This application claims the priority benefit of INDIAN Provisional Patent Application No. 201811025792, filed Jul. 10, 2018, the disclosures of which are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention relates generally to compounds useful in treatment of conditions associated with excessive activity of transforming growth factor beta (TGF-P), particularly type 1 or activin-like kinase 5 (ALK 5). The invention also provides method of using said compounds and pharmaceutically acceptable compositions comprising compounds of the present invention.
BACKGROUND OF THE INVENTION
[0003] Transforming growth factors, including TGF-P, play a key role in controlling cellular functions such as proliferation, differentiation, migration, extracellular matrix production, apoptosis, adhesion, and development. Dysregulated TGF-P signaling has been identified as a key factor in a number of pathological disorders.
[0004] TGF-P and other cytokines signal through a complex of two structurally and functionally distinct transmembrane receptor serine/threonine kinases, known as type 1 and type 2 TGF-P receptors, resulting in activation of TGF-P mediated pathways. The type 1 TGF-P receptor is also known as activin-like kinase 5 (ALK 5). Inhibition of ALK 5 antagonizes TGF-P mediated pathways and provides diverse biological effects in clinical applications, including the treatment of cancer, fibrosis, cardiovascular disorders, wound healing, and many others.
[0005] TGF-P superfamily of conserved cytokines, growth factors, and morphogens consists of isoforms TGF-pi (ALK 5), TGF-P2, and TGF-P3. These

proteins are pleiotropic modulators that regulates various biological processes including cell growth and differentiation, stimulating cell proliferation, inducing apoptosis, hematopoiesis, embryonic and bone development, immune and inflammatory responses and extracellular matrix formation (Roberts and Sporn Handbook of Experimental Pharmacology (1990) 95:419-58; Massague, et al, Ann. Rev. Cell. Biol. (1990) 6:597-646). Among the various isoforms, TGF-pi inhibits the growth of epithelial cells and stimulates the proliferation of mesenchymal cells. Activin, inhibin, bone morphogenic protein, and Mullerian inhibiting substance (MIS) are other members of this superfamily. TGF-P superfamily members are responsible for initiation of intracellular signaling pathways that ultimately leads to gene expressions that regulate cell cycle. The TGF-P superfamily also control proliferative responses, cell adhesion, intercellular communication, cellular migration and relate with extracellular matrix proteins that mediate outside-in cell signaling.
[0006] As TGF-P regulates many biological processes, dysregulation in its activity can be harmful. For example, TGF-P stimulates the proliferation of mesenchymal cells under normal conditions, however when dysregulated, TGF-P can be an autocrine growth factor for many tumors. Similarly, overexpression of TGF-P can lead to an excessive accumulation of extracellular matrix resulting in fibroproliferative diseases. Hence, there is need to develop compounds that modulate the TGF-P signaling pathway.
[0007] Inhibition of TGF-P intracellular signaling pathway can be primarily recognized for treatment of fibroproliferative diseases and cancer. Fibroproliferative diseases mainly involve kidney disorders that are associated with dysregulation of TGF-P activity and excessive fibrosis. The excessive fibrosis includes glomerulonephritis (GN) in form of mesangial proliferative GN, immune GN, and crescentic GN. Diabetic nephropathy, renal interstitial fibrosis and renal fibrosis in transplant patients receiving cyclosporine, and HIV-associated nephropathy are other renal conditions with enhanced TGF-P activity. Dermatomyositis, Eosinophilic fasciitis (Shulman's Syndrome), morphea,

