dioxane (8 mL) and H2O (2 mL) was stirred at 100 °C for 16 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to afford the crude product which was purified by flash chromatography on silica gel (EtO Ac/PE = 0/1 to 1/3) to give methyl 4-methyl-5-(quinolin-5- yl)thiophene-3-carboxylate (530 mg, 68.5% yield) as an oil. m/z: [M+H]+ Calcd for C16H13NO2S 284.1; Found 283.9. ¾ NMR (400 MHz, CDCh) d = 8.94 (dd, J= 1.6, 4.0 Hz,

1H), 8.23 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 7.99 (dd, .7= 0.8, 8.4 Hz, 1H), 7.76 (dd, .7= 7.2, 8.4 Hz, 1H), 7.54 (dd, J= 1.2, 7.2 Hz, 1H), 7.39 (dd, J= 4.4, 8.4 Hz, 1H), 3.90 (s, 3H), 2.19 (s, 3H).

Synthesis of 3-g:

[00132] To a solution of methyl 4-methyl-5-(quinolin-5-yl)thiophene-3-carboxylate (530 mg, 1.87 mmol) in THF (4 mL) and H2O (1.5 mL ) was added L1OH.H2O (156 mg, 3.74 mmol) and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was acidified with 1M HC1 to pH=5 and concentrated under reduced pressure to give 4-methyl-5-(quinolin-5- yl)thiophene-3-carboxylic acid (490 mg, 97.4% yield) as a solid m/z: [M + H]+ Calcd for C15H11NO2S 270.1; Found 269.9.

Synthesis of Example 3 (Compound 86):

[00133] To a solution of 4-methyl-5-(quinolin-5-yl)thiophene-3-carboxylic acid (150 mg, 389 pmol), 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine (76.0 mg, 389 pmol) in pyridine (1.5 mL) was added POCh (177 mg, 1.16 mmol) and the mixture was stirred at 25° C for 2 hours.

The reaction was quenched by adding saturated NaHCCh (20 mL) and was extracted with EtO Ac (15 mL x 2). The combined organic layers were washed with brine (20 mL ^c 2), dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude product which was purified by Prep-HPLC (column: Boston Prime C18 150*30mm*5pm, table: 53-75% water (0.05% ammonia hydroxide v/v)-ACN, flow rate: 25 mL/min, UV Detector 220nm) to afford N- [5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl]-4-methyl-5-(quinolin-5-yl)thiophene-3- carboxamide (43.8 mg, 25.3% yield) as a dry powder m/z: [M + H]+ Calcd for C22H15CIN6OS 447.1; Found 447.1. ¾ NMR (400 MHz, DMSO-d6) d = 10.97 (br s, 1H), 8.98 (dd, J= 1.6, 4.0 Hz, 1H), 8.91 (d, J= 2.4 Hz, 1H), 8.70 (d, J= 2.4 Hz, 1H), 8.49 (s, 1H), 8.24 - 8.12 (m, 3H), 8.01 (d, J= 8.4 Hz, 1H), 7.88 (dd, .7= 7.2, 8.4 Hz, 1H), 7.71-7.64 (m, 1H), 7.60 (dd, .7= 4.0, 8.4 Hz, 1H), 2.11 (s, 3H).

General Scheme 4:

[00134] A bis-halide with a B ring was reacted with a boronate ester with a C ring in the presence of a Pd catalyst to yield a halogenated B-C rings coupled intermediate, which was treated with CO in the presence of a Pd catalyst to form an acid intermediate. The acid intermediate was reacted with an amine with an A ring to provide a compound of formula I.

Synthesis of 4-c:

[00135] To a mixture of 3,5-dibromo-4-methylpyridine (10 g, 39.8 mmol), (quinolin-5- yl)boronic acid (5.50 g, 31.8 mmol), Na2C03 (8.43 g, 79.6 mmol) in 1,4-dioxane (90 mL) and H2O (15 mL ) was added Pd(dppf)Cl2.CH2Cl2 (1.62 g, 1.99 mmol) and the mixture was stirred at 100 °C under N2 for 2 hours. The reaction mixture was combined to another parallel reaction (1 g of 4-a was conducted), worked up and purified together. The combined reaction mixture was diluted with water (50 mL) and was extracted with EtOAc (100 mL ^c 2). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography on silica gel (EtO Ac/PE = 0/1 to 1/1) to give 5-(5-bromo-4-methylpyridin-3- yl)quinoline (5.40 g, 41.2% yield) as a solid m/z: [M + H]+ Calcd for Ci5HnBrN2299.0; Found 300.8. ¾NMR (400 MHz, CDCb) d = 8.96 (dd, J=1.6, 4.1 Hz, 1H), 8.77 (s, 1H), 8.36 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.79 (dd, J=7.2, 8.4 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.42 (dd, J=0.8, 7.1 Hz, 1H), 7.37 (dd, J=4.0, 8.5 Hz, 1H), 2.10 (s, 3H). Synthesis of 4-d:

[00136] To a mixture of 5-(5-bromo-4-methylpyridin-3-yl)quinoline (3 g, 10.0 mmol), triethylamine (3.03 g, 30.0 mmol) in H2O (6 mL) and DMF (25 mL) was added palladium(II) bis(2-(diphenylphosphanyl)cyclopenta-2,4-dien-l-yl) dichloromethane iron di chloride (816 mg, 1 mmol) and the mixture was stirred at 80 °C under CO (50 psi) for 20 hours. The reaction mixture was diluted with water (200 mL), basified with 2N NaOH to pH=8 and washed with CH2CI2 (100 mL x 3). The aqueous phase was acidified with 1M HC1 to pH=6 and extracted with isopropanol/CHCb=l/3 (150 mL ^c 3), the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4-methyl-5-(quinolin-5-yl)pyridine-3-carboxylic acid (1.92 g, 72.7% yield) as a solid m/z: [M + H]+ Calcd for C16H12N2O2265.1; Found 264.9. ¾ NMR (400MHz, CD3OD) d = 9.08 (s, 1H), 8.92 (dd, J= 1.6, 4.4 Hz, 1H), 8.51 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 7.92 (dd, J= 7.2, 8.4 Hz, 1H), 7.86 (d, J= 8.4 Hz, 1H), 7.63 - 7.48 (m, 2H), 2.28 (s, 3H).

[00137] A solution of 4-methyl-5-(quinolin-5-yl)pyridine-3-carboxylic acid (80 mg, 302 pmol) and 4-fluoroaniline (50.3 mg, 453 pmol) in pyridine (2 mL ) was cooled to 0 °C under N2. Phosphorus oxychloride (92.6 mg, 604 pmol) was added and the reaction mixture was stirred at 0 °C under N2 for 1 hour. The reaction was quenched by adding satd. NaHCCb (10 mL) and extracted with EtOAc (10 mL ^c 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (column: YMC Triart C18250 * 50 mm * 7 pm, table: 25 - 65%B (water (A=0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 60 mL/min, UV Detector 220 nm) to afford N-(4-methoxyphenyl)-4-methyl-5-(quinolin-5-yl)pyridine-3-carboxamide (23.3 mg, 20.9% yield) as a dry powder m/z: [M + H]⁺ Calcd for C23H19N3O2 370.4; Found 370.2. ¾ NMR (400MHz, CD3OD) d = 8.92 (br d, J= 3.2 Hz, 1H), 8.74 (s, 1H), 8.49 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 8.01-7.85 (m, 2H), 7.69-7.49 (m, 4H), 6.95 (br d , J= 8.8 Hz, 2H), 3.80 (s, 3H), 2.14 (s, 3H). General Scheme 5:

[00138] A starting material ester was treated with triethoxymethane to yield a methylene ester intermediate. The intermediate was reacted with a hydrazine with a C ring to form a B ring (= pyrazole) containing intermediate, which was hydrolyzed to provide an acid intermediate. The acid intermediate was reacted with an amine with an A ring to provide a compound of formula I.

