Kinase inhibitors

Abstract

The present disclosure relates to kinase inhibitors, in particular TNIK and / or MAP4K4 kinase inhibitors, which may include: Formula A, derivatives, prodrugs, salts, stereoisomers, tautomers, polymorphs or solvates thereof, or having chirality at any chiral center wherein: Ring 1 is an aromatic ring with or without a heteroatom; ring 2 is a heteroaromatic ring; ring 3 comprises at least one heteroaromatic ring and optionally at least one cycloaliphatic ring fused with the at least one heteroaromatic ring; ring 4 is an aromatic ring having or not having a heteroatom; y is a bond or a linker; y1 is a connector; each n is independently 0, 1 or 2; each o is independently 0, 1, 2, 3, 4 or 5; r1, R6, R11 and R12 are each independently a substituent group; and RA is a ring structure, a linear aliphatic group or a branched aliphatic group, which may be substituted or unsubstituted, either with or without a heteroatom.

Description

[0001] This application is a divisional application of Chinese patent application No. 202080030624.1, filed on February 21, 2020, entitled "Kinetic Inhibitor" (the corresponding PCT application was filed on February 21, 2020, and has the application number PCT / IB2020 / 051451).

[0002] Cross-referencing

[0003] This application claims priority to U.S. Provisional Application No. 62 / 809,413, filed February 22, 2019, the entire contents of which are incorporated herein by reference. Background Technology

[0004] The bioactive enzyme known as the TRAF2 and NCK-interacting protein kinase is an enzyme commonly referred to as TNIK kinase in humans, and it is encoded by the TNIK gene. TNIK kinase is involved in a variety of biological processes common to serine / threonine kinases, such as acting as an activator of the Wnt signaling pathway. TNIK kinase is recruited to the promoters of Wnt target genes and may be required to activate their expression. TNIK kinase may function by phosphorylating TCF4 / TCF7L2. TNIK kinase appears to function upstream of the JUNN-terminal pathway. TNIK kinase may play a role in responses to environmental stresses. It is also part of a signaling complex composed of NEDD4, RAP2A, and TNIK, which regulates neuronal dendritic extension and branching during development. More generally, TNIK may play a role in cytoskeletal rearrangement and regulating cell diffusion. TNIK kinase also phosphorylates SMAD1 on Thr-322.

[0005] TNIK kinase is also considered to be a germinal center kinase (GCK), characterized by an N-terminal kinase domain and a C-terminal GCK domain with regulatory functions.

[0006] TNIK kinase activation in Wnt signaling plays a crucial role in oncogenesis and embryonic development. Mutations in this gene are associated with an autosomal recessive form of cognitive impairment.

[0007] Furthermore, TNIK kinases are associated with colorectal cancer and other potential cancers. Therefore, TNIK kinases have been identified as an attractive candidate for drug targeting in colorectal cancer.

[0008] Current data suggest that TNIK kinases are potential targets for generating small molecule inhibitors to specifically block the Wnt pathway in disease states such as colorectal cancer or autosomal recessive cognitive impairment.

[0009] Furthermore, it is well known that TGF-β-activated EMT can be inhibited by attenuating Smad and non-Smad signaling pathways, including Wnt, NF-κB, FAK-Src-pile associated focal adhesion, and MAP kinase (ERK and JNK) signaling pathways. Therefore, EMT-related therapeutic targets, such as TNIK as an inhibitory target, could be used to treat and / or prevent EMT-based diseases, such as cancer metastasis and fibrosis.

[0010] Therefore, TNIK inhibitors that can inhibit TNIK activity would be advantageous. Specific TNIK inhibitors that selectively inhibit TNIK would also be advantageous. Summary of the Invention

[0011] In some embodiments, methods for inhibiting TNIK kinase and / or MAP4K4 kinase may include contacting TNIK kinase with a compound having the structure of formula A or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph or its solvate, or any chirality having any chiral center.

[0012]

[0013] In some respects: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a heteroaromatic ring; ring 3 comprises at least one heteroaromatic ring and at least one alicyclic ring optionally fused with at least one heteroaromatic ring; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or linker; Y 1 It is a connector; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; R 1 R 6 R 11 and R 12 Independently substituent; and R A It can be a cyclic structure, a straight-chain aliphatic chain, or a branched aliphatic chain, and can be substituted or unsubstituted, with or without heteroatoms. On the one hand, R 11 and R 12 It is absent or contains hydrogen. In some respects, at least one of ring 1 or ring 4 is at least 1.

[0014] In some embodiments, ring 1 is phenyl or pyridyl; ring 2 is a 5- or 6-membered heteroaromatic ring, or a combination thereof; ring 3 comprises a 5-membered heteroaromatic ring or a 5-membered heteroaromatic ring fused with a 6-membered heteroaromatic ring, said 6-membered heteroaromatic ring being fused with a 5-membered alicyclic ring, wherein the bond to Y is through a 5-membered heterocyclic aromatic ring or a combination thereof; ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine, or a combination thereof; Y is a bond or an aliphatic linker; Y 1 It is an amide connector; and R AIt is an alicyclic ring, a heterocyclic ring, a straight-chain aliphatic ring, or a branched aliphatic ring, which may be substituted or unsubstituted, have or not have heteroatoms, or a combination thereof.

[0015] In some embodiments, ring 1 is phenyl or pyridyl, and when ring 1 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; ring 2 is furanyl, thiophene, pyrroloyl, oxacyclopentanyl, thiazolyl, imidazolyl, triazolyl, or pyridyl; ring 3 is imidazolyl, triazolyl, or cyclopentadienylpyrrolopyridyl fused ring; or cyclopentadienylfuranolpyridyl; ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine, and when ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; when ring 4 is pyrimidinyl, the nitrogen atom is located at the meta or ortho position in the ring; Y is a bond or a mono- to 6-membered aliphatic chain; Y 1 It is a substituted or unsubstituted amide, iminosulfonamide, ketone, formamide linker, or combination thereof; and R A It can be a 3- to 6-membered alicyclic ring, a 5- to 6-membered heterocyclic ring; a 1- to 12-membered straight-chain alicyclic chain, or a 1- to 12-membered branched alicyclic chain, any of which can be substituted or unsubstituted, and any alicyclic chain can have or not have heteroatoms.

[0016] In some implementation schemes, R 1 R 6 R 11 and R 12 Each of these groups independently comprises hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, acetyl (i.e., CH3C=O), propionyl, butyryl, acetamide (i.e., acetamido), propionamide, butyrylamide, pentamide, hexamide, heptamide, octylamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, heptyl ester, octyl ester, methyl thioalkyl (i.e., thiomethyl), ethyl thioalkyl, propyl thioalkyl, butyl thioalkyl, pentyl thioalkyl, hexyl thioalkyl, heptyl thioalkyl, or octyl thioalkyl. In some aspects, R 11 and R 12 It is hydrogen or it does not exist.

[0017] In some embodiments, methods for inhibiting TNIK kinase and / or MAP4K4 kinase may include contacting TNIK kinase and / or MAP4K4 kinase with compounds having the structure of formula A1 or A2 or derivatives thereof, their prodrugs, their salts, their stereoisomers, their tautomers, their polymorphs or their solvates, or any chirality having any chiral center.

[0018]

[0019] In some respects: R A It is a ring structure, a straight-chain aliphatic ring, or a branched aliphatic ring, any of which may be substituted or unsubstituted, and any may or may not have heteroatoms; ring D is a ring structure in which one or more rings are linked together; X 1 X 2 X 3 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 and X 14 Each is independently a carbon or heteroatom with or without substituents; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is an independent substituent; Y is a bond or linker; Y 1 It is a connector; m is 1, 2, or 3; and n is 0, 1, or 2. In some respects, when the X group in the aromatic ring is N, the R group bonded to it is not present. In some respects, n is 0 and R... 11 and / or R 12 Neither of them exists. If they exist, R 11 and / or R 12 It can be on any suitable ring atom in any ring. When n is 0, then the bond and R 11 and / or R 12 It does not exist. In some respects, R A The ring is directly connected to X 1 For example, through a covalent bond (i.e., Y). When R A When it is a ring, it can be any alicyclic or heterocyclic group, or a combination thereof.

[0020] In some embodiments, the method may include administering a compound of the structure of formula 1A, 2A, 3A, 4A or 5A or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph or its solvate, or any chirality having any chiral center.

[0021]

[0022] In some respects: in Formula 1A, A is a ring structure with or without heteroatoms, which may be substituted or unsubstituted; in Formula 3A, B is a ring structure having at least one heteroatom, either substituted or unsubstituted; and in Formula 4A, R 13 It is a straight-chain aliphatic or branched-chain aliphatic ...

[0023] In some embodiments, ring A is an alicyclic or heterocyclic alicyclic group or a combination thereof, which may be substituted or unsubstituted by the R group. In some aspects, ring B can only be a heterocyclic alicyclic group. In some aspects, R... 13 Independently as a substituent, for example, for R 11 Those described. X 1 and / or X 2 It is CH or N. X 3 It is CH2, NH, O, or S. X 6 X 7 X 8 X 9 X 10 X 11 X 12 and / or X 13 It is CH or N. X 14 It is O or NH. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each of the following is independently hydrogen, halogen, hydroxyl, alkoxy, straight-chain aliphatic, branched-chain aliphatic, cyclic aliphatic, substituted aliphatic, unsubstituted aliphatic, saturated aliphatic, unsaturated aliphatic, aromatic, polyaromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, fatty amine, carbonyl, carboxyl, amide, ester, amino acid, or derivative thereof, either substituted or unsubstituted, or a combination thereof.

[0024] In some embodiments: ring A is an alicyclic ring having 3-12 ring atoms, a heterocyclic ring having 3-12 ring atoms, or a combination thereof, which may be substituted or unsubstituted; ring B is a heterocyclic ring having 3-12 ring atoms, which may be substituted or unsubstituted; ring D is a polycyclic ring having at least one aromatic ring fused with a cyclic alicyclic ring; X 1 and / or X 2It is CH or N; X 3 It is CH2, NH, O, or S; X 6 X 7 X 8 X 9 X 10 X 11 X 11 X 12 and / or X 13 It is CH or N; X 6 X 7 X 8 X 9 X 10 X 11 X 11 X 12 and / or X 13 It is CH, N, or O; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each of these groups independently represents hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, halogen, hydroxyl, mercapto, alkoxy, alkenyloxy, alkynoxy, aryloxy, acyl, alkyl carbonyl, aryl carbonyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, halocarbonyl, alkyl carbonate, aryl carbonate, carboxyl, carboxylic acid group, carbamoyl, mono(alkyl)-substituted carbamoyl, di(alkyl)-substituted carbamoyl, mono-substituted aryl carbamoyl, thiocarbamoyl, urea, cyano, isocyano, cyanate group, isocyanate, isothiocyanate, sigmacyanate, etc. Nitro, formyl, thioformyl, amino, monoalkyl-substituted amino and dialkyl-substituted amino, monoaryl-substituted amino and diaryl-substituted amino, alkylamide, arylamide, imino, alkylimino, arylimino, nitro, nitrosyl, sulfonyl, sulfonate, alkylthioalkyl, arylthioalkyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphonyl, phosphonate, phosphonite, phosphoryl, phosphonite, any having or not having a heteroatom, its derivatives, any substituted or unsubstituted, and combinations thereof. In some aspects, R 13 It is a C1-C24 straight-chain aliphatic or branched aliphatic compound, which may be substituted or unsubstituted, and may or may not have heteroatoms.