polymyositis, progressive systemic sclerosis, scleroderma, or those associated with the occurrence of Raynaud's syndrome are forms of collagen vascular disorders. In addition, excessive TGF-P activity can also contribute to lung fibroses that in turn include adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis and interstitial pulmonary fibrosis. Interstitial pulmonary fibrosis is usually associated with allergies, chemical contact, scleroderma and autoimmune disorders, such as systemic lupus erythematosus. Rheumatoid arthritis is another autoimmune disorder associated with fibroproliferative characteristics. Surgical eye procedures can also be linked with fibroproliferative conditions. These procedures include cataract extraction with intraocular lens implantation, post glaucoma drainage surgery and retinal reattachment surgery accompanying proliferative vitreoretinopathy.
[0008] Progression of various cancers is also mediated through members of the TGF-P superfamily (M. P. de Caestecker, E. Piek, and A. B. Roberts, J. National Cancer Inst., 92(17), 1388-1402 (2000) as these members are overexpressed significantly in many tumors. (Derynck, Trends Biochem. Sci., 1994, 19, 548-553). For example, TGF-pior ALK 5 is known to inhibit tumor formation by inhibition of the proliferation of non-transformed cells, however it promotes tumor growth once the tumor is formed. (N. Dumont and C. L. Arteaga, Breast Cancer Res., Vol. 2, 125-132 (2000)). Therefore, inhibition of the TGF-P pathway may be useful for the treatment of different types of cancer such as colorectal cancer, lung cancer and skin cancer. Particularly, TGF-P inhibition can be utilized for treatment of breast cancer, brain cancer, pancreatic cancer and glioma.
[0009] Many TGF-P inhibitors based on dihydropyrrolopyrazole, pyrazole, quinazoline, and imidazole cores were discovered by several companies including Eli Lilly, Scios, Biogen Idee, GlaxoSmithKline, Kyoto Pharmaceutical University and Kirin Brewery Company {Current Pharmaceutical Biotechnology, 2011, 72, 2190-2202). Among the reported small molecule TGF-P inhibitors, Eli Lilly's

LY2157299, Medpacto's TEW 7197 and Merck's M7824 were progressed to clinical trials. Fresolimumab, developed by Cambridge Antibody Technology, is a human monoclonal antibody targeting all isoforms of TGF-P which is currently in phase 2 clinical trials.
[00010] Small molecule modulator of TGF-P are described in patents/patent applications WO2005/065691 (PCT/US2004/043503), US 13 508090, WO2011/146287A1, WO2004/065392, WO2009/050183, and WO2009/133070 (see for more examples). Antibodies to TGF-P have been described in U.S. Pat.
Nos. 7,527,791; 7,927.593; 7,494,651; 7,369,111; 7,151,169; 6,492,497; 6,419,928; 6,090,383; 5,783,185; 5,772,998; 5,571,714; and 7,723,486.
[00011] There remains a continuing need for new therapies for the treatment of diseases and disorders related to the TGF-P dysregulation. Therefore, the present invention provides inhibitors of ALK 5.
SUMMARY OF THE INVENTION
[00012] In one aspect, the present invention provides a compound of formula (I):
Rl^Cy

O
formula (I), or a tautomer, salt, polymorph, solvate or stereoisomer thereof, wherein
x1
•2A-.
Cyis ^ A , wherein
X1 is N, CH or CR4; X2 is N, CH or CR5;

X3 is N, CH or CR6;
X4 is N, CH or CR7; wherein 0, 1 or 2 of X1, X2, X3 and X4 are N;
A is C6 aryl, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl or 5- to 6-membered heterocyclyl. wherein A is optionally substituted with 0 to 3 R9;
R1 is independently hydrogen, halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, -OR11, -NRUR12, -C(0)NR12R13, -C(0)Rn, -OC(0)Ru, -C(0)ORu, -OC(0)NR12R13, -NRnC(0)R12, -NRuC(0)OR12, -NRnC(0)NR12R13, -SRu,-S(0)Ru, -S(0)2Rn, -NRnS(0)R12, -C(0)NRnS(0)R12, -NRnS(0)2R12, -C(0)NRuS(0)2R12, -S(0)NR12R13, -S(0)2NR12R13, -(C1-C3 alkylene)CF3, -(C1-C3 alkylene)ORu, (Ci-C3 alkylene) cycloalkyl, -(C1-C3 alkylene)NR12R13, -(C1-C3 alkylene)C(0)Rn, -(C1-C3 alkylene)C(0)ORu, -(C1-C3 alkylene)C(0)NR12R13, -(C1-C3 alkylene) -C(0)ORu, -(C1-C3 alkylene)OC(0)NR12R13, -(C1-C3 alkylene)S(0)Rn or -(Ci-C3 alkylene)S(0)2Rn, wherein each R1 is optionally substituted with R10;
R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -C(O) R11 or -(C1-C3 alkylene)ORu;
or R1 and R2 are taken together with the atom to which they are attached to form a 5- to 7- membered heterocyclyl containing 1 to 3 heteroatom independently selected from N, O or S; each of which is optionally substituted by 0 to 3 R8;
R3 is hydrogen or C1-C6 alkyl;
R4, R5, R6 and R7 are independently hydrogen, halogen, oxo, -CN, Ci-C6 alkyl, C1-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, 3- to 6-membered heterocyclyl, 5- to 6- membered heteroaryl, -NRUR12 , -S(0)2NR12R13, -NRnS(0)2R12, -C(0)NR12R13, -NRnC(0)R12 or -C(0)ORn, each of which is optionally substituted by halogen, oxo, -CN, -OR15 or -NR15R16;