Exemplary procedure of scheme 5:

(Compound 103)

Synthesis of 5-c:

[00139] To a solution of (di ethoxy methoxy) ethane (48.0 g, 323 mmol) in acetic anhydride (20 mL) was added ethyl 4,4,4-trifluoro-3-oxobutanoate (20 g, 108 mmol). The reaction mixture was stirred at 135 °C for 16 hours. The mixture was concentrated under reduced pressure to give the crude product ethyl (2Z)-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (23.8 g, 91.8% yield) as an oil. ¾ NMR (400 MHz, CDCb) d =7.84 - 7.69 (m, 1H), 4.36 - 4.20 (m, 4H), 1.42-1.37 (m, 3H), 1.29-1.25 (m, 3H).

Synthesis of 5-e:

[00140] A solution of ethyl (2Z)-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (1.51 g, 3.78 mmol) , (2-methylphenyl)hydrazine hydrochloride (500 mg, 3.15 mmol), Et3N (875 pL, 6.30 mmol) in EtOH (10 mL ) was stirred at 80 °C for 12 hours. The resulting solution was Attorney Docket No. RSM-001WO cooled to temperature and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether= 0/1 to 1/4) to give ethyl 1-(2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (285 mg, 30.3 % yield) as an oil. m/z: [M + H]⁺ Calcd for C₁₄H₁₃F₃N₂O₂299.1; Found 298.9.¹H NMR (400 MHz, 5 CDCl3) į = 8.18 (s, 1H), 7.49 - 7.40 (m, 1H), 7.38 - 7.30 (m, 2H), 7.28 - 7.24 (m, 1H), 4.45 - 4.36 (m, 2H), 2.07 (s, 3H), 1.41 (t, J = 7.2Hz 3H). Synthesis of 5-f: [00141] A solution of ethyl 1-(2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4- 10 carboxylate (285 mg, 955 μmol) in water (1 mL ) and EtOH (2 mL) was added lithium hydroxide hydrate (120 mg, 2.86 mmol). The mixture was stirred at 25 °C for 16 hours. The resulting solution was concentrated to dryness under reduced pressure to afford the crude product, which was poured into water (5 mL) and acidified with 1M HCl till pH = 5. The resulting solution was filtered and the filter cake was washed water (5 mL) and then dried under 15 reduced pressure to afford 1-(2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg, 46.5% yield) as a solid. m/z: [M + H]⁺ Calcd for C₁₂H₉F₃N₂O₂270.1; Found 271.0 1H NMR (400 MHz, CDCl3) į = 8.27 (s, 1H), 7.50 - 7.44 (m, 1H), 7.40 - 7.32 (m, 2H), 7.29 (d, J = 3.6 Hz, 1H), 2.09 (s, 3H). 20 Synthesis of Example 5 (Compound 103): [00142] To a solution of 1-(2-methylphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (120 mg, 444 μmol) and 2-(trifluoromethyl)pyridin-4-amine (79.1 mg, 488 μmol) in pyridine (3 mL) was added phosphorus oxychloride (81.5 mg, 532 μmol) at 0 °C and the reaction was stirred at 0°C for 1 hour. The reaction mixture was diluted with saturated NaHCO3 25 (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude product which was purified by Prep-HPLC ^column: Phenomenex Gemini NX-C18 (75*30mm*3μm), condition: 41-81% B (A =water (0.05% ammonia hydroxide v/v), B = acetonitrile), flow rate: 25 mL/min, UV Detector 220nm) to afford 1-(2-methylphenyl)-5-(trifluoromethyl)-N-[2- 30 (trifluoromethyl)pyridin-4-yl]-1H-pyrazole-4-carboxamide (99.0 mg, 238 μmol, 54.0 % yield) as a dry powder. m/z: [M + H]⁺ Calcd for C18H12F6N4O 415.1; Found 415.1.¹H NMR (400MHz, DMSO-d₆) į = 11.21 (br s, 1H), 8.70 (d, J = 5.6 Hz, 1H), 8.44 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 1.6, 5.2 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.51 - 7.46 (m, 1H), 7.45 - 7.38 (m, 2H), 2.02 (s, 3H) 52 General Scheme 6:

[00143] A starting material amino aromatic ring (B’) with a carboxylic acid was hydrogenated to provide an acid with a saturated amino ring (B), which was reacted with a halide with a C ring to provide a B-C rings coupled intermediate with a carboxylic acid. The carboxylic acid intermediate was treated with an amine with an A ring to provide a compound of formula I.

Exemplary procedure of scheme 6:

Synthesis of 6-b:

[00144] A solution of 3-methylpyridine-4-carboxylic acid (1 g, 7.29 mmol), HC1 (265 mg, 7.29 mmol), PtCh (247 mg, 1.09 mmol) in CH3OH (15 mL) was stirred at 30 °C under H2 (50 psi) for 20 hours. TLC (CH3OH/CH2Cl2=l/10, Ninhydrin) showed the starting material (Rf=0.15) was consumed completely and anew main spot (Rf=0.1) was observed. Then, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the crude product 3-methylpiperidine-4-carboxylic acid hydrochloride (1.20 g, 6.68 mmol) as an oil. The crude product was used directly in next step without further purification. 'H NMR (400 MHz, CDCh) d = 9.52 (m, 2H), 8.41 - 7.92 (m, 1H), 3.37 (m,lH), 3.24 - 3.17 (m, 2H), 2.75 (m, 1H), 2.44 (m, 1H), 2.25 - 2.16 (m, 1H), 2.14 - 1.96 (m, 2H), 1.03 (d, J=7.0 Hz, 3H).

Synthesis of 6-d:

[00145] A mixture of 3-chloro-2-fluoropyridine (750 mg, 5.70 mmol), 3-methylpiperidine-4- carboxylic acid hydrochloride (1.27 g, 5.70 mmol) and DIEA (2.21 g, 17.1 mmol) inNMP (10 mL) was stirred at 120 °C for 16 hours. The reaction mixture was cooled to room temperature and brine (10 mL) was added. IN HC1 was added to adjust the pH to 7 and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give a product which was purified by flash chromatography on silica gel (CH3OH/CH2CI2 = 0/1 to 1/20) to give l-(3-chloropyridin-2-yl)-3-methylpiperidine-4-carboxylic acid (320 mg, 1.25 mmol) as an oil. m/z: [M+H]+ Calcd for C11H13CIN2O2255.1; Found 254.9. ¾NMR (400 MHz, CDCb) d = 8.17 (dd, J=1.7, 4.8 Hz, 1H), 7.57 (dd, J=1.6, 7.7 Hz, 1H), 6.82 (dd, J=4.8, 7.8 Hz, 1H), 3.90 - 3.60 (m, 2H), 3.11 - 2.87 (m, 2H), 2.80 - 2.63 (m, 1H), 2.56 - 2.43 (m, 1H), 2.21 - 2.09 (m, 1H), 1.86 (qd, J=3.8, 13.6 Hz, 1H).

Synthesis of Example 6 (Compounds 109 and 110):

[00146] To a mixture of l-(3-chloropyridin-2-yl)-3-methylpiperidine-4-carboxylic acid (50 mg, 196 pmol), 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine (42.0 mg, 215 pmol) in pyridine (1 mL ) was added POCb (60.1 mg, 392 pmol) at 0 °C and the mixture was allowed to warm to 25 °C over 1 hour. The reaction was quenched by adding saturated NaHCCb (5mL) and extracted with EtOAc (3 x 10 mL).The combined organic layers were concentrated under reduced pressure to give the crude product. The crude product was combined with another batch of Example 6 and purified by Prep-HPLC (column: Phenomenex Gemini NX- C18(75*30mm*3pm), table: 36-66% water (0.05% ammonia hydroxide v/v)-ACN, flow rate: 25 mL/min, UV Detector 220nm) to afford product (3R,4S)-N-[5-chloro-6-(2H-l,2,3-triazol-2- yl)pyridin-3-yl]-l-(3-chloropyridin-2-yl)-3-methylpiperidine-4-carboxamide (9.10 mg, 21.0 pmol) as a dry powder m/z: [M + H]+ Calcd for C19H19CI2N7O 432.1; Found 432.2. ¾ NMR (400 MHz, DMSO-d6) d = 10.77 (s, 1H), 8.70 (d, J=2.1 Hz, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.23 (br d, J=3.4 Hz, 1H), 8.16 (s, 2H), 7.81 (d, J=7.8 Hz, 1H), 7.00 (dd, J=4.7, 7.8 Hz, 1H), 3.85 (br d, J= 11.5 Hz, 1H), 3.75 (br d, J=10.3 Hz, 1H), 2.80 (br t, J=11.7 Hz, 1H), 2.58 - 2.54 (m, 1H), 2.30 - 2.20 (m, 1H), 2.13 - 2.01 (m, 1H), 2.01 - 1.92 (m, 1H), 1.91 - 1.76 (m, 1H), 0.92 (d, J=6.6 Hz, 3H) and (3R,4R)-N-[5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl]-l-(3-chloropyridin-2- yl)-3-methylpiperidine-4-carboxamide (14.2 mg, 32.8 pmol) as a dry powder m/z: [M + H]+ Calcd for C19H19CI2N7O 432.1; Found 432.2. ¾ NMR (400 MHz, DMSO-d6) d = 10.65 (s, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.22 (dd, J=1.6, 4.6 Hz, 1H), 8.15 (s, 2H), 7.78 (dd, J=1.6, 7.8 Hz, 1H), 6.98 (dd, J=4.8, 7.7 Hz, 1H), 3.76 - 3.56 (m, 2H), 3.05 (dd, J=2.9, 12.4 Hz, 1H), 2.99 - 2.88 (m, 1H), 2.80 (td, J=4.3, 10.6 Hz, 1H), 2.41 (br dd, J=3.5, 6.8 Hz, 1H), 2.18 - 2.02 (m, 1H), 1.73 (br dd, J=3.5, 13.5 Hz, 1H), 1.03 (d, J=7.0 Hz, 3H).