[0025] In some embodiments: ring A is an alicyclic ring having 3-6 ring atoms, a heterocyclic ring having 3-6 ring atoms, or a combination thereof, which may be substituted or unsubstituted; ring B is a heterocyclic ring having 3-6 ring atoms, which may be substituted or unsubstituted; ring D is cyclopentadienpyridine; X 1 and X 2 It is N; X 3 It is O or NH; X 4 It is NH; X 5 It is O; X 6 X 7 X 8 X 9 X 10 X 11 and / or X 12 It is CH or N; X 13 For N; X 14 It is O or NH; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is independently selected from hydrogen, C1-C 24 Alkyl, C2-C 24 alkenyl, C2-C 24 alkynyl group, C5-C 20 Aryl, C6-C 24 Alkyl, C6-C 24 Aryl groups, halogens, hydroxyl groups, mercapto groups, C1-C 24 Alkoxy, C2-C 24 Alkenyl groups, C2-C 24 Acryloxy group, C5-C 20 aryloxy group, acyl group, acyloxy group, C2-C 24 Alkoxycarbonyl, C6-C 20 aryloxycarbonyl, halocarbonyl, C2-C 24 Alkyl carbonate, C6-C 20 aryl carbonate, carboxyl, carboxylate, carbamoyl, mono(C1-C) 24 alkyl)-substituted carbamoyl, di(C1-C 24 Alkyl-substituted carbamoyl, monosubstituted aryl carbamoyl, disubstituted aryl carbamoyl, thiocarbamoyl, mono(C1-C2) car ... 24 alkyl)-substituted thiocarbamoyl, di(C1-C 24Alkyl-substituted thiocarbamoyl, monosubstituted aryl thiocarbamoyl, disubstituted aryl thiocarbamoyl, urea, mono(C1-C) 24 Alkyl)-substituted urea group, di(C1-C 24 Alkyl-substituted urea group, monosubstituted arylurea group, disubstituted arylurea group, isocyanate group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, azide group, formyl group, thioformyl group, amino group, mono(C1-C) substituted urea group, mono(C1-C) substituted urea group, monosubstituted arylurea group, disubstituted arylurea group, isocyanate group, cyanate group, isocyanate group, isothiocyanate group, azide group, formyl group, thioformyl group, amino group, mono(C1-C) substituted urea group, monosubstituted aryl ... 24 alkyl)-substituted amino and di(C1-C) 24 Alkyl) substituted amino, mono(C5-C) 20 aryl)-substituted amino groups and di(C5-C) 20 aryl-substituted amino groups, C2-C 24 Alkylamide group, C6-C 20 Arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfonic acid, sulfonate, C1-C 24 Alkyl thioalkyl, C5-C 20 arylthioalkyl, C1-C 24 Alkyl sulfinyl, C5-C 20 Arylsulfinyl, C1-C 24 Alkyl sulfonyl, C5-C 20 Arylsulfonyl, phosphonyl, phosphonate, phosphonite, phosphoryl, phosphonite, any one or more substituents having or not having heteroatoms, any substituted or unsubstituted, their derivatives and combinations thereof; and R 13 It is a C1-C12 straight-chain aliphatic or branched aliphatic compound, which may be substituted or unsubstituted, and may or may not have heteroatoms.

[0026] In some implementation schemes, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12Each of the following is independently H, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, acetyl (i.e., acetyl, CH3C=O), propionyl, butyryl, acetamide (i.e., acetamido), propionamide, butyrylamide, pentamide, hexamide, heptamide, octylamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methyl thioalkyl (i.e., thiomethyl), ethyl thioalkyl, propyl thioalkyl, butyl thioalkyl, pentyl thioalkyl, hexyl thioalkyl, heptyl thioalkyl, or octyl thioalkyl.

[0027] In some implementations, inhibition of TNIK can suppress certain TNIK-related biological pathways. In some aspects, TNIK inhibition suppresses the Wnt pathway. In some aspects, TNIK inhibition suppresses cytoskeleton rearrangement. In some aspects, TNIK inhibition suppresses carcinogenesis. In some aspects, TNIK inhibition suppresses embryonic development. In some aspects, TNIK inhibition suppresses colorectal cancer. In some aspects, TNIK inhibition suppresses TGFβ signaling. In some aspects, TNIK inhibition suppresses glycosaminoglycan formation. In some aspects, TNIK inhibition suppresses collagen formation. In some aspects, TNIK inhibition suppresses fibrosis.

[0028] In some implementations, inhibiting MAP4K4 kinase can suppress certain MAP4K4 pathways. MAP4K4 is involved in a wide range of physiological processes, including cell migration, proliferation, and adhesion; therefore, inhibition of MAP4K4 can suppress these processes. Consequently, compounds acting as MAP4K4 inhibitors may possess activities that inhibit systemic inflammation, metabolic disorders, cardiovascular disease, and cancer.

[0029] In some embodiments, the TNIK kinase and / or MAP4K4 kinase compound may include: a structure of formula A or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph or its solvate, or any chirality having any chiral center.

[0030] In some respects: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a heteroaromatic ring; ring 3 comprises at least one heteroaromatic ring and at least one alicyclic ring optionally fused with at least one heteroaromatic ring; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or linker; Y 1 It is a connector; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; R 1 R 6 R 11 and R12 Each is an independent substituent. In some respects, the compound includes at least one of the following: Y 1 It is an amide with nitrogen bonded to ring 1 and carbon bonded to ring 2; for Y, the compound includes at least one of the following: when Y is a bond, R A It is a C3 alicyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, any of which may be substituted or unsubstituted; or when Y is the chemical part, R A It is a C3 alicyclic ring, a 5-membered alicyclic ring, a 5-membered heterocyclic ring, a 6-membered alicyclic ring, a 6-membered heterocyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, which may be substituted or unsubstituted and have or not have heteroatoms; or the compound includes at least one of the following: when ring 1 is phenyl, at least one of the following: ring 2 is not furanyl; ring 3 is not imidazolyl; or ring 4 is not phenyl; when ring 2 is furanyl, at least one of the following: ring 1 is not phenyl; ring 3 is not imidazolyl; or ring 4 is not phenyl; when ring 3 is imidazolyl, at least one of the following: ring 1 is not phenyl; ring 2 is not furanyl; or ring 4 is not phenyl; or when ring 4 is phenyl, at least one of the following: ring 1 is not phenyl; ring 2 is not furanyl; or ring 3 is not imidazolyl.

[0031] In some aspects, ring 1 is phenyl or pyridyl; ring 2 is a 5- or 6-membered heteroaromatic ring; ring 3 comprises a 5-membered heteroaromatic ring or a 5-membered heteroaromatic ring fused with a 6-membered heteroaromatic ring, said 6-membered heteroaromatic ring being fused with a 5-membered alicyclic ring, wherein the bond to Y is through the 5-membered heteroaromatic ring; ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine; Y is a bond or an aliphatic linker; Y 1 It is an amide connector; and R A It is an alicyclic ring, a heterocyclic ring, a straight-chain aliphatic ring, or a branched aliphatic ring, which can be substituted or unsubstituted, and can have or not have heteroatoms, wherein when Y is a bond, R A It is not a 5-membered alicyclic ring.

[0032] In some embodiments, ring 1 is phenyl or pyridyl, and when ring 1 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; ring 2 is furanyl, thiophene, pyrroloyl, oxazoloyl, thiazolyl; imidazolyl, triazolyl, or pyridyl; ring 3 is imidazolyl, triazolyl, or cyclopentadienylpyrrolopyridyl fused ring group; or cyclopentadienylfuranylpyridyl; ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine, and when ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; when ring 4 is pyrimidinyl, nitrogen is located at the meta or ortho position in the ring; Y is a bond or a mono- to 6-membered aliphatic compound; Y 1 It is an amide connector; and when Y is a mono- to sept-ary (e.g., C1-C6) aliphatic connector, R AThese are 3- to 6-membered (e.g., C3-C6) alicyclic rings, 5- to 6-membered (e.g., C5-C6) heterocyclic rings; 1- to 12-membered (e.g., C1-C6) rings. 12 Straight-chain aliphatic or C1-C 12 Branched aliphatic chains, which may be substituted or unsubstituted, either having or not having heteroatoms, or when Y is a bond, R A It is not a 5- to 6-membered (e.g., non-C6-C6) alicyclic ring.

[0033] In some implementation schemes, R 1 R 6 R 11 and R 12 Each of these groups independently represents F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, acetyl (i.e., CH3C=O), propionyl, butyryl, acetamide (i.e., acetamido), propionamide, butyramide, pentamide, hexamide, heptamide, octylamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methyl thioalkyl (i.e., thiomethyl), ethyl thioalkyl, propyl thioalkyl, butyl thioalkyl, pentyl thioalkyl, hexyl thioalkyl, heptyl thioalkyl, or octyl thioalkyl. In some aspects, R 11 and R 12 It is hydrogen or it does not exist.

[0034] In some embodiments, TNIK kinase and / or MAP4K4 kinase can be compounds, including: structures of formula A1 or A2 or derivatives thereof, their prodrugs, their salts, their stereoisomers, their tautomers, their polymorphs or their solvates, or any chirality having any chiral center.

[0035]

[0036] In some respects: R A It is a C3 alicyclic, 4- to 12-membered (e.g., C4-C) 12 Heterocyclic alicyclic, straight aliphatic chain, or branched aliphatic chain, any substituted or unsubstituted, wherein the C3 alicyclic, straight aliphatic, or branched aliphatic chain has or does not have heteroatoms; ring D is a ring structure in which one or more rings are fused together; R 1 R 2 R 3 R 5 R 6 R 7 R 8 R 9R 10 R 11 and R 12 Each is an independent substituent; X 1 X 2 X 3 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 and X 14 Each is independently carbon or a heteroatom with or without substituents; Y is a bond or linker; Y 1 It is a connector; m is 1, 2, or 3; and n is 0, 1, or 2. In some respects, when the X group in the aromatic ring is N, the R group bonded to it does not exist.

[0037] The foregoing overview is illustrative only and is not intended to be limiting in any way. Further aspects, embodiments, and features will become apparent from the following detailed description, in addition to the illustrative aspects, embodiments, and features described above. Detailed Implementation

[0038] The illustrative embodiments described in the detailed description and claims are not intended to be limiting. Other embodiments may be utilized and other changes may be made without departing from the spirit or scope of the subject matter set forth herein. It will be readily understood that aspects of this disclosure as generally described herein and shown in the chemical structures can be arranged, substituted, combined, separated, and designed in a variety of different configurations, all of which are expressly contemplated herein.

[0039] Generally, this invention relates to at least one molecule that acts as a kinase inhibitor, such as TNIK kinase and / or MAP4K4 kinase. Therefore, the molecules described herein can be used in methods related to TNIK inhibition to inhibit the biological activity of TNIK, thereby inhibiting biological pathways associated with TNIK activation. Therefore, the molecule can be used in therapeutic methods that inhibit TNIK to provide treatment to a subject administering the molecule. Thus, the molecules described herein may each be referred to as TNIK kinase inhibitors, some of which may be broad-spectrum inhibitors of many kinases, and some are specific inhibitors of specific kinases such as TNIK kinase and / or MAP4K4 kinase.

[0040] method

[0041] Therefore, TNIK kinase inhibitors can be used to inhibit biological pathways downstream of TNIK inhibition. In some respects, TNIK inhibitors can inhibit fibrous collagen, thereby suppressing biological activities associated with the regulation and remodeling of the extracellular matrix. TNIK inhibitors can also inhibit the regulation of cell growth, differentiation, cell migration, proliferation, and metabolism.

[0042] In some implementations, inhibiting TNIK can suppress certain TNIK-related biological pathways. In some respects, TNIK inhibition suppresses the Wnt pathway.

[0043] In some implementations, inhibition of TNIK suppresses cytoskeletal rearrangement. Inhibition of TNIK can suppress the c-Jun N-terminal kinase pathway. Inhibition of TNIK can suppress phosphorylation of colloid proteins. Inhibition of TNIK can suppress cytoskeletal regulation, such as cytoskeletal rearrangement.

[0044] In some implementations, TNIK inhibition suppresses cancer development. In some aspects, the administration of a TNIK inhibitor comprises a therapeutically effective amount of a compound sufficient to treat the cancer by: inhibiting cancer cell growth; inhibiting cancer cell migration; inhibiting cancer cell proliferation; or inhibiting cancer cell migration. In some aspects, the cancer is colorectal cancer.

[0045] In some implementations, TNIK inhibition suppresses embryonic development. Therefore, TNIK inhibitors can suppress the pregnancy process, thereby terminating the pregnancy.

[0046] In some implementations, inhibition of TNIK suppresses TGFβ signaling. The TGFβ signaling pathway involves multiple processes, and inhibiting the TGFβ signaling pathway can suppress these processes, some of which are described herein. This can include inhibiting embryonic development as described herein for the purpose of suppressing pregnancy progression. This can include inhibiting cell growth, cell differentiation, which can be used to suppress pregnancy progression and cancer.