or R4 and R5 are taken together with the atom to which they are attached to form a 5- to 6- membered cycloalkyl or C6 aryl; or 5- to 6- membered heterocyclyl or heteroaryl containing 1 to 3 heteroatom independently selected from N, O or S; each of which is optionally substituted by 0 to 3 R8;
each R8 is independently hydrogen, halogen, oxo, -CN, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, 3- to 6-membered heterocyclyl, -NRUR12, -C(0)NR12R13, -NRnC(0)R12, -C(0)ORn, -OR11, -(C1-C3 alkylene)NRuR12 or -(C1-C3 alkylene)3- to 6-membered heterocyclyl, each of which is optionally substituted by C1-C6 alkyl, halogen, oxo, -CN, -OR15 or -NR15R16;
each R9is independently halogen, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C3 haloalkoxy, C1-C3 haloalkyl, -OR11, -NRUR12, -C(0)NR12R13, -C(0)Rn, -SR11, -S(0)R12 or -S(0)2Ru, each of which is optionally substituted by halogen, oxo, -CN, -OR15 or -NR15R16;
R10is independently hydrogen, halogen, oxo, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C3 haloalkoxy, C1-C3 haloalkyl, -OR15, -NR15 R16, -C(0)NR15 R16, -C(0)R15, -SR15, -S(0)R15 or -S(0)2R15;
R11, R12 and R13 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or -(C1-C3 alkylene)OR15, each of which is optionally substituted with C3-C6 cycloalkyl, halogen, oxo, C1-C3 alkoxy, 3- to 6-membered heterocyclyl, -OR15, -NR15R16, -C(0)NR15R16, -NR15C(0)R16, -C(O) R15, -S(0)2R15 -C(0)NR15S(0)2R16 or Ci-Ce alkyl optionally substituted by halogen, oxo, CN, -NH2 or -OH;
or R11 and R12 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by C1-C6 alkyl, halogen, oxo, -CN, -OR15 or -NR15R16;

or R and R are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by C1-C6 alkyl, halogen, oxo, -CN, -NH2 or -OH;
R15 and R16 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each is optionally substituted by C1-C6 alkyl, halogen, oxo, -CN, -NH2 or -OH;
or R15 and R16 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by halogen, oxo, -CN, -NH2 or -OH;
provided that:
i) when R1 is hydrogen and R4 and R5 are taken together with the atom to which they attached to form a 5- membered heteroaryl then R8 is other than 6-membered heterocyclyl; or
ii) when R3 is -CH3 then R4 or R7 is not -NRUR12.
[00013] In some embodiments, the compound of formula (I) or a tautomer, salt, polymorph, solvate or stereoisomer thereof, is a compound of formula (II), (II-A) to (II-X), (III), (III-A) to (III-P), (IV), (IV-A) to (IV-P), (V) or (V-A) to (V-L) or a tautomer, salt, polymorph, solvate or stereoisomer thereof, as detailed herein.
[00014] In another aspect, the present invention provides method of treating a disease or disorder associated with excessive activity of transforming growth factor beta (TGF-P), particularly type 1 or activin-like kinase 5 (ALK 5) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (I), (II), (II-A) to (II-X), (III), (III-A) to (III-P), (IV), (IV-A) to (IV-P), (V) or (V-A) to (V-L)), or a tautomer, salt, polymorph, solvate or stereoisomer thereof.
[00015] In another aspect, the present invention provides method of treating cancer in an individual in need thereof, wherein the method comprises

administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (I), (II), (II-A) to (II-X), (III), (III-A) to (III-P), (IV), (IV-A) to (IV-P), (V) or (V-A) to (V-L)), or a tautomer, salt, polymorph, solvate or stereoisomer thereof.
[00016] In another aspect, the present invention provides method of treating a disease or disorder associated with excessive activity of transforming growth factor beta (TGF-P), particularly type 1 or activin-like kinase 5 (ALK 5) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention (collectively, a compound of formula (I), (II), (II-A) to (II-X), (III), (III-A) to (III-P), (IV), (IV-A) to (IV-P), (V) or (V-A) to (V-L)), or a tautomer, salt, polymorph, solvate or stereoisomer thereof in combination with another therapeutic agent.
[00017] In another aspect, the present invention also provides pharmaceutical compositions, comprising a compound of the present invention (collectively, a compound of formula (I), (II), (II-A) to (II-X), (III), (III-A) to (III-P), (IV), (IV-A) to (IV-P), (V) or (V-A) to (V-L)) and at least one pharmaceutically acceptable excipient.
[00018] In another aspect, the present invention provides method of treating a disease or disorder associated with excessive activity of transforming growth factor beta (TGF-P), particularly type 1 or activin-like kinase 5 (ALK 5) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a pharmaceutical composition comprising a compound of the present invention (collectively, a compound of formula (I), (II), (II-A) to (II-X), (III), (III-A) to (III-P), (IV), (IV-A) to (IV-P), (V) or (V-A) to (V-L)), or a tautomer, salt, polymorph, solvate or stereoisomer thereof.
[00019] In another aspect, the present invention provides processes for preparing compounds and intermediates thereof disclosed in the present invention.

DETAILED DESCRIPTION OF THE INVENTION
Definitions
[00020] "Alkyl" refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a "C1-C20 alkyl"). More particular alkyl groups are those having 1 to 8 carbon atoms (a "Ci-Cs alkyl"), 3 to 8 carbon atoms (a "C3-C8 alkyl"), 1 to 6 carbon atoms (a "C1-C6 alkyl"), 1 to 5 carbon atoms (a "C1-C5 alkyl"), or 1 to 4 carbon atoms (a "C1-C4 alkyl"). Examples of alkyl include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
[00021] "Alkenyl" as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). The alkenyl group may be in "cis" or "trans" configurations, or alternatively in "E" or "Z" configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a "C2-C20 alkenyl"), having 2 to 8 carbon atoms (a "C2-C8 alkenyl"), having 2 to 6 carbon atoms (a "C2-C6 alkenyl"), or having 2 to 4 carbon atoms (a "C2-C4 alkenyl"). Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2-methylbuta-l,3-dienyl, homologs and isomers thereof, and the like.
[00022] "Alkylene" as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms (a "C1-C6 alkylene"), 1 to 5 carbon atoms (a "C1-C5 alkylene"), 1 to 4 carbon atoms (a "C1-C4 alkylene") or 1 to 3 carbon atoms (a "C1-C3 alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene

(-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), and the like.
[00023] "Alkynyl" as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a "C2-C20 alkynyl"), having 2 to 8 carbon atoms (a "C2-C8 alkynyl"), having 2 to 6 carbon atoms (a "C2-C6 alkynyl"), or having 2 to 4 carbon atoms (a "C2-C4 alkynyl"). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
[00024] "Aryl" refers to and includes polyunsaturated aromatic hydrocarbon groups. Aryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. In one variation, the aryl group contains from 6 to 14 annular carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.
[00025] "Carbonyl" refers to the group C=0.
[00026] "Cycloalkyl" refers to and includes cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantly, but excludes aryl groups. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.

[00027] "Halo" or "halogen" refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include fluoro, chloro, bromo and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be but are not necessarily the same halo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a "perhaloalkyl." A preferred perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).
[00028] "Heteroaryl" refers to and includes unsaturated aromatic cyclic groups
having from 1 to 10 annular carbon atoms and at least one annular heteroatom,
including but not limited to heteroatoms such as nitrogen, oxygen and sulfur,
wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen
atom(s) are optionally quaternized. A heteroaryl group can be attached to the
remainder of the molecule at an annular carbon or at an annular heteroatom.
Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including
additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings.
Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidyl,
imidazolyl,, pyrrolyl, pyrazolyl, 1,2,4-triazole, thiophenyl, furanyl, thiazolyl,
isothiazolyl, 1,3,4-thiadiazolyl oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, 1,2,3-
triazolyl, pyridazinyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl,
pyrazolopyridinyl, pyrazolopyrimidinyl, dihydropyrrolopyridinyl,
dihydrocyclopentapyridinyl, imidazopyridinyl, purinyl, quinolinyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, quinazolinyl, pyridopyrimidinyl, cinnolinyl and pyridopyridazinyl and the like.
[00029] "Heterocycle" or "heterocyclyl" refers to a saturated or an unsaturated non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4

annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heterocyclyl group may have a single ring or multiple condensed rings, but excludes heteroaryl groups. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl or heteroaryl. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, azepanyl tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.
[00030] "Oxo" refers to the moiety =0.
[00031] "ALK" refers to activin-like kinase, these include one or more like ALK1, ALK2, ALK3, ALK4, ALK5 or ALK6. More specifically the term "ALK"referestoALK5.
[00032] "TGF-beta" refers to transforming growth factor beta.
[00033] "Optionally substituted" unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents.
[00034] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[00035] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. For example, beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals. In reference to cancers or other unwanted cell proliferation, beneficial or desired results include shrinking a tumor (reducing tumor size); decreasing the growth rate of the tumor (such as to suppress tumor growth); reducing the number of cancer cells; inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibiting tumor growth; preventing or delaying occurrence and/or recurrence of tumor; and/or relieving to some extent one or more of the symptoms associated with the cancer. In some embodiments, beneficial or desired results include preventing or delaying occurrence and/or recurrence, such as of unwanted cell proliferation.
[00036] As used herein, "delaying development of a disease" means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.
[00037] As used herein, an "effective dosage" or "effective amount" of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and

intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In reference to cancers or other unwanted cell proliferation, an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay occurrence and/or recurrence. An effective amount can be administered in one or more administrations, in the case of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. An effective dosage can be administered in one or more administrations. For purposes of this disclosure, an effective dosage of compound or a salt thereof, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. It is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

We claim:

1.A compound of Formula (I):
RVCy
o
Formula (I), or a tautomer, salt, polymorph, solvate or stereoisomer thereof, wherein:
Cy is Y A , wherein
X1 is N, CH or CR4;
X2 is N, CH or CR5;
X3 is N, CH or CR6;
X4 is N, CH or CR7; wherein 0, 1 or 2 of X1, X2, X3 and X4 are N;
A is C6 aryl, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl or 5- to 6-membered heterocyclyl, wherein A is optionally substituted with 0 to 3 R9;
R1 is independently hydrogen, halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, C1-C3 alkoxy, Ci-C3haloalkoxy, Ci-C3haloalkyl, -OR11, -NRUR12, -C(0)NR12R13, -C(0)Rn, -OC(0)Ru, -C(0)ORu, -OC(0)NR12R13, -NRnC(0)R12, -NRuC(0)OR12, -NRnC(0)NR12R13, -SRu,-S(0)Ru, -S(0)2Rn, -NRnS(0)R12, -C(0)NRnS(0)R12, -NRnS(0)2R12, -C(0)NRuS(0)2R12, -S(0)NR12R13, -S(0)2NR12R13, -(C1-C3 alkylene)CF3, -(C1-C3 alkylene)ORu, (Ci-C3 alkylene) cycloalkyl, -(C1-C3 alkylene)NR12R13, -(C1-C3 alkylene)C(0)Rn, -(C1-C3 alkylene)C(0)ORu, -(C1-C3 alkylene)C(0)NR12R13, -(C1-C3 alkylene)

-C(0)ORu, -(C1-C3 alkylene)OC(0)NR12R13, -(C1-C3 alkylene)S(0)Rn or -(Ci-C3 alkylene)S(0)2Ru, wherein each R1 is optionally substituted with R10;
R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -C(O) R11 or -(C1-C3 alkylene)ORu;
or R1 and R2 are taken together with the atom to which they are attached to form a 5- to 7- membered heterocyclyl containing 1 to 3 heteroatom independently selected from N, O or S; each of which is optionally substituted by 0 to 3 R8;
R3 is hydrogen or C1-C6 alkyl;
R4, R5, R6 and R7 are independently hydrogen, halogen, oxo, -CN, Ci-C6 alkyl, C1-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, 3- to 6-membered heterocyclyl, 5- to 6- membered heteroaryl, -NRUR12, -S(0)2NR12R13, -NRnS(0)2R12, -C(0)NR12R13, -NRnC(0)R12 or -C(0)ORn, each of which is optionally substituted by halogen, oxo, -CN, -OR15 or -NR15R16;
or R4 and R5 are taken together with the atom to which they are attached to form a 5- to 6- membered cycloalkyl or C6 aryl; or 5- to 6- membered heterocyclyl or heteroaryl containing 1 to 3 heteroatom independently selected from N, O or S; each of which is optionally substituted by 0 to 3 R8;
each R8 is independently hydrogen, halogen, oxo, -CN, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, 3- to 6-membered heterocyclyl, -NRUR12, -C(0)NR12R13, -NRnC(0)R12, -C(0)ORn, -OR11, -(C1-C3 alkylene)NRuR12 or -(C1-C3 alkylene)3- to 6-membered heterocyclyl, each of which is optionally substituted by C1-C6 alkyl, halogen, oxo, -CN, -OR15 or -NR15R16;
each R9is independently halogen, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C3 haloalkoxy, C1-C3 haloalkyl, -OR11, -NR11 R12, -C(O) NR12 R13, -C(O) R11,, -SR11, -S(0)R12 or -S(0)2Ru, each of which is optionally substituted by halogen, oxo, -CN, -OR15 or -NR15R16;