General Scheme 7:

[00147] An amino ring B with a cyanide was reacted with a halide with a C ring to form a cyanide-containing B-C rings coupled intermediate, which was treated with an ethylmagnesium halide Grignard reagent to yield a cyclopropylamine intermediate. The amine intermediate was reacted with a halide with an A ring to provide a compound of formula I.

Synthesis of 7-c:

[00148] To a solution of 3-chloro-2-fluoropyridine (1.5 g, 11.4 mmol) and K2CO3 (3.15 g, 22.8 mmol) in DMSO (1 mL) was added piperidine-4-carbonitrile hydrochloride (1.83 g, 12.5 mmol). The mixture was stirred at 20 °C under air for 2 hours. The mixture was poured into water (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over Na2S04 and concentrated in vacuo to give the crude product which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 0/1 to 15/85) to give l-(3-chloropyridin-2-yl)piperidine-4-carbonitrile (2.10 g, 9.47 mmol, 83.3 %) as a solid m/z: [M + H]+ Calcd for C11H12C1N3 222.1; Found 221.9. ¾ NMR (400 MHz, CDCh) d = 8.11 (dd, J= 1.4, 4.8 Hz, 1H), 7.53 (dd, J= 1.5, 7.8 Hz, 1H), 6.80 (dd, J= 4.8, 7.8 Hz, 1H), 3.52 (ddd, J= 3.7, 6.3, 12.9 Hz, 2H), 3.10 - 3.10 (m, 1H), 3.19 - 3.00 (m, 2H), 2.75 (tt, J= 4.3, 8.4 Hz, 1H), 2.09 - 1.91 (m, 4H).

Synthesis of 7-d:

[00149] To a stirred solution of l-(3-chloropyridin-2-yl)piperidine-4-carbonitrile (500 mg, 2.25 mmol) and Ti(OiPr)4 (702 mg, 2.47 mmol) in dichloromethane (5 mL) was added EtMgBr (3M in Et20 ,1.65 mL, 4.95 mmol) dropwise at 0 °C under argon atmosphere. The mixture was stirred at 20 °C for 2 hours under argon atmosphere. To the above mixture was added BF3.Et20 (638 mg, 4.50 mmol) dropwise at 20 °C. The mixture was stirred at 20 °C for additional 1.5 h, quenched with 3 mL of 1 N HC1 solution, and then basified to pH 9 with 10% NaOH. The mixture was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous MgSCri and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 0/1 to 3/7) to give l-[l-(3-chloropyri din-2 -yl)piperidin- 4-yl]cyclop^ropan-l -amine (137 mg, 544 pmol, 24.2 %) as an oil. m/z: [M + H]+ Calcd for C13H18CIN3 252.1; Found 251.9. Synthesis of Example 7 (Compound 111):

[00150] To a solution of 1-[1 -(3-chloropyri din-2 -yl)piperidin-4-yl] cyclopropan- 1 -amine (136 mg, 540 pmol) in 1,4-dioxane (1 mL) was added CS2CO3 (351 mg, 1.08 mmol), xphos (51.4 mg, 108 pmol) and Pd(OAc)2 (12.1 mg, 54.0 pmol). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash chromatography on silica gel (dichloromethane/MeOH = 100/0 to 9/1) to give the crude product. The crude product was further purified by Prep-HPLC (column: YMC Triart C18 150*25mm*5pm, table: 60-80% B (A =water (0.225% FA), B = acetonitrile), flow rate: 35 mL/min, UV Detector 220 nm) to afford 5-chloro-N-{l-[l-(3-chloropyridin-2- yl)piperidin-4-yl]cyclopropyl}-6-methoxypyri din-3 -amine (15.6 mg, 39.9 pmol, 7.35 %) as an oil. m/z: [M + H]+ Calcd for C19H22CI2N4O 393.1; Found 394.1. ¾ NMR (400 MHz, CDCh) d = 8.19 (dd, J= 1.6, 4.8 Hz, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.60 (dd, J= 1.6, 7.6 Hz, 1H), 7.53 (d, J= 2.0 Hz, 1H), 6.85 (dd, J= 4.4, 8.0 Hz, 1H), 4.02 (s, 3H), 3.91 - 3.82 (m, 2H), 2.91 - 2.79 (m, 6H), 2.57 - 2.44 (m, 1H), 1.98 - 1.90 (m, 2H), 1.89 - 1.76 (m, 2H).

[00151] The following intermediates were synthesized and used for the synthesis of the compounds.

Intermediate 1:

INT 1-a INT 1-b INT 1

Synthesis of INT 1-b:

[00152] A mixture of 1 ,4-diethyl 2-methyl-3-oxobutanedioate (5 g, 24.7 mmol) , acetic acid; methanimidamide (3.85 g, 37.0 mmol), K2CO3 (6.82 g, 49.4 mmol) in EtOH (50 mL) was stirred at 90 °C for 3 h, then cooled to 25 °C. The reaction was concentrated under reduced pressure to removed ethanol, diluted with water (50 mL), acidified with 1 M HC1 to pH =7 and extracted with EtOAc (50 mL ^c 3). The combined organic layers were washed with brine (50 mL ^c 2), dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtO Ac/PE = 0/1 to 1/1) to give ethyl 6-hydroxy-5-methylpyrimidine-4-carboxylate (1.33 g, 29.6% yield) as a solid. ¾ NMR (400 MHz, CDCh) d = 13.07 (br s, 1H), 8.19 (s, 1H), 4.44 (q, J= 7.2 Hz, 2H), 2.31 (s, 3H), 1.42 (t, J = 12 Hz, 3H). Synthesis of INT 1 :

[00153] A solution of ethyl 6-hydroxy-5-methylpyrimidine-4-carboxylate (0.9 g, 4.94 mmol) in CHCh (8 mL ) and DMF (0.1 mL) was added oxalic dichloride (1.87 g, 14.8 mmol) and the mixture was stirred at 70 °C for 2 hours. The reaction was cooled to 25 °C, poured into saturated NaHCO3(30 mL) and was extracted with EtOAc (15 mL ^c 3). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give ethyl 6-chloro-5-methylpyrimidine-4-carboxylate (770 mg, 77.6% yield) as an oil. m/z: [M + H]+ Calcd for C8H9CIN2O2201.0; Found 201.1. ¾NMR (400 MHz, CDCh) d =8.88 (s, 1H), 4.46 (q, J= 7.2 Hz, 2H), 2.52 (s, 3H), 1.42 (t, J= 7.2 Hz, 3H).