[0047] In some implementations, inhibition of TGFβ signaling can be used to suppress the formation or excessive formation of the extracellular matrix and related problems (e.g., fibrosis). In some aspects, TGFβ signaling is inhibited by inhibiting TNIK, thus suppressing glycosaminoglycan formation. In some aspects, TGFβ is inhibited by inhibiting TNIK, thus suppressing collagen formation. In some aspects, inhibition of TNIK inhibits fibrosis. In some respects, the suppressed fibrosis is selected from pulmonary fibrosis (e.g., idiopathic or radiation-induced), cystic fibrosis, liver fibrosis (e.g., cirrhosis), myocardial fibrosis (e.g., atrial fibrosis, endocardial myocardial fibrosis, old myocardial infarction), renal fibrosis, cerebral fibrosis (e.g., glial scars), arterial fibrosis, joint fibrosis (e.g., knee, shoulder, other joints), intestinal fibrosis (e.g., Crohn's disease), Duchenne contracture fibrosis (e.g., hand, fingers), keloid fibrosis (e.g., skin), mediastinal fibrosis (e.g., mediastinal soft tissue), myelofibrosis (e.g., bone marrow), Peronis disease fibrosis (e.g., penis), progressive massive fibrosis (e.g., lung, complications of coal worker's pneumoconiosis), retroperitoneal fibrosis (e.g., retroperitoneal soft tissue), sclerodermatic fibrosis (e.g., skin, lung), adhesive capsulitis fibrosis (e.g., shoulder), or combinations thereof.

[0048] In some embodiments, TNIK inhibitors can be used to inhibit the development of epithelial-mesenchymal phenotypic transformation and / or fibrosis in cancer cells. In some aspects, this may include inhibition of the Smad signaling pathway. In some aspects, this may include inhibition of non-Smad signaling pathways. In some aspects, this may include inhibition of Wnt, NF-KB, FAC-Src-pile protein-associated focal adhesion, and MAP kinase (e.g., ERK and JNK) signaling pathways.

[0049] The therapeutic treatments described herein can be used to prevent or suppress the occurrence, development, or progression of the disease state. Therefore, TNIK inhibitors can be used for the prevention or treatment of the aforementioned disease state.

[0050] In some embodiments, the TNIK inhibitor has the structure of any of the formulas provided herein, or a derivative thereof, a prodrug thereof, a salt thereof, or a stereoisomer thereof, or any chirality having any chiral center, or a tautomer, polymorph thereof, solvate thereof, or combination thereof, as described herein. In some cases, the compound may be a pharmaceutically acceptable salt. In these formulas, the R substituent may be any substituent. For example, the R substituent may be one or more of the substituents described herein, or a combination thereof.

[0051] Similarly, inhibiting MAP4K4 kinase can suppress its associated biological functions.

[0052] In some embodiments, a method of inhibiting a kinase (e.g., TNIK kinase and / or MAP4K4 kinase) may include contacting the kinase with a compound having the structure of formula A or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph or its solvate, or any chirality having any chiral center.

[0053]

[0054] In some respects: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a heteroaromatic ring; ring 3 comprises at least one heteroaromatic ring and at least one alicyclic ring optionally fused with at least one heteroaromatic ring; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or linker; Y 1 It is a connector; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; R 1 R 6 R 11 and R 12 Each is an independent substituent; and R A It is a ring structure, a straight-chain fatty chain, or a branched fatty chain, which may be substituted or unsubstituted, and may or may not have heteroatoms.

[0055] In some embodiments, ring 1 is phenyl, pyridyl, or pyrimidinyl; ring 2 is a 5- or 6-membered heteroaromatic ring; ring 3 comprises a 5-membered heteroaromatic ring or a 5-membered heteroaromatic ring fused with a 6-membered heteroaromatic ring, wherein the 6-membered heteroaromatic ring is fused with a 5-membered alicyclic ring, wherein the bond to Y is through the 5-membered heteroaromatic ring; ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine; Y is a bond or an aliphatic linker; Y 1 It is an amide connector; and R A It is an aromatic ring, a heteroaromatic ring, an alicyclic ring, or a heterocyclic ring; a straight-chain aliphatic or branched aliphatic ring, which may be substituted or unsubstituted, and may or may not have heteroatoms.

[0056] In some embodiments, ring 1 is phenyl, pyridyl, or pyrimidinyl, and when ring 1 is pyridyl or pyrimidinyl, nitrogen is located at the para, meta, or ortho position in the ring; ring 2 is furanyl, thiophene, pyrroloyl, oxazoloyl, thiazolyl, imidazolyl, triazolyl, or pyridyl; ring 3 is imidazolyl, triazolyl, or cyclopentadienylpyrrolopyridyl fused ring group; or cyclopentadienylfuranolpyridyl; ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine, and when ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; when ring 4 is pyrimidinyl, the nitrogen atom is located at the meta or ortho position in the ring; Y is a bond or a mono- to 6-membered (e.g., C1-C6) aliphatic; Y 1 It is an amide connector; and R AIt is an aromatic ring, a heteroaromatic ring, a 1- to 6-membered (e.g., C3-C6) alicyclic ring, a 5- to 6-membered heterocyclic ring; a 1- to 12-membered (e.g., C1-C6) alicyclic ring. 12 Straight-chain aliphatic chains, or 1-to-12-to-12-chain (e.g., C1-C) 12 A branched aliphatic chain, which may be substituted or unsubstituted, and may or may not have heteroatoms.

[0057] In some implementation schemes, R 1 R 6 R 11 and R 12 Each of these groups independently represents F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, acetyl (i.e., CH3C=O), propionyl, butyryl, acetamide (i.e., acetamido), propionamide, butyramide, pentamide, hexamide, heptamide, octylamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methyl thioalkyl (i.e., thiomethyl), ethyl thioalkyl, propyl thioalkyl, butyl thioalkyl, pentyl thioalkyl, hexyl thioalkyl, heptyl thioalkyl, or octyl thioalkyl. In some aspects, R 11 and R 12 It is hydrogen or it does not exist.

[0058] In some implementations, when Y is a C1-C6 aliphatic connector, R A It is a C3-C6 alicyclic ring, a C5-C6 heterocyclic ring, an aromatic ring, or a C1-C6 alicyclic ring. 12 Linear aliphatic or C1-C 12 Branched aliphatic chains, which may be substituted or unsubstituted, any with or without heteroatoms, or when Y is a bond, R A It is not a C6-C6 alicyclic ring.

[0059] In some implementation schemes, R 1 R 6 R 11 and R 12Each of these groups independently represents hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0060] In some implementation schemes, R 11 and R 12 Each is either hydrogen or does not exist, and R 1 or R 6 Each of these groups independently represents hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0061] In some implementations, each R 1Independently, it is hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethoxy, or a combination thereof.

[0062] In some implementation schemes, R 11 and R 12 It is either hydrogen or absent, and each R 6 Independently, it is hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, heptaylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0063] In some implementation schemes, Y 1 It is an amide, hydrazide, carbazide, hydroxy-substituted amide, alkyl-substituted amide, carboxyoximamide, or iminosulfonamide.

[0064] In some implementation schemes, R A Derived from hydrogen, cyclopentyl, tetrahydrofuranyl, pyrrolyl, piperidinyl, pyridyl, pyrimidinyl, dicycloheptyl, dicyclooctyl, dicyclo[3.1.1]heptyl-3-yl, dicyclo[2.2.2]octyl-2-yl, dicyclo[3.2.1]octane-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxacyclobutyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, phenyl, or combinations thereof.

[0065] In some embodiments, methods for inhibiting kinases (e.g., TNIK kinase and / or MAP4K4 kinase) may include contacting the kinase with compounds having a structure of one of formulas A1 or A2, or derivatives thereof, their prodrugs, their salts, their stereoisomers, their tautomers, their polymorphs, or their solvates, or any chirality having any chiral center.

[0066]

[0067] Where: R A It is a ring structure, straight-chain aliphatic or branched-chain aliphatic, which may be substituted or unsubstituted, and may or may not have heteroatoms; ring D is a ring structure in which one or more rings are linked together; X 1 X 2 X 3 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 and X 14 Each is independently a carbon or heteroatom with or without substituents; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is an independent substituent; Y is a bond or linker; Y 1 It is a connector; m is 1, 2, or 3; and n is 0, 1, or 2. In some respects, when the X group in the aromatic ring is N, the R group bonded to it is not present. In some respects, n is 0 and R... 11 and / or R 12 Neither of them exists. If they exist, R 11 and / or R 12 It can be on any suitable ring atom in any ring. When n is 0, then the bond and R 11 and / or R 12 It does not exist. In some respects, R A The ring is directly connected to X 1 For example, through a covalent bond (i.e., Y). When R A When it is a ring, it can be any alicyclic or heterocyclic group, or a combination thereof.

[0068] In some implementation schemes, Y 1 It could be:

[0069] It can be Or, for example, for other connectors of Y, or X 4 and / or X 5 It can be as defined in this article. In some respects, X 4 It is C (e.g., CH, CH2) or N (e.g., N, NH, NR). 1 NOR 1 ), any group with or without substituents (e.g., R 1 ); and X 5 It is O or N (e.g., NH, NR) 1 NOR 1 ). Here, R 1 As defined herein, H, OH, methyl, ethyl, and trifluoromethyl are examples. X 4 It can be C, NH, or NOH, or NOR. 1 X 5 Is it O or NR? 1 , or NOR 1 .

[0070] In some embodiments, the method may include administering a compound of one of the structures of formula 4A-4K or 5A-5K or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph or a solvate thereof, or any chirality having any chiral center.

[0071]

[0072] Among them, R 13 Selected from: hydrogen, straight-chain aliphatic, branched-chain aliphatic. Y-ring A; Ring B; Ring C; Fused ring D; Fused ring E; or -YR A Each of them may be substituted or unsubstituted, and may or may not have heteroatoms.

[0073] In some respects: in Formula 1A, A is a ring structure with or without heteroatoms, substituted or unsubstituted; in Formula 3A, B is a ring structure with at least one heteroatom, substituted or unsubstituted; and in Formula 4A, R 13 It includes straight-chain aliphatic, branched aliphatic, alicyclic, cyclopropane, aryl, polyaryl, and -YR compounds. A RB Fused ring D (e.g., with X) 1 and X 6 Fused rings), fused rings E (e.g., instances of fused rings D), and combinations thereof, wherein any one may be substituted or unsubstituted, and any one may or may not have heteroatoms.

[0074] In some embodiments, ring A is an alicyclic or heterocyclic alicyclic group or a combination thereof, which may be substituted or unsubstituted by the R group. In some aspects, ring B can only be a heterocyclic alicyclic group. In some aspects, R... 13 Independently as a substituent, for example, for R 11 Those described. X 1 and / or X 2 It is CH or N. X 3 It is CH2, NH, O, or S. X 6 X 7 X 8 X 9 X 10 X 11 X 12 and / or X 13 It is CH or N. X 14 It is O or NH. R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each of the following is independently hydrogen, halogen, hydroxyl, alkoxy, straight-chain aliphatic, branched-chain aliphatic, cyclic aliphatic, substituted aliphatic, unsubstituted aliphatic, saturated aliphatic, unsaturated aliphatic, aromatic, polyaromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, fatty amine, carbonyl, carboxyl, amide, ester, amino acid, its derivatives, any substituted or unsubstituted, or a combination thereof.

[0075] In some embodiments: ring A is an alicyclic ring having 3-12 ring atoms, a heterocyclic ring having 3-12 ring atoms, or a combination thereof, which may be substituted or unsubstituted; ring B is a heterocyclic ring having 3-12 ring atoms, which may be substituted or unsubstituted; ring D is a polycyclic ring having at least one aromatic ring fused with a cyclic alicyclic ring; X 1 and / or X 2 It is CH or N; X 3 It is CH2, NH, O, or S; X 6 X 7 X8 X 9 X 10 X 11 X 11 X 12 and / or X 13 It is CH or N; X 6 X 7 X 8 X 9 X 10 X 11 X 11 X 12 and / or X 13 It is CH, N, or O; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each of these groups independently represents hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, aralkyl, halogen, hydroxyl, mercapto, alkoxy, alkenyloxy, alkynoxy, aryloxy, acyl, alkyl carbonyl, aryl carbonyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, halocarbonyl, alkyl carbonate, aryl carbonate, carboxyl, carboxylic acid group, carbamoyl, mono(alkyl)-substituted carbamoyl, di(alkyl)-substituted carbamoyl, mono-substituted aryl carbamoyl, thiocarbamoyl, urea, cyano, isocyano, cyanate group, isocyanate, isothiocyanate, and azide. alkyl, formyl, thioformyl, amino, monoalkyl-substituted amino and dialkyl-substituted amino, monoaryl-substituted amino and diaryl-substituted amino, alkylamide, arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfonyl, sulfonate, alkylthioalkyl, arylthioalkyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphonyl, phosphonate, phosphonite, phosphoryl, phosphonite, any having or not having a heteroatom, its derivatives, any substituted or unsubstituted, and combinations thereof; and R 13 It is from 1-yuan to 24-yuan (e.g., C1-C) 24 Straight-chain aliphatic or branched-chain aliphatic, which may be substituted or unsubstituted, and either has or does not have heteroatoms.