R is independently hydrogen, halogen, oxo, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C1-C3 haloalkoxy, C1-C3 haloalkyl, -OR15, -NR15 R16, -C(O) NR15 R16, -C(O) R15, -SR15, -S(0)R15 or -S(0)2R15;
R11, R12 and R13 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or -(C1-C3 alkylene)OR15, each of which is optionally substituted with C3-C6 cycloalkyl, halogen, oxo, C1-C3 alkoxy, 3- to 6-membered heterocyclyl, -OR15,, -NR15R16, -C(0)NR15R16, -NR15C(0)R16, -C(0)R15, -S(0)2R15 -C(0)NR15S(0)2R16 or Ci-Ce alkyl optionally substituted by halogen, oxo, CN, -NH2 or -OH;
or R11 and R12 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by C1-C6 alkyl, halogen, oxo, -CN, -OR15 or -NR15R16;
or R12 and R13 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by C1-C6 alkyl, halogen, oxo, -CN, -NH2 or -OH;
R15 and R16 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each is optionally substituted by C1-C6 alkyl, halogen, oxo, -CN, -NH2 or -OH; or
or R15 and R16 are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl optionally substituted by halogen, oxo, -CN, -NH2 or -OH;
provided that:
i) when R1 is hydrogen and R4 and R5 are taken together with the atom to which they attached to form a 5- membered heteroaryl then R8 is other than 6-membered heterocyclyl; or
ii) when R3 is -CH3 then R4 or R7 is not -NRUR12.

V^Y3
The compound as claimed in the claim 1, wherein Cy ^ A
wherein:
Jtss.
X1 is N, CH or CR4;
X2 is N, CH or CR5;
X3 is N, CH or CR6;
X4 is N, CH or CR7; wherein 0, 1 or 2 of X1, X2, X3 and X4 are N;
R4, R5, R6 and R7 are independently hydrogen, halogen, oxo, -CN, Ci-C6 alkyl, C1-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, 3- to 6-membered heterocyclyl, 5- to 6- membered heteroaryl, -NRUR12 , -S(0)2NR12R13, -NRnS(0)2R12, -C(0)NR12R13, -NRnC(0)R12 or -C(0)ORn, each of which is optionally substituted by halogen, oxo, -CN, -OR15 or -NR15R16;
R11, R12, R13, R15 and R16 are as defined in claim 1;
provided that when R3 is -CH3 then R4 or R7 is not -NRUR12.
,A°3X<
3. The compound as claimed in the claim 1, wherein Cy Y A
wherein:
X1 is CR4;
X2 is CR5;
X3 is N, CH or CR6;
X4 is N, CH or CR7; wherein 0, 1 or 2 of X1, X2, X3 and X4 are N;
R4 and R5 are taken together with the atom to which they attached to form a 5- membered cycloalkyl; or 5- membered heterocyclyl or heteroaryl containing 1 to 3 heteroatom independently selected from N, O or S; each of which is optionally substituted by 0 to 3 R8;
R6 R7 and R8 are as defined in claim 1;