Intermediate 2:

Synthesis of INT 2-b:

[00154] To a mixture of 5-bromoisoquinoline (5 g, 24.0 mmol) in dichloromethane (75 mL) was added m-CPBA (7.76 g, 36.0 mmol) at 0 °C and the mixture was stirred at 25 °C for 1 hour dichloromethane (100 mL) was added and the mixture was washed with saturated Na2SC>3 aqueous solution (200 mL), saturated Na2CCh aqueous solution (200 mL ^c 2) and brine (300 mL). The organic layer was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The obtained residue was dissolved in AC2O (50 mL ) and the mixture was stirred at 120 °C for 2 hours. The mixture was concentrated under reduced pressure and 2N NaOH (75 mL) was added. The mixture was stirred at 100 °C for 2 hours. The mixture was cooled to room temperature and neutralized with 2N HC1 to pH = 7 to form a suspension. The suspension was filtered and the filter cake was washed with water (300 mL ^c 2). The solid was dried under reduced pressure to afford 5-bromo-l,2-dihydroisoquinolin-l-one (4.50 g, 83.7% yield) as a solid. ¾ NMR (400 MHz, CDCh) d = 10.64 (br s, 1H), 8.40 (d, J= 8.0 Hz, 1H), 7.94 (dd, J = 0.8, 8.0 Hz, 1H), 7.36 (t, J= 8.0 Hz, 1H), 7.23 (d, J= 7.2 Hz, 1H), 6.93 (d, J= 7.2 Hz, 1H)

Synthesis of INT 2:

[00155] A mixture of 5-bromo-l,2-dihydroisoquinolin-l-one (4.6 g, 20.5 mmol), 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (7.79 g, 30.7 mmol), Pd(dppf)Cl2.CH2Cl2 (1.67 g, 2.05 mmol) and KOAc (4.02 g, 41.0 mmol) in dioxane (20 mL ) was stirred at 100 °C for 16 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to afford the crude product which was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 0/1 to 1/3) to afford 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2-dihydroisoquinolin-l-one (2.80 g, 50.4% yield) as a solid. ¾ NMR (400 MHz, CDCh) d = 11.92 (br s, 1H), 8.57 (dd, J= 0.8, 8.0 Hz, 1H), 8.24 (dd, J= 1.2, 7.2 Hz, 1H), 7.55 (d, J= 7.2 Hz, 1H), 7.51 (t, J= 7.6 Hz, 1H), 7.24 (d, J= 7.2 Hz, 1H), 1.40 (s, 12H)

Intermediate 3:

INT 3-a INT 3

Synthesis of INT 3:

[00156] To a mixture of methyl 3-bromo-2-methylbenzoate (2 g, 8.73 mmol) in THF (5 mL) and H2O (1 mL) was added lithium hydroxide monohydrate (545 mg, 13.0 mmol) and the mixture was stirred at 25 °C for 16 hours. IN HC1 was added to adjust the pH to 2-3 and the mixture was extracted with EtOAc (10 mL ^c 2). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to give 3-bromo-2-methylbenzoic acid (1.80 g, 96.2% yield) as a solid. ¾ NMR (400 MHz, DMSO-de) d = 13.23 (br s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.71 (d, J= 7.6 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 2.54 (s, 3H)

Intermediate 4:

INT 4-a INT 4-b INT 4

Synthesis of INT 4-b:

[00157] To a mixture of 3-methylthiophene-2-carboxylic acid (5 g, 35.1 mmol) in MeOH (50 mL) was added cone sulfuric acid (2.5 mL, 35.1 mmol). The reaction mixture was stirred at 70 °C under nitrogen for 16 hours. The reaction mixture was concentrated to give an oil which was dissolved in EtOAc (100 mL), washed with water (50 mL ^c 2), saturated NaHC03 (50 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give methyl 3-methylthiophene-2-carboxylate (4.00 g, 72.9% yield) as an oil. m/z: [M + H]⁺ Calcd for C7H8O2S 157.0; Found 156.9. ¾ NMR (400MHz, CDCb) d = 7.39 (d, J= 5.2 Hz, 1H), 6.92 (d, J= 5.2 Hz, 1H), 3.87 (s, 3H), 2.57 (s, 3H).

Synthesis of INT 4:

[00158] A mixture of methyl 3-methylthiophene-2-carboxylate (1 g, 6.40 mmol) and sodium hydroxide (767 mg, 19.2 mmol) in AcOH (3 mL) was heated to 60 °C. Bromine (1.02 g, 6.40 mmol) was added dropwise to maintain the temperature of the reaction mixture below 85 °C. The resulting mixture was stirred at 85 °C under nitrogen for 6 hours. Then the mixture was cooled to 50 °C and zinc (961 mg, 14.7 mmol) was added in portions to maintain the temperature of the reaction mixture below 85 °C. The resulting mixture was stirred at 85 °C under nitrogen for 1 hour. The reaction mixture was diluted with EtO Ac (40 mL) and filtered. The filtrate was washed with water (20 mL ^c 2), saturated NaHC03 (20 mL) and brine (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude product which was purified by flash chromatography on silica gel (petroleum ether = 100%) and prep-HPLC (column: Phenomenex Gemini-NX 150*30mm*5pm, condition: 65-95% B (A = water(0.05% HC1), B = acetonitrile), flowrate: 30 mL/min, UV Detector 220nm) to give methyl 4-bromo-3-methylthiophene-2-carboxylate (350 mg, 23.3% yield) as a solid. 'H NMR (400MHz, CDCb) d = 7.44 (s, 1H), 3.89 (s, 3H), 2.56 (s, 3H).

Intermediate 5:

Synthesis of INT 5-b:

[00159] A mixture of 5-bromo-2-chloro-4-methylpyrimidine (2.5 g, 12.0 mmol), sodium cyanide (0.56 g, 11.4 mmol), and DABCO (500 mg, 4.45 mmol) in DMSO (40 mL ) and water (40 mL) was stirred at 20 °C for 5 hours. TLC showed two new spots were formed and pyrimidine was consumed completely. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (80 mL ^c 3). The ethyl acetate layers were combined, washed with brine (50 mL ^c 2), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtO Ac/hexane = 0/1 to 1/9) to give 5-bromo-4- methylpyrimidine-2-carbonitrile (1 g, 5.04 mmol, 42.1 % yield) as a solid m/z: [M + H]+ Calcd for CeHrBrNs 197.96; Found 199.7m/z: [M + H]+ Calcd for CeHrBrNs 197.96; Found 199.7. ¾ NMR (400 MHz, CDCb) d = 8.83 (s, 1H), 2.73 (s, 3H). Synthesis of INT 5:

[00160] 5-bromo-4-methylpyrimidine-2-carbonitrile (1.18 g, 5.95 mmol) was dissolved in 4N aqueous NaOH (4.45 mL, 17.8 mmol) and heated at 60 °C for 2 hours. The reaction mixture was acidified by addition of IN aqueous HC1 to pH =2. The mixture was filtered and the filter cake was washed with water (5 mL x3) and then dried under reduced pressure to afford 5-bromo-4- methylpyrimidine-2-carboxylic acid (938 mg, 72.7% yield) as a dry powder m/z: [M + H]+ Calcd for C6H₅BrN₂0₂217.0; Found 218.9 ¾ NMR (400MHz, DMSO-d6) d = 13.69 (br s, 1H), 9.04 (s, 1H), 2.63 (s, 3H).

Intermediate 6:

Synthesis of INT 6:

[00161] A mixture of 6-chloro-5-methylpyridine-2-carboxylic acid (500 mg, 2.91 mmol), (quinolin-5-yl)boronic acid (553 mg, 3.20 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (237 mg, 291 pmol) and Na₂C03 (616 mg, 5.82 mmol) in dioxane (5 mL) and H₂0 (1 mL) was stirred at 80 °C for 10 hours under N₂ atmosphere. The mixture was filtered and the filter cake was washed with EtOAc (20 mL x 2). IN HC1 was added to the filtrate to adjust the pH to 2-3 and the mixture was concentrated under reduced pressure to afford the crude product which was purified by flash chromatography on silica gel (Methanol/Dichloromethane = 1/10 to 1/1) to give 5-methyl-6- (quinolin-5-yl)pyridine-2-carboxylic acid (300 mg, 39.0% yield) as a solid m/z: [M+H]⁺ Calcd for Ci6Hi3N₂0₂265.1; Found 265.2. ¾ NMR (400 MHz, MeOD) d = 9.32 - 9.23 (m, 1H), 8.72 (d, J=6.8 Hz, 1H), 8.38 (d, J=7.6 Hz, 1H), 8.33 - 8.23 (m, 2H), 8.12 (d, J=7.6 Hz, 1H), 8.07 - 7.98 (m, 2H), 2.25 (s, 3H).