[0076] In some embodiments: ring A is an alicyclic ring having 3-6 ring atoms, a heterocyclic ring having 3-6 ring atoms, or a combination thereof, which may be substituted or unsubstituted; ring B is a heterocyclic ring having 3-6 ring atoms, which may be substituted or unsubstituted; ring D is cyclopentadienpyridine; X 1 and X 2 It is N; X 3 It is O or NH; X 4 It is NH, CH2, O, or S; X 5 It is O; X 6 X 7 X 8 X 9 X 10 X 11 and / or X 12 It is CH or N; X 13 For N; X 14 It is O or NH; and R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each of the following is independently selected as one or more substituents: hydrogen, C1-C 24 Alkyl, C2-C 24 alkenyl, C2-C 24 alkynyl group, C5-C 20 Aryl, C6-C 24 Alkyl, C6-C 24 Aryl groups, halogens, hydroxyl groups, mercapto groups, C1-C 24 Alkoxy, C2-C 24 Alkenyl groups, C2-C 24 Acryloxy group, C5-C 20 aryloxy group, acyl group, acyloxy group, C2-C 24 Alkoxycarbonyl, C6-C 20 aryloxycarbonyl, halocarbonyl, C2-C 24 Alkyl carbonate, C6-C 20 aryl carbonate, carboxyl, carboxylate, carbamoyl, mono(C1-C) 24 alkyl)-substituted carbamoyl, di(C1-C 24 Alkyl-substituted carbamoyl, monosubstituted aryl carbamoyl, disubstituted aryl carbamoyl, thiocarbamoyl, mono(C1-C2) car ... 24alkyl)-substituted thiocarbamoyl, di(C1-C 24 Alkyl-substituted thiocarbamoyl, monosubstituted aryl thiocarbamoyl, disubstituted aryl thiocarbamoyl, carbamoylamino, mono(C1-C) 24 Alkyl)-substituted urea group, di(C1-C 24 Alkyl)-substituted urea group, monosubstituted arylurea group, disubstituted arylurea group, isocyanate group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, azide group, formyl group, thioformyl group, amino group, mono(C1-C) 24 alkyl)-substituted amino and di(C1-C) 24 Alkyl) substituted amino, mono(C5-C) 20 aryl)-substituted amino groups and di(C5-C) 20 aryl-substituted amino groups, C2-C 24 Alkylamide group, C6-C 20 Arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfonic acid, sulfonate, C1-C 24 Alkyl thioalkyl, C5-C 20 arylthioalkyl, C1-C 24 Alkyl sulfinyl, C5-C 20 Arylsulfinyl, C1-C 24 Alkyl sulfonyl, C5-C 20 arylsulfonyl, phosphonyl, phosphonate, phosphonite, phosphoryl, phosphonite, any derivative thereof with or without heteroatoms, any substituted or unsubstituted form, and combinations thereof; and R 13 It ranges from 1 yuan to 12 yuan (e.g., C1-C). 12 Straight-chain aliphatic or branched-chain aliphatic, which may be substituted or unsubstituted, and either has or does not have heteroatoms.

[0077] In some implementation schemes, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12Each of the following is independently H, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, acetyl (i.e., acetyl, CH3C=O), propionyl, butyryl, acetamide (i.e., acetamido), propionamide, butyrylamide, pentamide, hexamide, heptamide, octylamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methyl thioalkyl (i.e., thiomethyl), ethyl thioalkyl, propyl thioalkyl, butyl thioalkyl, pentyl thioalkyl, hexyl thioalkyl, heptyl thioalkyl, or octyl thioalkyl.

[0078] In some implementation schemes, R 13 It is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, or –C(R) 14 )2, where each R 14 It is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl.

[0079] In the formulas and other formulas provided in this article, X 4 It is a carbon or heteroatom with or without substituents; and X 5 It is a heteroatom. In some respects, X 4 It is C (e.g., CH, CH2) or N (e.g., N, NH, NR). 1 NOR 1 ), any group with or without substituents (e.g., R 1 ); and X 5 It is O or N (e.g., NH, NR) 1 NOR 1 ). Here, R 1 As defined herein, H, OH, methyl, ethyl, and trifluoromethyl are examples. X 4 It can be C, NH, or NOH, or NOR. 1 X 5 Is it O or NR? 1 , or NOR 1 .

[0080] In some embodiments, the kinase inhibitor (e.g., TNIK kinase and / or MAP4K4 kinase) may comprise a structure of one of formula 4B-4K or 5B-5K or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph or its solvate, or any chirality having any chiral center.

[0081]

[0082]

[0083]

[0084]

[0085] In some embodiments, ring A can be any ring structure having a monocyclic or two or more fused rings having 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms, which can be alicyclic, heterocyclic, aryl, heteroaryl, polyaryl, polyheteroaryl, or combinations thereof. When heteroatoms are included, they can be C, O, N, or S, depending on the number bonded to them, and any ring A can include 1, 2, 3, 4, 5, 6, or more heteroatoms. Ring A can be substituted with one or more R groups, which can be the same as defined for any other R group. When the monocyclic ring is n-1, the number of R group substituents in ring A can be determined by the number of atoms in the ring, where n is the number of ring atoms. Each R group substituent on the ring can be different from each other.

[0086] In some embodiments, ring A represents a 5- or 6-membered alicyclic or heterocyclic alicyclic group, or a combination thereof, which may be substituted or unsubstituted. This may include cyclopentyl or cyclohexyl, which may be substituted or unsubstituted.

[0087] In some embodiments, the X ring atom can be carbon (C) or a heteroatom, such as O, N, or S, or others. As noted, when carbon, the X ring atom may or may not have substituents, such as R. 11 and R 12 As shown, it can be on any atom of the corresponding ring, for example on an atom of ring X, if present, for example on ring X. 1 X 2 X 3 X 6 X 10 and X 11 Therefore, X 1 It can be C (e.g., CH) or N with suitable hydrogen atoms. X 2 It can be C (e.g., CH) or N with suitable hydrogen atoms. X 3 It can be C (e.g., CH2) or NH, O, or S. X 4 It can be C (e.g., CH2) or NH, O, or S. X 5 It can be O or S. In some respects, Y 1 It could be connector Y. In some respects, X 4 It is C (e.g., CH, CH2) or N (e.g., N, NH, NR). 1NOR 1 ), any having or not having substituents (e.g., R 1 ); and X 5 It is O or N (e.g., NH, NR) 1 NOR 1 ). Here, R 1 As defined herein, H, OH, methyl, ethyl, and trifluoromethyl are examples. X 4 It can be C, NH, or NOH, or NOR. 1 X 5 Is it O or NR? 1 , or NOR 1 .

[0088] In some implementations, when Y 1 When it's the chemical part and not just the bond, Y 1 It can be a connector Y, and Y can be any connector, such as a chemical moiety or a bond. In some cases, Y is a bond, but most commonly it is a chemical moiety. When Y is one or more chain atoms, at least one R can be present on one or more chain atoms. 13 , where R 13 It can be any R group as defined herein. The linker can be O, S, CH2, NH, or a hydrocarbon chain with or without heteroatoms, such as those listed herein with respect to the X ring atom. Linkers can include O, S, CH2, NH, straight-chain aliphatic, branched aliphatic, cyclic aliphatic, substituted aliphatic, unsubstituted aliphatic, saturated aliphatic, unsaturated aliphatic, aromatic, polyaromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, aliphatic amine, carbonyl, carboxyl, amide, ester, amino acid, its derivatives, substituted or unsubstituted, or combinations thereof. In some aspects, the linker can include C1-C... 24 Alkyl, C2-C 24 alkenyl, C2-C 24 alkynyl group, C6-C 20 Aryl, C7-C 24 Alkyl, C7-C 24 Aryl, amino, monoalkyl-substituted amino and dialkyl-substituted amino, monoaryl-substituted amino and diaryl-substituted amino, alkylamide, arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfonyl, sulfonate, alkylthioalkyl, arylthioalkyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphonyl, phosphonate, phosphonite, phosphoryl, phosphonite, any having or not having a heteroatom, any substituted or unsubstituted, derivatives thereof, and combinations thereof. In some cases, Y is formed by at least one R. 13 Replacement connector, R 13These can be substituents as described in this article.

[0089] In some implementation schemes, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each of the following is independently selected as one or more substituents: hydrogen, C1-C 24 Alkyl, C2-C 24 alkenyl, C2-C 24 alkynyl group, C5-C 20 Aryl, C6-C 24 Alkyl, C6-C 24 Aryl groups, halogens, hydroxyl groups, mercapto groups, C1-C 24 Alkoxy, C2-C 24 Alkenyl groups, C2-C 24 Acryloxy group, C5-C 20 Aryloxy groups, acyl groups (including C2-C) 24 Alkyl carbonyl (-CO-alkyl) and C6-C 20 aryl carbonyl (-CO-aryl)), acyloxy (-O-acyl), C2-C 24 Alkoxycarbonyl (—(CO)—O-alkyl), C6-C 20 aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (—CO)—X, where X is a halogen), C2-C 24 Alkyl carbonate (—O—(CO)—O-alkyl), C6-C 20 aryl carbonate (—O—(CO)—O-aryl), carboxyl (-COOH), carboxylate (—COO) - ), carbamoyl (—(CO)—NH2), mono(C1-C 24 alkyl)-substituted carbamoyl (—(CO)—NH(C1-C) 24 Alkyl), di(C1-C) 24 alkyl)-substituted carbamoyl (—(CO)—N(C1-C) 24 Alkyl)2), monosubstituted arylcarbamoyl (-(CO)-NH-aryl), disubstituted arylcarbamoyl (-(CO)-NH-aryl)2, thiocarbamoyl (—(CS)—NH2), mono(C1-C 24 alkyl)-substituted thiocarbamoyl (—(CS)—NH(C1-C)24 Alkyl), di(C1-C) 24 alkyl)-substituted thiocarbamoyl (—(CS)—N(C1-C) 24 Alkyl)2), monosubstituted arylthiocarbamoyl (-(CS)-NH-aryl), disubstituted arylthiocarbamoyl (—(CS)—NH-aryl)2, ureoyl (—NH—(CO)—NH2), mono(C1-C 24 Alkyl-substituted urea group (—NH—(CO)—NH(C1-C) 24 Alkyl), di(C1-C) 24 Alkyl-substituted urea group (—NH—(CO)—N(C1-C) 24 Alkyl)2), monosubstituted arylureoyl (—NH—(CO)—NH-aryl), disubstituted arylureoyl (—NH—(CO)—N-(aryl)2), cyano (-C≡N), isocyano (—N + ≡C - ), cyanate group (—O—C≡N), isocyanate group (—O—N) + ≡C - ), thiocyanate (—S—C≡N), isothiocyanate (—S—N) + ≡C - ), azide group (—N=N + =N - ), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (—NH2), mono(C1-C 24 alkyl)-substituted amino and di(C) 1 -C 24 Alkyl) substituted amino, mono(C6-C) 20 aryl-substituted amino groups and di(C6-C) 20 aryl-substituted amino groups, C2-C 24 Alkylamide group (-NH-(CO)-alkyl), C5-C 20 Aryl amide group (-NH-(CO)-aryl), imino group (-CR=NH, where R is hydrogen, C1-C) 24 Alkyl, C5-C 20 Aryl, C6-C 24 Alkyl, C6-C 24 Aryl alkyl, etc.), alkyl imino (-CR=N(alkyl), where R=hydrogen, C1-C 24 Alkyl, aryl, alkylaryl, aralkyl, etc.), aryl imino (-CR=N(aryl), where R=hydrogen, alkyl, aryl, alkylaryl, etc.), nitro (-NO2), nitroso (-NO), sulfonic acid (-SO2-OH), sulfonic acid group (-SO2-O) - C1-C 24Alkylthioalkyl (-S-alkyl; also known as "alkylthio"), C5-C 20 Arylthioalkyl (-S-aryl; also known as "arylthio"), C1-C 24 alkylsulfinyl (-(SO)-alkyl), C5-C 20 arylsulfinyl (-(SO)-aryl), C1-C 24 alkylsulfonyl (—SO2-alkyl), C5-C 20 arylsulfonyl (—SO2-aryl), phosphonic acid (—P(O)(OH)2), phosphonic acid (—P(O)(O) - )2) Phosphite group (-P(O)(O-)), phosphorus (—PO2), phosphine group (-PH2), any group having or not having a heteroatom (e.g., N, O, S or others) wherein the heteroatom may be substituted for carbon (e.g., a heteroatom substituted for a carbon in a chain or ring) or otherwise exchanged to that (e.g., a heteroatom added to a carbon chain or ring), any including straight chain, any including branched chain and any induced ring, any substituted or unsubstituted, derivatives thereof and combinations thereof.