provided that when R1 is hydrogen and R4 and R5 are taken together with the atom to which they attached to form a 5- membered heteroaryl then R8 is other than 6-membered heterocyclyl.
x1
\^x3'
J2&
4. The compound as claimed in the claim 1, wherein Cy
wherein:
X1 is CR4;
X2 is CR5;
X3 is N, CH or CR6;
X4 is N, CH or CR7; wherein 0, 1 or 2 of X1, X2, X3 and X4 are N;
R4 and R5 are taken together with the atom to which they attached to form a 6- membered cycloalkyl or C6 aryl; or 6- membered heterocyclyl or heteroaryl containing 1 to 3 heteroatom independently selected from N, O or S; each of which is optionally substituted by 0 to 3 R8;
R6, R7 and R8 are as defined in claim 1.
5. The compound as claimed in the claim 2, wherein Cy is selected from
R4
^N r^N r^N f^N
^XJ ^ ^N ^J
J^H
the group consisting of
R4 R4
ii
, and
The compound of claim 5, wherein R4 is selected from the group
H H /\ H H
VNY" vNY^ VN^^CF3 VNY^f^>
consisting of-NH2, ° , ° , ° ° *^A

v v< v«v ,ACN Av ^ Y» vN/>
o V V^ N-y N-N N-N

H H H H r-n H f^P
VN^°v VN^Nv VN^sv JC/ VN-^H
N-J\ N^/0r N^\ ^ 0_ or O
H
vv
7. The compound as claimed in the claim 5, wherein R4 is ° .
8. The compound as claimed in the claim 5, wherein R5 is selected from
the group consisting of, -CN, F, ^ NH2, H I , H
o o r0H o r0H o
V^N^OOH \AN^OH \Al^ \^N^<0H
H /\ H H H /1 11 1
O
XX^ X1NC V*p VXH^HH,
H H y H
5 5 5 1
XX ^ v^B^V Y^°H \AN^°.
" o "OH H
1 111
5 5 5 5
OH
A0 vl^ Y*0 VV^ ^
O OH
^ A /\ O r-^0H O r\ O o
^^OH H H H

-o P
XXN£? XANX> V^° ^SP OH
H H " OV H |

OH s ^N
0 0 0 0
\ANyoH VS^NH2 XANMNH2 V^N VH v^
H O H H I H
5 5 5 ;
O O I H
ys".N^OH V"
H
H
VN~A o o

H I H
V
OH ^^N^^^OH N ^ OH
O H
0*0

N' ^OH V*V ^OH
I
O O
1 1
o , . P, O

V^o-
o o
^H^or^H^OH
9. The compound as claimed in the claim 5, wherein R5 is selected from
0 ° 1 ° r0H
^UY" V^N^°H \^N^°H
the group consisting of
O

,A
or
H or V^NH2

10.
The compound as claimed in the claim 3, wherein Cy is selected from
(R8)0-3 (R8>0-3 (R8)0-3 (R8)O-3
-NH
the group consisting of


(R8)o-:
N
(R8)o-3
N
HN

0-3
(R8),
HN
XJ

11.

The compound as claimed in the claim 3, wherein Cy is selected from

the group consisting of

/7-NH N-NH N-NH
V^N S^N V^N NV^N NV^N
\/-N- V
\/-N- V
AA AJ1 AA AJ1 AA
\^N'



,«- K^}R )o-3 T^
o^x Tr^X «^ythe groups consisting of, * '°-3, "N , * '°-3,

/^N /
> CN JQ A^v(RV
^X(R9)0-3 V)0-3 V)0-3 O-lf
5 5 5
/\^\ /\^N A^-M A
N A ^ A \N Hii \N
w yC U^X. U^ys. HN^X
(R )o-3 C )o-3 C )o-3 C )()■
5 5 5
A^ti J Q <£ (R9)o-3 A^^.N

3

(R9)o-3 HN./ ^B X(RV3
5 5 5 5
AN-VR9>o-3 T^ AN^/(R9)O-3 £^J*>»
J, ^> ^N' I ^> T />
N^/ H W HN-Jf
1 111
20. The compound as claimed in the claim 16, wherein A is selected from
the groups consisting of \ S^y S-^y


5 5 :



N N /N^
/

A^N A^N c J J AN^N
l/> •/>
XNV HA,/ M >,r" >-^~ N~N\ N~Nx
5 5 5 5 5 5
"Vv \> ^ M ^ AD M
\ \ \ \ \ \ NV
5 5 5 5^5
/x£^_ ^ A^_ 1^- "K^ ^

•^N'^

*d- M M ^ ^> ^