Intermediate 7:

INT 7 -a INT 7-b INT 7

Synthesis of INT 7-b:

[00162] To a solution of 1 ,4-diethyl 2-methyl-3-oxobutanedioate (5 g, 24.7 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (3 g, 43.1 mmol). The reaction was heated at 78 °C for 14 hours. The reaction mixture was directly concentrated under reduced pressure. The residue was triturated with petroleum ether to give ethyl 4-methyl-5-oxo-2,5-dihydro-l,2- oxazole-3-carboxylate as a solid (4.00 g, 94.7%).m/z: [M + H]+ Calcd for C7H9NO4 172.1; Found 172.1. ¾NMR (400MHz, DMSO-d6) d = 4.32 (q, J=7.2 Hz, 2H), 1.92 (s, 3H), 1.29 (t, J=7.2 Hz, 3H).

Synthesis of INT 7:

[00163] To a mixture of ethyl 4-methyl-5-oxo-2,5-dihydro-l,2-oxazole-3-carboxylate (4 g, 23.3 mmol) in phosphoryl tribromide (33.2 g, 115 mmol) was added triethylamine (4.71 g, 46.6 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature and then poured to ice. The mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography eluting with EtOAc:PE (0/10 to 1/10) to give a title compound ethyl 5-bromo-4-methyl-l,2-oxazole-3-carboxylate (3.90 g, 71.5% yield) as an oil. ¾ NMR (400MHz, CDCh) d = 4.37 (q, J=7.2 Hz, 2H), 2.11 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).

Intermediate 8:

Synthesis of INT 8-b:

[00164] To a stirred solution of 5-bromoquinoline (10 g, 48.0 mmol) in THF (200 mL ) was slowly added n-BuLi (23.0 mL, 57.5 mmol) at -78 °C under an argon atmosphere. After stirring for 1 hour at the same temperature, N,N-dimethylformamide (17.5 g, 240 mmol) was added. After stirring for 1.5 hours at -78 °C, the reaction was quenched with saturated aqueous NLLCl solution (100 mL) and extracted with EtOAc (200 mL). The organic layer was dried over Na2S04, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 10% EA in PE) to give quinoline-5-carbaldehyde (4.30 g, 57.0% yield) as a solid ml z: [M + H]⁺ Calcd for C10H7NO 158.1; Found 158.0. ¾ NMR (400 MHz, CDCb) d = 10.37 (s, 1H), 9.62 (dd , J= 0.8, 8.8 Hz, 1H), 9.02 (dd, J= 1.6, 4.4 Hz, 1H), 8.38 (d, J= 8.4 Hz, 1H), 8.07 (dd, J= 1.2, 7.2 Hz, 1H), 7.89 (dd, J= 7.2, 8.4 Hz, 1H), 7.60 (dd, J= 4.4, 8.8 Hz, 1H).

Synthesis of INT 8-c:

[00165] To a stirred solution of quinoline-5 -carbaldehyde (3.87g, 24.6 mmol) in THF (50 mL ) was slowly added magnesium(II) ethanide bromide (9.8 mL, 29.5 mmol) at 20 °C under an argon atmosphere. The mixture was stirring at 20 °C for 3 hours. The reaction was quenched with saturated aqueous NH4CI solution (100 mL) and extracted with EtOAc (100 mL ^c 2). The organic layer was dried over Na2S04, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 30% EA in PE) to give l-(quinolin-5-yl)propan-l-ol (2.95 g, 64.1% yield) as a solid m/ z: [M + H]⁺ Calcd for C12H13NO 188.1; Found 188.1.

Synthesis of INT 8-d:

[00166] To a stirred solution of l-(quinolin-5-yl)propan-l-ol (2.9 g, 15.4 mmol) in CH2CI2 (30 ml ) was added l,l-bis(acetyloxy)-3-oxo-l -lambda-5, 2-benziodaoxol- 1-yl acetate (7.8 g, 18.4 mmol) at 0 °C. The mixture was stirring for 1 hour at the same temperature. The reaction was quenched by addition of 30 mL of water and extracted with CH2CI2 (40 ml ^c 2). The organic layer was dried over Na2S04, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 50 % EtOAc in PE) to give l-(quinolin-5-yl)propan-l- one (2.6 g, 91.2 % yield) as a solid m/z: [M + H]⁺ Calcd for C12H11NO 186.1; Found 185.9. ¾ NMR (400 MHz, CDCb) d = 9.09 (d, J= 8.8 Hz, 1H), 8.97 (dd, J= 1.2, 4.0 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.02 (d, J= 7.2 Hz, 1H), 7.79 - 7.71 (m, 1H), 7.52 (dd, J= 4.0, 8.4 Hz, 1H), 3.12 (q, J = 7.2 Hz, 2H), 1.29 (t, J= 7.2 Hz, 3H).

Synthesis of INT 8-e:

[00167] To a stirred solution of l-(quinolin-5-yl)propan-l-one (1 g, 5.4 mmol) in ethyl oxalate (10 mL) was slowly added sodium hydride (535 mg, 13.4 mmol). The mixture was stirred at 20 °C for 3 hours. The reaction was quenched by adding water (40 mL) and was extracted with EtOAc (50 mL). The aqueous phase was acidified with aqueous IN HC1 (10 mL) to pH = 4 and extracted with EtOAc (100 mL ^c 2). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (EtOAc/ PE = 0/ 1 to 1/ 3) to give 3- methyl-2,4-dioxo-4-(quinolin-5-yl)butanoate and 3-methyl-2,4-dioxo-4-(quinolin-5-yl)butanoic acid (a mixture of acid and ester, 600 mg, 39.2 %) as a solid m/z: [M + H]+ Calcd for CirHiiNOr 258.1; Found 257.9.

Synthesis of INT 8:

[00168] To a solution of ethyl 3-methyl-2,4-dioxo-4-(quinolin-5-yl)butanoate (600 mg, 2.1 mmol) in EtOH (10 mL) was added hydrazine hydrate (135 mg, 2.3 mmol). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, and then diluted with water (10 mL). The mixture was acidified with aqueous solution of IN HC1 (5 mL) and a solid precipitate was formed. The mixture was filtered and the filter cake was washed with 10 mL of water, dried in vacuum to give 4-methyl-5-(quinolin-5-yl)- lH-pyrazole-3-carboxylic acid (330 mg, 62.1% yield) as a solid m/z: [M + H]⁺ Calcd for C14H11N3O2254.1; Found 254.0.

Intermediate 9:

INT 9 -a INT 9

Synthesis of INT 9:

[00169] A solution of 5 -bromo-1 -methyl- lH-imidazole (5 g, 31.0 mmol) in THF (20 mL) was cooled to -78°C. LDA (3.65 g, 34.1 mmol) was added at -78 °C for and then stirred for 5 min. The result reaction mixture was added into a solution of ethyl carbonochloridate (16.8 g, 155 mmol) in THF (30 mL) at -78 °C and the reaction mixture was stirred at -78 °C for 2 hours. The reaction mixture was quenched by adding saturated NaHCCh (100 mL) and extracted with EtOAc (100 mL ^c 3). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel (EtO Ac/PE = 0/1 to 1/1) to give ethyl 5-bromo-l-methyl-lH-imidazole-2-carboxylate (2.87 g, 39.7% yield) as an oil. m/z: [M + H]+ Calcd for CrHgBri^Ch 233.0; Found 232.9. ¾NMR (400 MHz, CDCb) d = 7.16 (s, 1H), 4.40 (q, J= 7.2 Hz, 2H), 3.99 (s, 3H), 1.42 (t, J= 7.2 Hz, 3H). Intermediate 10:

Synthesis of INT 10-b:

[00170] To a solution of ethyl 2-nitroacetate (5 g, 37.5 mmol) in toluene (10 mL) was added 1,1,1 -tri ethoxy ethane (6.68 g, 41.2 mmol) and the reaction mixture was allowed to warm to 110 °C . A Dean Stark trap was used to azeotrope the ethanol. Approximately every 30 min, the solvent was removed from the Dean Stark and additional toluene (10 mL) was added to the reaction flask. After 7 h, the reaction was stopped and it was cooled to room temperature. The solvent was removed under reduced pressure to give crude product which was purified by flash chromatography on silica gel (EtO Ac/PE = 1/10) to give ethyl (2E)-3-methoxy-2-nitrobut-2- enoate (1.70 g, 22.2% yield) as a liquid. ¾ NMR (400MHz, CDCb) d = 4.26 (q, J= 7.1 Hz, 2H), 4.18 (q, J= 7.0 Hz, 2H), 2.53 (s, 3H), 1.36 (t, J= 7.0 Hz, 3H), 1.30 (t, J= 7.1 Hz, 3H).