[0090] In some embodiments, the method uses compounds of formula B or B1, whose ring C is as defined herein, for example, a C5-C6 ring structure with or without heteroatoms (e.g., alicyclic).

[0091]

[0092] In some respects: the ring C is a C5-C6 aliphatic ring structure without heteroatoms; R 1 R 2 R 3 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is an independent substituent; and n is 0, 1, or 2. In some respects, the ring C is a C5-C6 aliphatic ring structure without heteroatoms; and R 1 R 2 R 3 R 5 R 6 R 7 R 8 R 9 and R 10 Each is an independent substituent and R 11 and R 12 It either does not exist or is hydrogen.

[0093] In some embodiments, the compound has the structure of formula 7, 8, 9, 10, 11, 12, 13 or 14, its derivatives, its prodrugs, its salts, its stereoisomers, its tautomers, its polymorphs or solvates thereof, or any chirality having any chiral center.

[0094]

[0095] In some implementations, R in any formula 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 The substituents may be H, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, acetyl (i.e., acetyl, CH3C=O), propionyl, butyryl, acetamide (i.e., acetamido), propionamide, butyrylamide, pentamide, hexamide, heptamide, octylamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methyl thioalkyl (i.e., thiomethyl), ethyl thioalkyl, propyl thioalkyl, butyl thioalkyl, pentyl thioalkyl, hexyl thioalkyl, heptyl thioalkyl, or octyl thioalkyl.

[0096] In some implementation schemes, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each of these can be independently a halogen, alkyl, branched alkyl, alkoxy, alkyl ester, alkylthioalkyl (i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy, trifluoroalkyl, or acetamide (i.e., acetamido).

[0097] In some embodiments, the compound comprises at least one of the following: R 3 For substituents; R 6 For substituents; R7 For substituents; R 8 For substituents; R 9 For substituents; and / or R 10 The R group is a substituent. The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0098] In some embodiments, the compound comprises at least one of the following: R 3 For F; R 6 For F, Br, Cl, methoxy, or methyl ester; R 7 F or methoxy; R 8 F is methoxy or methyl; R 9 It is F or methoxy; and / or R 10 The R group can be F, Br, Cl, methoxy, or methyl ester. The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0099] In some embodiments, the compound comprises the following: R 3 Let F be the value of R; and R be the value of F. 1 R 2 R 4 and R 5 The R group is H. The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0100] In some embodiments, the compound comprises one of the following: R having a substituent 6 and R 9 , and R for H 7 R 8 and R 10 R with substituents 7 and R 10 , and R for H 6 R 8 and R 9 R with substituents 6 , and R for H 7 R 8 R 9 and R 10 R with substituents 8 , and R for H 6 R 7 R 9 and R 10 R with substituents 10 , and R for H 6 R 7 R 8 and R 9 R with substituents 6 and R 8, and R for H 7 R 9 and R 10 ; or R with substituents 8 and R 10 , and R for H 6 R 7 and R 9 The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0101] In some embodiments, the compound comprises: R of F 3 ; for H of R 1 R 2 R 4 and R 5 R is F, Br, Cl, methoxy, or methyl ester. 6 R is F or methoxy 9 ; and R for H 7 R 8 and R 10 The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0102] In some embodiments, the compound comprises: R of F 3 ; for H of R 1 R 2 R 4 and R 5 R is F, Br, Cl, methoxy, or methyl ester. 6 ; and R for H 7 R 8 R 9 and R 10 The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0103] In some embodiments, the compound comprises: R of F 3 ; for H of R 1 R 2 R 4 and R 5 R is F, methoxy, or methyl ester. 8 ; and R for H 6 R 7 R 9 and R 10 The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0104] In some embodiments, the compound comprises: R of F 3 ; for H of R 1R 2 R 4 and R 5 R is F, Br, Cl, methoxy, or methyl ester. 10 , and R for H 6 R 7 R 8 and R 9 The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0105] In some embodiments, the compound comprises: R of F 3 ; for H of R 1 R 2 R 4 and R 5 R is F, Br, Cl, methoxy, or methyl ester. 6 ; R is F-methoxy or methyl 8 ; and R for H 7 R 9 and R 10 The remaining R groups may be hydrogen or absent. This applies to all formulas described herein.

[0106] In some embodiments, the inhibitory compound used in the method (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) can be one of the following:

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121] In some embodiments, the compound used in this method is one of the following: 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide; 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide; N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide; N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide; 5-(1-cyclopentyl-4- (4-Fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide; 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide; 2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)methyl benzoate; 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide; or 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide.

[0122] In some embodiments, the R group substitution patterns and substituents shown in the structures of compounds 17-87 can be applied to any of the formulas provided herein.

[0123] In some embodiments, the compound is included in a pharmaceutical composition comprising: the compound; and a pharmaceutically acceptable carrier having the compound.

[0124] Kinase inhibitors can be formulated for experimental or therapeutic purposes. Formulations for storage and use are prepared by combining the purified kinase inhibitors of the present invention with pharmaceutically acceptable mediators (e.g., carriers, excipients) (Remington, The Science and Practice of Pharmacy 20th Edition, Mack Publishing, 2000). Suitable pharmaceutically acceptable mediators include, but are not limited to, non-toxic buffers such as phosphates, citrates, and other organic acids; salts such as sodium chloride; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride; hexachlorocyclohexane quaternary ammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight peptides (e.g., less than about 10 amino acids). Amino acids (amino acid residues); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; carbohydrates, such as monosaccharides, disaccharides, glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc-protein complexes); and nonionic surfactants, such as Tween or polyethylene glycol (PEG).

[0125] The pharmaceutical compositions of the present invention can be administered in a variety of ways for local or systemic treatment. Administration can be local (e.g., applied to mucous membranes, including vaginal and rectal delivery), such as transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders; pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers, intratracheal, intranasal, epidermal, and transdermal); oral; or parenteral, including intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; intratumoral or intracranial (e.g., intrathecal or intraventricular) administration.

[0126] Therapeutic formulations can be unit dosage forms. Such formulations include tablets, pills, capsules, powders, granules, solutions or suspensions in aqueous or non-aqueous media, or suppositories for oral, parenteral, or rectal administration or for inhalation. In solid compositions such as tablets, the main active ingredient is mixed with a drug carrier. Conventional tableting ingredients include corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and other diluents (e.g., water) to form a solid pre-formulation composition containing a homogeneous mixture of the compounds of the present invention or their non-toxic, pharmaceutically acceptable salts. The solid pre-formulation composition is then subdivided into unit dosage forms of the types described above. Tablets, pills, etc., of the new composition may be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, tablets or pills may contain an inner composition covered by an outer component. Furthermore, the two components may be separated by an enteric coating layer that resists disintegration and allows the inner component to pass through the stomach intact or with delayed release. A variety of materials can be used for such enteric coatings or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0127] In some embodiments, the pharmaceutical formulation may include the kinase inhibitor of the present invention complexed with liposomes (Epstein et al., 1985, Proc. Natl. Acad. Sci. USA 82:3688);

[0128] Hwang et al., 1980, Proc. Natl. Acad. Sci. USA 77:4030; and U.S. Patent Nos. 4,485,045 and 4,544,545. Liposomes with enhanced cycle time are disclosed in U.S. Patent No. 5,013,556. Some liposomes can be produced by reverse-phase evaporation with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derived phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter defining the pore size to produce liposomes with a desired diameter.

[0129] Kinase inhibitors can also be encapsulated in microcapsules. Such microcapsules can be prepared, for example, by coagulation techniques or by interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in crude emulsions as described in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000), for example, from hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively.

[0130] In addition, sustained-release formulations can be prepared. Suitable examples of sustained-release formulations include semi-permeable matrices of solid hydrophobic polymers containing kinase inhibitors, in the form of molded articles (e.g., membranes or microcapsules). Examples of sustained-release matrices include polyesters, hydrogels such as poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol), polylactide (US Patent No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamic acid esters, non-degradable ethylene-vinyl acetate, and degradable lactic acid-glycolic acid copolymers, such as LUPRON DEPOT. TM (Injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose isobutyrate acetate and poly-D-(-)-3-hydroxybutyric acid.

[0131] In some embodiments, the treatment comprises the combined administration of the TNIK inhibitor of the present invention and a chemotherapeutic agent or a mixture of multiple different chemotherapeutic agents. Combination therapy typically uses agents that act through different mechanisms of action. Combination therapy using agents with different mechanisms of action often produces additive or synergistic effects. Compared to monotherapy, combination therapy can allow for lower doses of each agent, thereby reducing toxic side effects. Combination therapy may reduce the likelihood of developing drug-resistant cancer cells. In some embodiments, the combination therapy comprises a kinase inhibitor that binds to a kinase (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) and a chemotherapeutic agent.

[0132] Pharmaceutical compositions include, but are not limited to, lyophilized powders or aqueous or non-aqueous sterile injectable solutions or suspensions, which may also contain antioxidants, buffers, antibacterial agents, and solutes that enable the composition to be substantially compatible with the tissues or blood of the intended recipient. Other components that may be present in such compositions include water, surfactants (e.g.,...) ( ), alcohols, polyols, glycerol, and vegetable oils. Temporary injectable solutions and suspensions can be prepared from sterile powders, granules, tablets, or concentrated solutions or suspensions. The composition can, for example, but not limited to, be provided in the form of lyophilized powder, which is reconstituted with sterile water or saline prior to administration to a patient.

[0133] Suitable pharmaceutically acceptable carriers include substantially chemically inert and non-toxic compositions that do not interfere with the efficacy of the bioactivity of the pharmaceutical composition. Examples of suitable pharmaceutical carriers include, but are not limited to, water, saline solutions, glycerol solutions, ethanol, N-(1(2,3-dioleoyloxy)propyl)N,N,N-trimethylammonium chloride (DOTMA), diolenoylphosphatidylethanolamine (DOPE), and liposomes. Such compositions should contain a therapeutically effective amount of the compound along with an appropriate amount of carrier to provide a form for direct administration to the patient.

[0134] The compositions described herein can be administered, for example, via parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intraspinal, intracisional, intraperitoneal, intranasal, aerosol, or oral administration. Common carriers or excipients can be used to prepare pharmaceutical compositions designed for such routes of administration.

[0135] For the treatment of diseases, the appropriate dosage of the kinase inhibitor of the present invention depends on the type of disease being treated, the severity and course of the disease, the responsiveness of the disease, whether the kinase inhibitor is administered for therapeutic or preventative purposes, previous treatments, the patient's clinical history, etc., and is determined at the discretion of the attending physician. The kinase inhibitor may be administered once or in a series of treatments lasting from several days to several months, or until a cure is achieved or a reduction in the disease state is reached (e.g., a reduction in tumor size). The optimal dosing regimen can be calculated by measuring the accumulation of the drug in the patient's body and will vary depending on the relative potency of the individual kinase inhibitor. The administering physician can easily determine the optimal dosage, method of administration, and repetition rate. Typically, the dosage is from 0.01 μg to 100 mg per kilogram of body weight and may be administered once or multiple times daily, weekly, monthly, or annually. The treating physician can estimate the repetition rate of administration based on the measured residence time and concentration of the drug in body fluids or tissues.

[0136] This invention provides kits containing the kinase inhibitors described herein and usable for performing the methods described herein. In some embodiments, the kit contains at least one purified kinase inhibitor in one or more containers. In some embodiments, the kit contains all components necessary and / or sufficient for performing the assay, including all controls, instructions for performing the assay, and any necessary software for analyzing and presenting results. Those skilled in the art will readily recognize that the kinase inhibitors disclosed herein can be readily incorporated into one of the established kit formats well known in the art.