Synthesis of INT 10-d:

[00171] To a solution of quinolin-5-amine (1.48 g, 10.3 mmol) in ethanol (10 mL) was added ethyl (2E)-3-methoxy-2-nitrobut-2-enoate (1.3 g, 6.87 mmol) and the reaction mixture was stirred at 80 °C for 16 hours. The mixture was concentrated to remove ethanol. The residue was purified by flash chromatography (SiCh, 50% ethyl acetate in PE) to give ethyl (2E)-2-nitro-3- [(quinolin-5-yl) amino] but-2-enoate (580 mg, 28.1% yield) as a semisolid. m/z: [M + H]+ Calcd for C15H15N3O4 302.1; Found 302.2. ¾ NMR (400MHz, CDCb) d = 12.05 (br s, 0.5H), 11.21 (br s, 0.5H), 9.10 - 8.99 (m, 1H), 8.29 (br d, J=8.6 Hz, 1H), 8.25 - 8.14 (m, 1H), 7.85 - 7.74 (m, 1H), 7.63 - 7.52 (m, 1H), 7.50 - 7.39 (m, 1H), 4.45 - 4.32 (m, 2H), 2.11 - 2.01 (m, 3H), 1.43 - 1.36 (m, 3H).

Synthesis of INT 10:

[00172] To a mixture of ethyl (2E)-2-nitro-3-[(quinolin-5-yl)amino]but-2-enoate (400 mg, 1.32 mmol) and (diethoxymethoxy)ethane (3 mL) in AcOH (3 mL) was added iron (500 mg, 8.95 mmol). The mixture was refluxed for 4 hours. LCMS showed the desired MS was observed. The reaction mixture was quenched by Na2CCb solution (50 mL) and extracted with ethyl acetate (30 mL ^c 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude product which was purified by flash column chromatography on silica gel (50% to 100% ethyl acetate in PE) to give ethyl 5-methyl-l-(quinolin-5-yl)-lH- imidazole-4-carboxylate (340 mg, 91.6% yield) as a solid m/z: [M + H]+ Calcd for C16H15N3O2 282.1; Found 282.1. ¾ NMR (400MHz, DMSO-d6) d = 9.04 (dd, J= 2.3, 3.4 Hz, 1H), 8.27 (d, =8.4 Hz, 1H), 8.00 - 7.93 (m, 2H), Ί.Ί9 (dd, .7=1.0, 7.4 Hz, 1H), 7.66 - 7.62 (m, 2H), 4.34 - 4.25 (m, 2H), 2.19 (s, 3H), 1.32 (t, J= 7.1 Hz, 3H).

Intermediate 11:

Synthesis of INT 11-b:

[00173] To a solution of ethyl 2-nitroacetate (5 g, 37.5 mmol) in toluene (10 mL) was added 1,1,1 -tri ethoxy ethane (6.68 g, 41.2 mmol), and the reaction mixture was allowed to warm to 110 °C . A Dean Stark trap was used to azeotrope the ethanol. Approximately every 30 min, the solvent was removed from the Dean Stark and additional toluene (10 mL) was added to the reaction flask. After 7 h, the reaction stopped and it was cooled to room temperature. The solvent was removed under reduced pressure to give crude product which was purified by flash chromatography on silica gel (EtO Ac/PE = 1/10) to give ethyl (2E)-3-methoxy-2-nitrobut-2- enoate (2.34 g, 80% purity, 26.3% yield) as a liquid. ¾ NMR (400MHz, CDCb) d = 4.25 (q,

J= 7.1 Hz, 2H), 4.17 (q, .7=7.0 Hz, 2H), 2.52 (s, 3H), 1.34 (t, .7=7.0 Hz, 3H), 1.28 (t, .7=7.2 Hz, 3H).

Synthesis of INT 11-d:

[00174] To a solution of 5-amino-l,2-dihydroisoquinolin-l-one (980 mg, 6.12 mmol) in ethanol (10 mL ) was added ethyl (2E)-3-methoxy-2-nitrobut-2-enoate (1.82 g, 7.66 mmol) and the reaction mixture was stirred at 80 °C for 16 hours. A solid was collected by filtration and dried under reduced pressure to give ethyl (2E)-2-nitro-3-[(l-oxo-l, 2-dihydroisoquinolin-5- yl)amino]but-2-enoate (1.10 g, 45.2% yield) as a solid. ¾ NMR (400MHz, DMSO-d6) d = 11.51 (br d, J= 6.0 Hz, 2H), 8.24 (d, J= 7.9 Hz, 1H), 7.77 (d, J= 7.6 Hz, 1H), 7.56 (t, J= 7.9 Hz, 1H), 7.37 - 7.26 (m, 1H), 6.39 (d, J= 7.3 Hz, 1H), 4.24 (q, J= 7.1 Hz, 2H), 1.93 (s, 3H), 1.25 (t, J= 7.1 Hz, 3H).

Synthesis of INT 11 : [00175] To a mixture of ethyl (2E)-2-nitro-3-[(l-oxo-l, 2-dihydroisoquinolin-5-yl) amino] but-2-enoate (1.5 g, 4.72 mmol) and (diethoxymethoxy) ethane (10 mL) in AcOH (10 mL) was added iron (1.84 g, 33.0 mmol). The mixture was refluxed for 4 hours. The reaction mixture was quenched by Na2C03 solution (100 mL) and extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give ethyl 5-methyl-l-(l-oxo-l,2-dihydroisoquinolin-5-yl)-lH-imidazole-4-carboxylate (800 mg, 57.1% yield) as a solid which was used for next step directly m/z: [M + H]+ Calcd for C16H15N3O3 298.1; Found 298.1.

Intermediate 12:

INT 12-a INT 12-b INT 12

Synthesis of INT 12-b:

[00176] A mixture of quinolin-5-amine (700 mg, 4.85 mmol) in sulfuric acid (1.25 mL) and H2O (0.7 mL ) was cooled to 0 °C, and then sodium nitrite (400 mg, 5.81 mmol) in H2O (0.5 mL) was added. The mixture was stirred at 0 °C for 5 min. Then, NaN3 (315 mg, 4.85 mmol) in H2O (0.5 mL) was added and the reaction mixture was stirred at 20 °C for 10 min. The reaction mixture was neutralized with NH3.H2O. The solid was collected by filtration to give 5- azidoquinoline (800 mg, 96.9% yield) as a solid which was used for next step directly m/z: [M + H]⁺ Calcd for CoHeNr 171.1; Found 170.9.

Synthesis of INT 12:

[00177] To a mixture of sodium methanolate (330 mg, 6.11 mmol) in MeOH (8 mL) was added 5-azidoquinoline (800 mg, 4.70 mmol) and methyl 3-oxobutanoate (545 mg, 4.70 mmol). The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated and dissolved in THF (10 mL) and FLO (3 mL). Then lithium hydroxide hydrate (591 mg, 14.1 mmol) was added and the reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was concentrated, diluted with water (40 mL) and extracted with EtOAc (20 mL ^c 3). The aqueous phase was acidified with 1 M HC1 to pH = 6 and washed with EtOAc (20 mL ^c 3). The aqueous phase was concentrated to dryness and then MeOH (30 mL) was added. The mixture was filtered and the filtrate was concentrated to give 5-methyl-l-(quinolin-5-yl)-lH- l,2,3-triazole-4-carboxylic acid (1.10 g, 92.4% yield) as a solid m/z: [M + H]⁺ Calcd for C13H10N4O2255.1; Found 255.1. ¾NMR (400MHz, CD3OD) d = 9.00 (dd, J= 1.6, 4.4 Hz, 1H), 8.33 (d, J= 8.8 Hz, 1H), 8.04 - 7.97 (m, 1H), 7.79 (d, J= 7.2 Hz, 1H), 7.73 (d, J= 8.8 Hz, 1H), 7.62 (dd, J= 4.0, 8.4 Hz, 1H), 2.39 (s, 3H).