[0137] In some embodiments, the compound may have inhibitory activity against wild-type or mutant (especially clinically relevant mutant) kinases, having an IC50 value of 1 μM or less (as determined using any scientifically acceptable kinase inhibition assay), preferably having an IC50 of 500 nM or less, preferably 250 nM or less, preferably 100 nM or less, preferably 50 nM or less, preferably 25 nM or less, preferably 10 nM or less.

[0138] In some embodiments, the compound may have an IC50 value measured in a TNIK enzymatic assay as provided in Table 1 below, and may be used to inhibit TNIK, for example for the therapeutic benefits described herein.

[0139] Table 1

[0140]

[0141]

[0142]

[0143]

[0144] The compounds of the present invention can also be used as standards and reagents for characterizing various kinases, particularly but not limited to TNIK kinase and / or MAP4K4 kinase, and for studying the role of such kinases in biological and pathological phenomena; for studying intracellular signal transduction pathways mediated by such kinases; for comparative evaluation of new kinase inhibitors; and for studying various cancers in cell lines and animal models.

[0145] This invention provides, but is not limited to, the following embodiments:

[0146] 1. A compound comprising:

[0147] The structure of Formula A or its derivatives, its prodrugs, its salts, its stereoisomers, its tautomers, its polymorphs or their solvates, or any chirality having any chiral center.

[0148]

[0149] in:

[0150] Ring 1 is an aromatic ring with or without heteroatoms;

[0151] Ring 2 is a heteroaryl ring;

[0152] Ring 3 includes at least one heteroaromatic ring and at least one alicyclic ring optionally fused with at least one heteroaromatic ring;

[0153] Ring 4 is an aromatic ring with or without heteroatoms;

[0154] Y stands for key or connector;

[0155] Y 1 It's a connector;

[0156] Each n is independently 0, 1, or 2;

[0157] Each 'o' can be 0, 1, 2, 3, 4, or 5 independently;

[0158] R 1 R 6 R 11 and R 12 Each is an independent part of chemistry; and

[0159] The compound said compound includes at least one of the following:

[0160] When Y is the key, R A It is a hydrogen ring, an aromatic ring, an alicyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, any of which may be substituted or unsubstituted, or have or not have heteroatoms, or a combination thereof; or

[0161] When Y is the chemical component, R A It is an aromatic ring, an alicyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, which may be substituted or unsubstituted, or have or not have heteroatoms, or a combination thereof; or

[0162] The compound includes at least one of the following:

[0163] When ring 1 is phenyl, at least one of the following is true: ring 2 is not furanyl; ring 3 is not imidazolyl; or ring 4 is not phenyl.

[0164] When ring 2 is furanyl, at least one of the following is true: ring 1 is not phenyl; ring 3 is not imidazolyl; or ring 4 is not phenyl;

[0165] When ring 3 is an imidazolium group, at least one of the following is true: ring 1 is not phenyl; ring 2 is not furanyl; or ring 4 is not phenyl; or

[0166] When ring 4 is phenyl, at least one of the following is true: ring 1 is not phenyl; ring 2 is not furanyl; or ring 3 is not imidazolyl.

[0167] 2. The compound according to embodiment 1, wherein the compound comprises at least one of the following:

[0168] Y 1 Including amides having a nitrogen bonded to ring 1 and a carbon bonded to ring 2;

[0169] When Y is the key, R A It can be a C3 alicyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a straight-chain fatty acid chain, or a branched fatty acid chain, any of which can be substituted or unsubstituted;

[0170] When Y is the chemical component, R A It is a C3 alicyclic ring, a 5-membered alicyclic ring, a 5-membered heterocyclic ring, a 6-membered alicyclic ring, a 6-membered heterocyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, which may be substituted or unsubstituted and may or may not have heteroatoms; or

[0171] The compound includes at least one of the following:

[0172] When ring 1 is phenyl, at least one of the following is true: ring 2 is not furanyl; ring 3 is not imidazolyl; or ring 4 is not phenyl.

[0173] When ring 2 is furanyl, at least one of the following is true: ring 1 is not phenyl; ring 3 is not imidazolyl; or ring 4 is not phenyl;

[0174] When ring 3 is an imidazolium group, at least one of the following is true: ring 1 is not phenyl; ring 2 is not furanyl; or ring 4 is not phenyl; or

[0175] When ring 4 is phenyl, at least one of the following is true: ring 1 is not phenyl; ring 2 is not furanyl; or ring 3 is not imidazolyl.

[0176] 3. The compound according to embodiment 1, wherein the compound comprises:

[0177] Ring 1 is phenyl, pyridinyl, or pyrimidinyl;

[0178] Ring 2 is a 5- or 6-membered heteroaryl ring;

[0179] Ring 3 includes a 5-membered heteroaryl ring or a 5-membered heteroaryl ring fused with a 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring is fused with a 5-membered alicyclic ring, wherein the bond to Y is through the 5-membered heteroaryl ring;

[0180] Ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine;

[0181] Y is a bond or aliphatic linker; and

[0182] Where Y is a bond, R A It is not a 5-membered alicyclic ring.

[0183] 4. The compound according to Embodiment 1, wherein:

[0184] Ring 1 is phenyl, pyridyl, or pyrimidinyl. When ring 1 is pyridyl or pyrimidinyl, nitrogen is located at the para, meta, or ortho position in the ring.

[0185] Ring 2 can be furanyl, phenylthio, pyrrolithyl, oxaconityl, thiazolyl; imidazolyl, triazolyl, or pyridinyl.

[0186] Ring 3 is an imidazolyl, triazolyl, or cyclopentadienylpyrrolopyridinyl fused ring group; or cyclopentadienylfuranopyridinyl;

[0187] Ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine; when ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; when ring 4 is pyrimidinyl, nitrogen is located at the meta or ortho position in the ring; and

[0188] Y represents a bond or a C1-C6 aliphatic bond.

[0189] 5. The compound according to embodiment 1, wherein:

[0190] When Y is a C1-C6 aliphatic connector, R A It is a C3-C6 alicyclic ring, a C5-C6 heterocyclic ring, an aromatic ring, or a C1-C6 alicyclic ring. 12 Linear aliphatic or C1-C 12 Branched aliphatic chains, which may be substituted or unsubstituted, either having or not having heteroatoms, or

[0191] When Y is a bond, R A It is not a C6-C6 alicyclic ring.

[0192] 6. The compound according to embodiment 1, wherein R 1 R 6 R 11 and R 12 Each of these groups independently represents hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0193] 7. The compound according to embodiment 1, wherein R 11 and R 12 It is hydrogen or does not exist, and R 1 or R 6Each of these groups independently represents hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0194] 8. The compound according to embodiment 7, wherein each R 1 Independently, it is hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethoxy, or a combination thereof.

[0195] 9. The compound according to embodiment 1, wherein R 11 and R 12 It is either hydrogen or absent, and each R 6Independently, it is hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, heptaylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0196] 10. The compound according to embodiment 1, wherein Y 1 It is an amide, hydrazide, carbazide, hydroxy-substituted amide, alkyl-substituted amide, carboxyoximamide, or iminosulfonamide.

[0197] 11. The compound according to embodiment 1, wherein R A Derived from hydrogen, cyclopentyl, tetrahydrofuranyl, pyrrolyl, piperidinyl, pyridyl, pyrimidinyl, dicycloheptyl, dicyclooctyl, dicyclo[3.1.1]heptyl-3-yl, dicyclo[2.2.2]octyl-2-yl, dicyclo[3.2.1]octane-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxacyclobutyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, phenyl, or combinations thereof.

[0198] 12. The compound according to embodiment 1, comprising:

[0199] The structure of formula A1 or A2 or its derivatives, its prodrugs, its salts, its stereoisomers, its tautomers, its polymorphs or their solvates, or any chirality having any chiral center.

[0200]

[0201] Ring D is a ring structure having one or more rings fused together;

[0202] R1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is an independent chemical component;

[0203] X 1 X 2 X 3 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 and X 20 Each is an independent carbon or heteroatom, with or without substituents;

[0204] Y stands for key or connector;

[0205] Y 1 It's a connector;

[0206] m is 1, 2, or 3; and

[0207] n is 0, 1, or 2;

[0208] When Y is the key, R A It is hydrogen, aromatic alicyclic, straight-chain alicyclic or branched alicyclic, any substituted or unsubstituted, any having or not having a heteroatom;

[0209] When Y is a connector, R A It is aromatic, alicyclic, straight-chain aliphatic or branched aliphatic, either substituted or unsubstituted, and either has or does not have a heteroatom;

[0210] When the X group in the aromatic ring is N, the R group bonded to it does not exist;

[0211] When the dashed line forms a double bond, X 12 It is N.

[0212] 13. The compound according to embodiment 1, comprising:

[0213] The structure of Formula 4A or Formula 5A or its derivatives, its prodrugs, its salts, its stereoisomers, its tautomers, its polymorphs or their solvates, or any chirality having any chiral center.

[0214]

[0215] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is an independent chemical component;

[0216] X 1 X 2 X 3 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 and X 20 Each is an independent carbon or heteroatom, with or without substituents;

[0217] Y1 is the connector;

[0218] m is 1, 2, or 3; and

[0219] n is 0, 1, or 2;

[0220] When the X group in the aromatic ring is N, the R group bonded to it does not exist;

[0221] R 13 Independently selected from hydrogen, straight-chain aliphatic, branched-chain aliphatic, (-Y-ring A); (Ring B); any of which may be substituted or unsubstituted, any of which may or may not have a heteroatom,

[0222] in:

[0223] Y stands for key or connector;

[0224] Ring A is aromatic, alicyclic, or heterocyclic alicyclic or a combination thereof, either substituted or unsubstituted; and

[0225] Ring B is an aromatic, alicyclic, or heterocyclic compound or a combination thereof, either substituted or unsubstituted.

[0226] 14. The compound according to embodiment 13, comprising:

[0227] A structure of any one of Formula 4B-4E or Formula 5B-5E, or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph, or its solvate, or any chirality having any chiral center.

[0228]

[0229]

[0230] 15. The compound according to embodiment 13, comprising:

[0231] A structure of any one of Formula 4F-Formula 4K or Formula 5F-Formula 5K, or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph, or its solvate, or any chirality having any chiral center.

[0232]

[0233]

[0234]

[0235] in,

[0236] X 4 For C, CH, CH2, CR 1 C(R) 1 )2N, NH, NR 1 NOH, any substance with or without substituents; and

[0237] X 5 Is it O or NH, NR1, NOR? 1 .

[0238] 16. The compound according to embodiment 13 comprises a structure of formula 5K1 or formula 5L1, its derivatives, its prodrugs, its salts, its stereoisomers, its tautomers, its polymorphs, or its solvates, or any chirality having any chiral center.

[0239]

[0240] 17. The compound according to embodiment 13, comprising:

[0241] R 1 R 2R 3 R 4 and R 5 Each of the following is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethoxy, or a combination thereof;

[0242] R 6 R 7 R 8 R 9 or R 10 Each of these groups independently represents hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof;

[0243] Each R 11 and R 12 It is hydrogen or it does not exist.

[0244] 18. The compound according to embodiment 13, comprising:

[0245] X 1 X 2 X 6 X 7 X 8 X 9 X 12 X 13 and X 20 Independently CH or N;

[0246] X 3 It can be NH, O, or S;

[0247] X 10 and X 11Independently CH or N; and

[0248] X 14 It can be NH or O independently.

[0249] 19. The compound according to embodiment 13, wherein Y 1 This includes amides, acylhydrazides, carbazides, hydroxylated amides, alkylated amides, carboxyoxime amides, or iminosulfonamides.

[0250] 20. The compound according to embodiment 13, wherein R 13 Independently a C1-C6 alkyl group or coupled with at least one of the following: hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, any substituted or unsubstituted, or a combination thereof.

[0251] 21. The compound according to embodiment 13, wherein R 13 Independently a bond coupled to at least one of the following or a C1-C6 alkyl group: hydrogen, cyclopentyl, tetrahydrofuran, fluorotetrahydrofuran, difluorotetrahydrofuran, pyrrolyl, piperidinyl, phenyl, pyridinyl, pyrimidinyl, dicycloheptyl, dicyclooctyl, dicyclo[3.1.1]heptyl-3-yl, dicyclo[2.2.2]octyl-2-yl, dicyclo[3.2.1]octane-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, phenyl, or combinations thereof.