Intermediate 13:

Synthesis of INT 13-b:

[00178] A mixture of isoquinolin-5 -amine (1.4 g, 9.71 mmol) in sulfuric acid (2.5 mL) and H2O (7 mL) was cooled to 0 °C and sodium nitrite (800 mg, 11.6 mmol) in H2O (5 mL ) was added. The mixture was stirred at 0 °C for 5 min. Then NaN3 (631 mg, 9.71 mmol) in H2O (5 mL) was added and the reaction mixture was stirred at 20 °C for 10 min. The reaction mixture was neutralized with NH3.H2O. The solid was collected by filtration to give 5-azidoisoquinoline (1.60 g, 96.9% yield) as a solid which was used for next step directly m/z: [M + H]⁺ Calcd for C9H6N4 171.1; Found 170.9.

Synthesis of INT 13-c:

[00179] To a mixture of sodium methanolate (556 mg, 10.3 mmol) in MeOH (15 mL) was added 5-azidoisoquinoline (1.6 g, 9.40 mmol) and methyl 3-oxobutanoate (1.09 g, 9.40 mmol). The reaction mixture was stirred at 20 °C under nitrogen for 14 hours. The solid was collected by filtration, washed with EtOH (50 mL) and dried to give methyl l-(isoquinolin-5-yl)-5-methyl- lH-l,2,3-triazole-4-carboxylate (920 mg, 36.5% yield) as a solid. ¾NMR (400MHz, CDCb) d = 9.44 (d, J= 0.8 Hz, 1H), 8.62 (d, J= 6.0 Hz, 1H), 8.27 (d, J= 8.0 Hz, 1H), 7.84 - 7.80 (m,

1H), 7.79 - 7.76 (m, 1H), 7.08 (d, J= 6.0 Hz, 1H), 4.05 (s, 3H), 2.45 (s, 3H).

Synthesis of INT 13-d:

[00180] To a mixture of methyl l-(isoquinolin-5-yl)-5-methyl-lH-l,2,3-triazole-4- carboxylate (920 mg, 3.42 mmol) in CH2CI2 (10 mL) was added 3-chlorobenzene- 1- carboperoxoic acid (883 mg, 4.10 mmol). The reaction mixture was stirred at 10 °C under nitrogen for 16 hours. The reaction mixture was diluted with CH2CI2 (50 mL) and washed with saturated Na2S03 (30 mL ^c 3). The organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 5-[4- (methoxycarbonyl)-5-methyl-lH-l,2,3-triazol-l-yl]isoquinolin-2-ium-2-olate (890 mg, 91.5% yield) as a solid m/z: [M + H]⁺ Calcd for C14H12N4O3285.1; Found 284.9.

Synthesis of INT 13-e:

[00181] A mixture of 5-[4-(methoxycarbonyl)-5-methyl-lH-l,2,3-triazol-l-yl]isoquinolin-2- ium-2-olate (790 mg, 2.77 mmol) in acetyl acetate (10 mL) was stirred at 120 °C under nitrogen for 8 hours. The reaction mixture was concentrated to give crude product which was purified by flash chromatography on silica gel (37-40% EtOAc in petroleum ether) to give methyl 1-[1- (acetyloxy)isoquinolin-5-yl]-5-methyl-lH-l,2,3-triazole-4-carboxylate (260 mg, 28.7% yield) as a solid. ¾ NMR (400MHz, CDCh) d = 8.71 - 8.65 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.72 - 7.68 (m, 2H), 5.88 (d, J= 8.4 Hz, 1H), 4.04 (s, 3H), 2.89 (s, 3H), 2.46 (s, 3H).

Synthesis of INT 13:

[00182] To a mixture of methyl l-[l-(acetyloxy)isoquinolin-5-yl]-5-methyl-lH-l,2,3-triazole- 4-carboxylate (260 mg, 796 pmol) in THF (3 mL ) and H2O (1 mL ) was added lithium(l+) hydrate hydroxide (99.8 mg, 2.38 mmol). The reaction mixture was stirred at 10 °C for 14 hours. The reaction mixture was concentrated, diluted with water (10 mL) and extracted with EtOAc (10 mL). The aqueous phase was acidified with 1 M HC1 to pH = 3 and concentrated to give 5-methyl-l-(l-oxo-l,2-dihydroisoquinolin-5-yl)-lH-l,2,3-triazole-4-carboxylic acid tris(chlorolithium) (300 mg, 94.9% yield) as a solid m/z: [M + H]⁺ Calcd for C13H10N4O3 271.1; Found 271.1.

Intermediate 14:

Synthesis of INT 14-c:

[00183] To a mixture of 2,3-dichloro-5-nitropyridine (30 g, 155 mmol) and K2CO3 (42.8 g, 310 mmol) in THF (300 mL) was added 2H-1, 2, 3-triazole (12.8 g, 186 mmol) and the reaction mixture was stirred at 25 °C for 30 hours. The reaction was quenched by adding water (200 mL) and a white solid was separated from the aqueous solution by filtration to afford 3-chloro-5- nitro-2-(2H-l,2,3-triazol-2-yl)pyridine (32.0 g, 91.6% yield) as a solid. ¾ NMR (400MHz, CDCb) d = 9.34 (d, J= 2.5 Hz, 1H), 8.80 (d, J= 2.3 Hz, 1H), 8.04 (s, 2H).

Synthesis of INT 14: [00184] To a solution of 3-chloro-5-nitro-2-(2H-l,2,3-triazol-2-yl)pyridine (32 g, 141 mmol) in THF (240 mL) and water (80 mL) was added disodium dithionite (73.6 g, 423 mmol) and the reaction mixture was stirred at 50 °C for 1.5 hours. The reaction was quenched by adding water (100 mL) and was extracted with EtOAc (100 mL x3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography on silica gel (CH3OH/CH2CI2 = 1/50 to 1/20) to give product 5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-amine (10.2 g, 37% yield). 'H NMR (400MHz, DMSO-d6) d = 8.04 (s, 2H), 7.82 (d, J= 2.5 Hz, 1H), 7.20 (d, J= 2.5 Hz, 1H), 6.18 (s, 2H). Intermediate 15:

Synthesis of INT 15:

A mixture of methyl 1 -methyl- lH-imidazole-5-carboxylate (3 g, 21.4 mmol) , NBS (4.94 g, 27.8 mmol) and AIBN (702 mg, 4.28 mmol) in CHC13 (30 mL ) was stirred at 50°C for 12 hours. The mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/Petroleum ether = 0/1 to 3/17) to give methyl 2-bromo-l-methyl-lH-imidazole-5- carboxylate (2.60 g, 11.8 mmol, 55.5%) as ayellow crystal m/z: [M + H]+ Calcd forC6H7BrN202219.0; Found 220.8. NMR: 1H NMR (400 MHz, CDC13) d = 7.70 (s, 1H),

3.94 (s, 3H), 3.88 (s, 3H).

[00185] The following compounds in Table 1 were synthesized according to General Schemes 1-7 as described above with the identified intermediates.

Table 1.

Example 2. MALT1 Biochemical Assay

[00186] Inhibitor potency of the compounds was evaluated by measuring enzymatic activity of full length MALT1 at varying concentrations of compound. The enzymatic assay consists of a single substrate reaction that monitors the release of a fluorescent dye upon cleavage of the peptide substrate. The peptide substrate has the following sequence: Ac-Met-Phe-Leu-Pro-Leu- Arg-Ser-Arg-AMC (custom synthesis from BioPeptide Co., Inc., San Diego, CA). The assay buffer consists of 50 mM Hepes, pH 7.5, 0.8 M sodium citrate, 1 mM DTT, 0.004% tween-20, and 0.005% bovine skin gelatin (BSG). Steady-state kinetic analysis of peptide substrate binding resulted in a Michaelis-Menten constant (AM) of 8 mM. The assay was performed in a 384-well F-bottom polypropylene, black microplate (Greiner Bio One, Catalog no. 781209) at 15 nM enzyme under balanced substrate conditions (10 pM peptide substrate). The reaction was quenched after 60 minutes with the addition of iodoacetate at a final concentration of 10 mM. Total fluorescence was measured using an Envision (PerkinElmer) with fluorescence excitation at 350 nm and emission at 450 nm.