[0252] 22. The compound according to embodiment 13, wherein the compound comprises R which is hydrogen. 1 R 2 R 4 and R 5 and at least one of the following:

[0253] R for substituents 3 ;

[0254] R for substituents 6 / R 10 ;

[0255] R for substituents 7 / R 9 ;

[0256] R for substituents 8 ;

[0257] R with substituents 6 and R 9, and R for H 7 R 8 and R 10 ;

[0258] R with substituents 6 , and R for H 7 R 8 R 9 and R 10 ;

[0259] R with substituents 8 , and R for H 6 R 7 R 9 and R 10 ;or

[0260] R with substituents 6 and R 8 , and R for H 7 R 9 and R 10 .

[0261] 23. The compound according to embodiment 13, wherein n is 0 and R 11 and R 12 It does not exist.

[0262] 24. The compound according to embodiment 1, wherein the compound is one of the following:

[0263] 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound 80);

[0264] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 81);

[0265] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 82);

[0266] 5-(1-Cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 83);

[0267] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide (compound 84);

[0268] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 85);

[0269] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 86);

[0270] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 87);

[0271] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 88);

[0272] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 89);

[0273] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 90);

[0274] 5-(1-Cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 91);

[0275] 5-(1-Cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 92);

[0276] 5-(1-Cyclopentyl-4-(6-Fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-Fluorophenyl)furan-2-carboxamide (Compound 93);

[0277] 5-(1-Cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 94);

[0278] N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide (compound 95);

[0279] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide (Compound 96);

[0280] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide (Compound 97);

[0281] 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-5-carboxamide (Compound 98);

[0282] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-2-carboxamide (Compound 99);

[0283] 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)triazole-5-carboxamide (Compound 100);

[0284] 3'-Cyclopentyl-N-(2-fluorophenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-Bimidazole]-5-carboxamide (Compound 101);

[0285] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazol-3-carboxamide (compound 102);

[0286] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound 103);

[0287] 6-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)pyridineamide (compound 104);

[0288] N-(5-fluoro-2-methoxyphenyl)-5-(2-phenyl-3,6,7,8-tetrahydrocyclopentadien[d]pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrolo-2-carboxamide (compound 105); or

[0289] N-(4-fluoro-2-methoxyphenyl)-5-(2-phenyl-7,8-dihydro-6H-cyclopentadien[d]furan[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide (compound 106).

[0290] 25. The compound according to embodiment 1, wherein the compound is one of the following:

[0291] 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-1);

[0292] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-2);

[0293] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-3);

[0294] 5-(1-Cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-4);

[0295] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide (compound A-5);

[0296] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-6);

[0297] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-8);

[0298] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-9);

[0299] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-10);

[0300] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-11);

[0301] N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-12);

[0302] 5-(1-Cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-13);

[0303] 5-(1-Cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-14);

[0304] 5-(1-Cyclopentyl-4-(6-Fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-Fluorophenyl)furan-2-carboxamide (Compound A-15);

[0305] 5-(1-Cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-16);

[0306] N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide (compound A-17);

[0307] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide (Compound A-18);

[0308] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide (compound A-19);

[0309] 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-5-carboxamide (Compound A-20);

[0310] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-2-carboxamide (compound A-21);

[0311] 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)triazole-5-carboxamide (compound A-22);

[0312] 3'-Cyclopentyl-N-(2-fluorophenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-Bimidazole]-5-carboxamide (compound A-23);

[0313] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazol-3-carboxamide (compound A-24);

[0314] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound A-25);

[0315] 6-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)pyridineamide (compound A-26);

[0316] 5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-36);

[0317] 5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-37);

[0318] 5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-38);

[0319] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-39);

[0320] 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-40);

[0321] 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-5-hydroxypyridin-4-yl)furan-2-carboxamide (compound A-41);

[0322] 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-42);

[0323] 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(5-fluoro-2-methylpyridin-4-yl)furan-2-carboxamide (compound A-43);

[0324] 5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-44);

[0325] N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-45);

[0326] 5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-46);

[0327] 5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)furan-2-carboxamide (compound A-47);

[0328] N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-48);

[0329] 5-(4-(4-fluorophenyl)-1-methyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-49);

[0330] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-aminosulfonylphenyl)furan-2-carboxamide (Compound A-50);

[0331] N-(2-fluoro-4-aminosulfonylphenyl)-5-(4-(4-fluorophenyl)-1-(1-hydroxypropane-2-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-51);

[0332] 4-(4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carbamoyl)-3-fluorophenyl)-1-methylpiperazin-1-onium (compound A-52);

[0333] 5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-53);

[0334] rac-5-(4-(4-fluorophenyl)-1-((3R,4S)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-54);

[0335] 5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-55);

[0336] N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-56);

[0337] rac-5-(4-(4-fluorophenyl)-1-((4R)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-57);

[0338] N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-58);

[0339] rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-60);

[0340] rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-61);

[0341] rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-62); or

[0342] rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-63).

[0343] 26. The compound according to embodiment 1, wherein the compound is one of the following:

[0344] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide (compound B-1);

[0345] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide (compound B-2);

[0346] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide (compound B-3);

[0347] 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (compound B-4);

[0348] 5-(1-Cyclohexyl-4-(p-Tolyl)-1H-Imidazol-5-yl)-N-(4-Methoxyphenyl)furan-2-carboxamide (Compound B-5);

[0349] 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (compound B-6);

[0350] 5-(1-Cyclohexyl-4-(p-Tolyl)-1H-Imidazol-5-yl)-N-(2-Fluorophenyl)furan-2-carboxamide (Compound B-7);

[0351] 5-(1-Cyclohexyl-4-(p-Tolyl)-1H-Imidazol-5-yl)-N-(4-Fluorophenyl)furan-2-carboxamide (Compound B-8)

[0352] N-(4-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-9);

[0353] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)phenyl)furan-2-carboxamide (compound B-10);

[0354] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide (compound B-11);

[0355] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (compound B-12);

[0356] N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-13);

[0357] N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-14);

[0358] N-(4-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-15);

[0359] N-(4-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-16);

[0360] N-(5-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-17);

[0361] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide (compound B-18);

[0362] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (compound B-19);

[0363] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylyl)furan-2-carboxamide (compound B-20);

[0364] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylyl)furan-2-carboxamide (compound B-21);

[0365] 3-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carbamate)ethyl benzoate (compound B-22);

[0366] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethylphenyl)furan-2-carboxamide (compound B-23);

[0367] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound B-24);

[0368] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide (compound B-25);

[0369] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide (compound B-26);

[0370] 2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carbamate)methyl benzoate (compound B-27);

[0371] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide (compound B-28);

[0372] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide (compound B-29);

[0373] N-(3-chloro-4-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-30);

[0374] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethylyl)furan-2-carboxamide (compound B-31);

[0375] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylyl)furan-2-carboxamide (compound B-32);

[0376] 4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)ethyl benzoate (compound B-33);

[0377] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-isopropylideneacetonefuran-2-carboxamide (Compound B-34)

[0378] N-(3-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-35);

[0379] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide (compound B-36);

[0380] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethyl-6-methylphenyl)furan-2-carboxamide (compound B-37);

[0381] 5-(1-Cyclopentyl-4-(4-Fluorophenyl)-1H-Imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide (Compound B-38);

[0382] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide (compound B-39);

[0383] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-4-methylphenyl)furan-2-carboxamide (compound B-40);

[0384] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (compound B-41);

[0385] N-(4-chloro-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-42);

[0386] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluoro-2-methylphenyl)furan-2-carboxamide (compound B-43);

[0387] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)furan-2-carboxamide (compound B-44);

[0388] N-(3-chloro-4-methoxyphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-45);

[0389] N-(4-acetamidophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-46);

[0390] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide (compound B-47);

[0391] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(m-tolyl)furan-2-carboxamide (compound B-48);

[0392] N-(4-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-49);

[0393] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide (compound B-50);

[0394] N-(4-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-51);

[0395] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide (compound B-52);

[0396] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (compound B-53);

[0397] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide (compound B-54);

[0398] N-(2-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-55);

[0399] N-(4-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-56);

[0400] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide (compound B-57);

[0401] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (compound B-58);

[0402] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylyl)furan-2-carboxamide (compound B-59);

[0403] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylyl)furan-2-carboxamide (compound B-60);

[0404] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethylphenyl)furan-2-carboxamide (compound B-61);

[0405] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound B-62);

[0406] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide (compound B-63);

[0407] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide (compound B-64);

[0408] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide (compound B-65);

[0409] N-(3-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-66);

[0410] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylyl)furan-2-carboxamide (compound B-67);

[0411] N-(2-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-68);

[0412] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethylyl)furan-2-carboxamide (compound B-69);

[0413] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-isopropylidenepropanefuran-2-carboxamide (Compound B-70);

[0414] N-(3-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-71);

[0415] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide (compound B-72);

[0416] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide (compound B-73);

[0417] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide (compound B-74);

[0418] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (compound B-75);

[0419] N-(4-chloro-2-fluorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-76);

[0420] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-methylphenyl)furan-2-carboxamide (compound B-77);

[0421] N-(4-acetaminophen)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-78); or

[0422] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide (compound B-79).

[0423] 27. The compound according to embodiment 1, wherein the compound is one of the following:

[0424] 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamido)-3-fluoropyridine 1-oxide (compound C-1);

[0425] 3'-(tert-butyl)-N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-2);

[0426] 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carbamate)-3-methoxybenzoic acid (compound C-3);

[0427] 3-(4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carbamate)-3-fluorophenyl)propionic acid (compound C-4);

[0428] 3'-(tert-butyl)-N-(2-chloro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-5);

[0429] 3'-(tert-butyl)-5'-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-6);

[0430] N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-7);

[0431] 3-Chloro-4-(5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)pyridine 1-oxide (compound C-8);

[0432] 5'-(4-fluorophenyl)-N-(4-(2-hydroxyethyl)-2-methoxyphenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-9);

[0433] 3-Fluoro-4-(5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)benzoic acid (compound C-10);

[0434] 3-(3-chloro-4-(5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carbamate)phenyl)propionic acid (compound C-11);

[0435] 5'-(4-fluorophenyl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-12);

[0436] N-(2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-13);

[0437] N-(4-(bis(2-hydroxyethyl)amino)-2-chlorophenyl)-5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-14);

[0438] 4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carbamate)-3-methoxypyridine 1-oxide (compound C-15);

[0439] N-(2-fluoro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-16);

[0440] 3-Chloro-4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carbamate)benzoic acid (compound C-17);

[0441] 3-(4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carbamate)-3-methoxyphenyl)propionic acid (compound C-18);

[0442] N-(2-fluoro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-19);

[0443] N-(2-chloro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-20);

[0444] N-(4-(bis(2-hydroxyethyl)amino)-2-methoxyphenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-21);

[0445] 3-Fluoro-4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamido)pyridine 1-oxide (compound C-22);

[0446] N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-23);

[0447] 4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carbamate)-3-methoxybenzoic acid (compound C-24);

[0448] 3-(3-fluoro-4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carbamate)phenyl)propionic acid (compound C-25);

[0449] N-(2-chloro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-26);

[0450] 5'-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-27);

[0451] N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-28);

[0452] 5-(4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-29);

[0453] 4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)-3-fluoropyridine 1-oxide (compound C-30);

[0454] 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-31);

[0455] 5-(1-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-32);

[0456] 5-(4-(4-fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-33);

[0457] 5-(4-(4-fluorophenyl)-1-(1-methylcyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-34);

[0458] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)furan-2-carboxamide (compound C-35)

[0459] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-morpholinophenyl)furan-2-carboxamide (compound C-36);

[0460] N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound C-37);

[0461] 5-(1-Benzyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-38);

[0462] 5-(4-(4-fluorophenyl)-1-(pyridin-4-ylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-39);

[0463] 5-(4-(4-fluorophenyl)-1-(pyrimidin-4-ylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-40);

[0464] 5-(1-(bicyclo[3.2.1]octane-3-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-41);

[0465] 5-(1-(bicyclo[2.2.2]octane-2-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-42);

[0466] 5-(1-(bicyclo[3.1.1]heptane-3-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-43);

[0467] 5-(4-(4-chlorophenyl)-1-cyclopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-44);

[0468] 5-(1-Cyclopentyl-4-(p-Tolyl)-1H-Imidazol-5-yl)-N-(3-Fluoropyridin-4-yl)furan-2-carboxamide (Compound C-45);

[0469] 5-(1-Cyclopentyl-4-(2,4-Difluorophenyl)-1H-imidazol-5-yl)-N-(3-Fluoropyridin-4-yl)furan-2-carboxamide (compound C-46);

[0470] 5-(1-Cyclopentyl-4-(4-isopropylphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-47);

[0471] 5-(1-Cyclopentyl-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-48);

[0472] 5-(4-(4-chlorophenyl)-1-(cyclopentylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-49);

[0473] 5-(1-(cyclopentylmethyl)-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-50);

[0474] 5-(1-(cyclopentylmethyl)-4-(4-isopropylphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-51);

[0475] 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N-methylfuran-2-carboxamide (compound C-52);

[0476] 5'-(4-fluorophenyl)-N-(3-fluoropyridin-4-yl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-iminosulfonamide (compound C-56);

[0477] 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxyoxime amide (compound C-57);

[0478] 5'-(4-fluorophenyl)-N-(3-fluoropyridin-4-yl)-N-hydroxy-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound C-58); or

[0479] 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N'-methylfuran-2-carbazide (compound C-59).