[00187] For potency determination, 1 pL of serially diluted compound (in 100% DMSO) was pre-incubated with 40 pL of enzyme for 30 minutes. The reaction was initiated with the addition of 10 pL of peptide substrate. The relative fluorescence units were transformed to percent inhibition by using 0% and 100% inhibition controls as reference. The 100% inhibition control consisted of 1 pM final concentration of (S)-l-(5-chloro-6-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)- 3-(2-chloro-7-(l-methoxyethyl)pyrazolo[l,5-a]pyrimidin-6-yl)urea (IC50 = 15 nM), while the 0% inhibition control consisted of 2% DMSO. IC50 values were calculated by fitting the concentration-response curves to a four-parameter logistic equation in GraphPad Prism.

[00188] Results from this assay are summarized in Table 2 below. In this table, “A” indicates IC50 of less than 1 mM; “B” indicates IC50 from 1 pM up to 10 pM; and “C” indicates IC50 of greater than 10 pM. “N/A” indicates not tested.

Table 2.

Equivalents and Scope

[00189] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[00190] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[00191] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims.

Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[00192] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R^la and Rl^b are independently hydrogen or Ci-6alkyl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents; or R^la and R^lb together with the carbon to which they are attached form C=O, C=S, C3- 6cycloalkylene, or 3-6 membered heterocyclylene;

R^A is each independently hydrogen or Ci-6alkyl;

R^B is hydrogen or Ci-6alkyl; and R^g is selected from the group consisting of cyano, halogen, hydroxyl, oxo, Ci-6alkyl, -

C(0)0R^b, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 5-6 membered heteroaryl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents; wherein the compound is not a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein:

R^A is each independently hydrogen or Ci-6alkyl;

R^B is hydrogen or Ci-6alkyl; and

R^g is selected from the group consisting of cyano, halogen, hydroxyl, oxo, Ci-6alkyl, - C(0)OR^b, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 5-6 membered heteroaryl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents; wherein when

phenyl or 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl may be optionally substituted on one or more available carbons by one, two, three, or more substituents each independently selected from cyano, halogen, hydroxyl, oxo, Ci-6alkyl, -C(0)0R^B, -0-Ci-6alkyl, -0-C3-6cycloalkyl, -N(R^A)2, and 6 membered heteroaryl. 3. The compound of claim 1 or 2, wherein R¹ and R² together with the carbon to which they are attached form C=O.

4. The compound of any one of claims 1-3, wherein A is selected from the group consisting of phenyl,

wherein A may be optionally substituted with one or two substituents independently, for each occurrence, selected from the group consisting of halogen, Ci-6alkyl, -0-Ci-6alkyl, and 5-6 membered heteroaryl, wherein the Ci-6alkyl may be optionally substituted with one, two, three, or more fluorine.

5. The compound of any one of claims 1-4, wherein A is phenyl, wherein A may be optionally substituted with halogen, Ci-6alkyl, or -0-Ci-6alkyl.

6. The compound of any one of claims 1-5, wherein A is selected from the group consisting

7. The compound of any one of claims 1-4, wherein

optionally substituted with two substituents independently, for each occurrence, selected from the group consisting of chlorine,

12. The compound of any one of claims 1-11, wherein B is selected from the group consisting of phenylene,

, wherein B may be optionally substituted with Ci-6alkyl.

13. The compound of any one of claims 1-12, wherein B is selected from the group

substituted with CH3. 14. The compound of any one of claims 1-13, wherein B is selected from the group consisting

15. The compound of any one of claims 1-13, wherein B is selected from the group

16. The compound of any one of claims 1-14, wherein C is selected from the group consisting of phenyl,

wherein C may be optionally substituted with chlorine, fluorine, oxo, or NTh.

17. The compound of any one of claims 1-16, wherein C is phenyl

18. The compound of any one of claims 1-16, wherein C is selected from the group consisting of phenyl,

wherein C may be optionally substituted with chlorine, fluorine, oxo, or NTh.

19. The compound of any one of claims 1-16 and 18, wherein C is selected from the group

20. The compound of claim 1 or 2, wherein R^la and R^lb together with the carbon to which they are attached form C3-6cycloalkylene.

21. The compound of any one of claims 1, 2, or 20, wherein R^la and R^lb together with the carbon to which they are attached form

22. The compound of any one of claims 1, 2, 20 and 21, wherein A is

, wherein

A may be optionally substituted with two substituents independently, for each occurrence, selected from halogen and -0-Ci-6alkyl. 23. The compound of any one of claims 1 , 2 and 20-22, wherein

wherein

A may be optionally substituted with two substituents independently, for each occurrence, selected from chlorine and -O-CH3.

24. The compound of any one of claims 1, 2 and 20-23, wherein

25. The compound of any one of claims 1, 2 and 20-24, wherein B is

26. The compound of any one of claims 1, 2 and 20-25, wherein B is

27. The compound of any one of claims 1, 2 and 20-26, wherein C is

wherein C may be optionally substituted with halogen.

28. The compound of any one of claims 1, 2 and 20-27, wherein

wherein C may be optionally substituted with chlorine.

29. The compound of any one of claims 1, 2 and 20-28, wherein

or a pharmaceutically acceptable salt, wherein:

B is selected from the group consisting of phenylene, 5-10 membered heteroarylene having one heteroatom, and 5-6 membered heterocyclylene, wherein B may be optionally substituted on one or more available carbons with Cmalkyl; and C is 5-10 membered heteroaryl, wherein C may be optionally substituted on one or more available carbons with oxo; wherein when

denotes the point of attachment t

31. The compound of claim 30, wherein B is selected from the group consisting of phenylene,

wherein B may be optionally substituted with

CH₃ and wherein * denotes the point of attachment

denotes the point of attachment

32. The compound of claim 30 or 31, wherein B is selected from the group consisting of

wherein B may be optionally substituted with CTh and wherein * denotes the

33. The compound of any one of claims 30-32, wherein B is selected from the group consisting

34. The compound of claim 30, wherein

substituted with CTb.

35. The compound of claim 30 or 34, wherein

36. The compound of any one of claims 30-33, wherein C is

37. The compound of any one of claims 30-34, wherein

38. The compound of any one of claims 30-33, wherein C is

wherein

may be optionally substituted with oxo.

39. The compound of any one of claims 30-33 and 38, wherein

40. A compound represented by Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R^g is halogen or Ci-6alkyl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more halogen substituents. 41. The compound of claim 40, wherein A is

, wherein A may be optionally substituted with Ci-6alkyl, wherein the Ci-6alkyl may be optionally substituted on one or more available carbons by one, two, three, or more fluorine.

42. The compound of claim 40 or 41, wherein

, wherein A may be optionally substituted with CF3.

43. The compound of any one of claims 40-42, wherein

44. The compound of any one of claims 40-43, wherein C is phenyl or

wherein C may be optionally substituted with one or two substituents independently, form each occurrence, selected from CTb and chlorine.

45. The compound of any one of claims 40-44, wherein C is phenyl.

46. The compound of any one of claims 40-44, wherein C is phenyl or

wherein C may be optionally substituted with CTb or chlorine.

48. The compound of any one of claims 40-44, wherein C is phenyl optionally substituted with two substituents independently, for each occurrence, selected from CTb and chlorine.

50. A compound selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. 51. A pharmaceutical composition comprising a compound of any one of claims 1-50 and a pharmaceutically acceptable carrier.

52. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-50 or a pharmaceutical composition of claim 51.

53. A method of treating an autoimmune or inflammatory disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-50 or a pharmaceutical composition of claim 51.

54. The method of claim 53, wherein the autoimmune or inflammatory disorder or disease is selected from the group consisting of acute graft-versus-host disease, chronic graft-versus-host disease, lupus, scleroderma, psoriatic arthritis, primary sclerosing cholangitis and an inflammatory bowel disease.