[0480] 28. The compound according to embodiment 1, wherein the compound is not one of the following:

[0481] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide (Compound 1);

[0482] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide (compound 2);

[0483] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide (compound 3);

[0484] 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (compound 4);

[0485] 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide (compound 5);

[0486] 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (compound 6);

[0487] 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound 7);

[0488] 5-(1-Cyclohexyl-4-(p-Tolyl)-1H-Imidazol-5-yl)-N-(4-Fluorophenyl)furan-2-carboxamide (Compound 8);

[0489] N-(4-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 9);

[0490] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound 10);

[0491] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide (compound 11);

[0492] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (Compound 12);

[0493] N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 13);

[0494] N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 14);

[0495] N-(4-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 15);

[0496] N-(4-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 16);

[0497] N-(5-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 17);

[0498] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide (compound 18);

[0499] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (compound 19);

[0500] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylyl)furan-2-carboxamide (Compound 20);

[0501] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylyl)furan-2-carboxamide (compound 21);

[0502] 3-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carbamate)ethyl benzoate (compound 22);

[0503] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethylphenyl)furan-2-carboxamide (Compound 23);

[0504] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 24);

[0505] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide (Compound 25);

[0506] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide (Compound 26);

[0507] 2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carbamate)methyl benzoate (compound 27);

[0508] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide (Compound 28);

[0509] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide (Compound 29);

[0510] N-(3-chloro-4-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 30);

[0511] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethylyl)furan-2-carboxamide (compound 31);

[0512] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylyl)furan-2-carboxamide (compound 32);

[0513] 4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carbamate)ethyl benzoate (compound 33);

[0514] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-isopropylidenepropanefuran-2-carboxamide (compound 34);

[0515] N-(3-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 35);

[0516] 5-(1-Cyclopentyl-4-(4-Fluorophenyl)-1H-Imidazol-5-yl)-N-(3-(Methylthio)phenyl)furan-2-carboxamide (Compound 36);

[0517] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethyl-6-methylphenyl)furan-2-carboxamide (Compound 37);

[0518] 5-(1-Cyclopentyl-4-(4-Fluorophenyl)-1H-Imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide (Compound 38);

[0519] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide (compound 39);

[0520] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-4-methylphenyl)furan-2-carboxamide (Compound 40);

[0521] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (compound 41);

[0522] N-(4-chloro-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 42);

[0523] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluoro-2-methylphenyl)furan-2-carboxamide (compound 43);

[0524] 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)furan-2-carboxamide (compound 44);

[0525] N-(3-chloro-4-methoxyphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 45);

[0526] N-(4-acetamidophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 46);

[0527] 5-(1-Cyclopentyl-4-(4-Fluorophenyl)-1H-imidazol-5-yl)-N-(p-Tolyl)furan-2-carboxamide (Compound 47);

[0528] 5-(1-Cyclopentyl-4-(4-Fluorophenyl)-1H-imidazol-5-yl)-N-(m-Tolyl)furan-2-carboxamide (Compound 48);

[0529] N-(4-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 49);

[0530] 5-(1-Cyclopentyl-4-(4-Fluorophenyl)-1H-Imidazol-5-yl)-N-(2-Methoxyphenyl)furan-2-carboxamide (Compound 50);

[0531] N-(4-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 51);

[0532] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide (compound 52);

[0533] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (compound 53);

[0534] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide (compound 54);

[0535] N-(2-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 55);

[0536] N-(4-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 56);

[0537] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide (compound 57);

[0538] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (compound 58);

[0539] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylyl)furan-2-carboxamide (compound 59);

[0540] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylyl)furan-2-carboxamide (Compound 60);

[0541] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethylphenyl)furan-2-carboxamide (Compound 61);

[0542] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound 62);

[0543] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide (compound 63);

[0544] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide (Compound 64);

[0545] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide (Compound 65);

[0546] N-(3-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 66);

[0547] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylyl)furan-2-carboxamide (compound 67);

[0548] N-(2-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 68);

[0549] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethylyl)furan-2-carboxamide (compound 69);

[0550] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-isopropylidenepropanefuran-2-carboxamide (compound 70);

[0551] N-(3-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 71);

[0552] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide (compound 72);

[0553] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide (Compound 73);

[0554] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide (Compound 74);

[0555] 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (compound 75);

[0556] N-(4-chloro-2-fluorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 76);

[0557] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-methylphenyl)furan-2-carboxamide (Compound 77);

[0558] N-(4-acetaminophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 78); or

[0559] 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide (Compound 79).

[0560] Example

[0561] TNIK inhibition

[0562] The compound's function as a TNIK inhibitor was investigated to produce the data in Table 1. The compound was incubated with 8 mM MMOPS, 0.2 mM EDTA, 250 μM TNIK control peptide, 10 mM magnesium acetate, and [γ-33P-APT] (specific activity and concentration as needed) at pH 7.0. The reaction was initiated by adding a Mg / ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding 0.5% phosphate. 10 μL of the reaction was then spotted onto a P30 filter pad and washed four times in 0.425% phosphate for 4 min, followed by one wash in methanol, before drying and scintillation counting. Additional information is available in the Eurofins Kinase Profiler. TM The Service Assay Protocols v85.2 was found, and its entire contents are incorporated into this article through a specific reference.

[0563] Fibrosis determination

[0564] Cell culture

[0565] HDF / TERT166 working batches of cells can be thawed in liquid nitrogen and expanded under standard conditions (medium: DMEM / Ham's F12 basal medium supplemented with 1x GlutaMax-I and 10% FBS, antibiotic-free; 37°C, 5% CO2). For treatment, cells can be cultured at 7500 cells / cm² the day before the first treatment. 2Cells were seeded at the specified density in 12-well plates. Cells were seeded in starvation medium (DMEM / Ham's F12 basal medium supplemented with 1xGlutaMax-I and 0.5% FBS, antibiotic-free). Approximately 24 hours post-seeding, the substance was dissolved in DMSO (stock solution: 10 mM) and diluted to a final concentration of 10 μM in starvation medium. Half of this working dilution was supplemented with 100 pg / mL TGF-β. For each substance, two wells were treated with a 10 μM concentration of the substance and a 10 μM concentration supplemented with 100 pg / mL TGF-β. Simultaneously, cells could be treated alone with 100 pg / mL TGF-β. Cells in starvation medium served as a control. All cells could be treated by changing the medium. Treatment could be repeated with fresh dilution 24 hours after the first treatment (48 hours post-seeding). 24 hours after the second treatment (72 hours after inoculation), the culture medium can be removed, and the cells can be washed once with PBS. Cells can then be directly lysed using 1 mL of Tri-reagent (Sigma Aldrich) per well. The lysates can be collected in 1.5 mL tubes and stored at -80°C until RNA is isolated.

[0566] qPCR analysis

[0567] RNA isolation

[0568] RNA extraction can be performed using 200 μL of chloroform, and phase separation can be achieved by centrifugation at 12,000 g for 15 minutes at 4 °C. 500 μL of the upper aqueous phase can be extracted and then further precipitated and purified using the miRNeasy mini-kit (Qiagen) on a QIAcube liquid handling robot. Precipitation can be performed by adding 150 μL of nuclease-free water and 7 μL of glycogen to 500 μL, followed by 750 μL of 100% ethanol. The column can be washed with RWT and RPE buffers, and circulating RNA can be eluted in a single run with 30 μL of nuclease-free water and stored at –80 °C. RNA concentration can be determined spectrophotometrically using a Nanodrop instrument.

[0569] mRNA qPCR quantification

[0570] cDNA can be synthesized from isolated total RNA using the GrandScript cDNA Synthesis Kit. Reverse transcription can be performed with 200 ng of total RNA in 20 μL of reaction (10 μL of RNA can be used for low-concentration samples if possible). For each sample, qPCR can be performed in duplicate in 10 μL of reaction using 2 μL of 1:2 diluted cDNA and 8 μL of qPCR mixture. The qPCR mixture consists of 5 μL of SYBR Grandmaster mixture, 0.8 μL of forward and reverse primers (10 μM), and 2.2 μL of nuclease-free water. qPCR can be performed on a Roche LightCycler 480II instrument. The following thermal cycling conditions can be used: 45 cycles of 95°C for 30 s, 95°C for 5 s, 63°C for 15 s, 72°C for 10 s, followed by melting curve analysis. The Cq value can be calculated using the second derivative maxima method provided in the LC480 II software.

[0571] TNIK Linked to Fibrosis and Cancer Metastasis

[0572] Collagen production was assessed using a known TNIK inhibitor (5-(4-acetamidobenzamido)-2-(aniline)-1,3-triazole-4-carboxamide). Data showed that this TNIK inhibitor reduced collagen type 1 α1 (COL1A1) mRNA expression. Furthermore, this TNIK inhibitor suppressed the effect of TGF-β treatment on COL1A1 mRNA expression. COL1A1 expression is associated with fibrosis, and upregulation of COL1A1 can increase fibrosis in subjects. Therefore, reducing COL1A1 mRNA expression, especially when initially overexpressed, can be used to treat or inhibit fibrosis in subjects. It is well known that elevated TGF-β expression in affected organs, followed by deregulation of TGF-β function, is associated with abnormal connective tissue deposition observed during fibrotic disease flare-ups. By inhibiting the effect of TGF-β treatment on COL1A1 mRNA expression, fibrosis can be treated and reduced. Since it is well known that TGF-β-activated EMT can be inhibited by attenuating Smad and non-Smad signaling pathways, including Wnt, NF-κB, FAK-Src-pile associated focal adhesion, and MAP kinase (ERK and JNK) signaling pathways, there is evidence that TNIK inhibitors can be used to inhibit TGF-β-activated EMT. Therefore, TNIK is an inhibitory target for therapies that can be used to treat and / or prevent EMT-based diseases such as cancer metastasis and fibrosis. Thus, the evidence suggests that the TNIK inhibitors described herein may be used in the treatment of EMT-based diseases such as cancer metastasis and fibrosis.

[0573] The link between TNIK and lung cancer

[0574] Furthermore, TGF-β is known to mediate epithelial mesenchymal phenotypic transformation in cancer cells (e.g., lung cancer). Inhibition of TNIK is known to suppress TGF-β activity, thereby inhibiting the development or progression of cancers such as lung cancer. Therefore, inhibition of TNIK using the TNIK inhibitors described herein can be used in methods for treating cancers such as lung cancer.

[0575] Furthermore, TNIK inhibitors can be administered, for example, before, during, or after the onset of a disease or condition, to individuals who are susceptible to or suspected of being susceptible to the diseases or conditions described herein. Specifically, TNIK inhibitors can be used to suppress, prevent, or delay the onset or progression of diseases or conditions such as cancer and fibrosis.

[0576] Therefore, the TNIK inhibitors described herein can be used in methods of inhibiting TNIK to suppress diseases or conditions associated with TNIK activity or increased TNIK activity or downstream upregulation or increased activity.

[0577] compound

[0578] In some embodiments, the present invention includes novel compounds as kinase inhibitors (e.g., TNIK kinase inhibitors and / or MAP4K4 kinase inhibitors). For example, the compounds listed in this section may be novel.

[0579] In some embodiments, the kinase inhibitor compound (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) may include: a structure of formula A or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph or its solvate, or any chirality having any chiral center.

[0580]

[0581] In some respects: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a heteroaromatic ring; ring 3 comprises at least one heteroaromatic ring and at least one alicyclic ring optionally fused with at least one heteroaromatic ring; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or linker; Y 1 It is a connector; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; R 1 R 6 R 11 and R 12 Each is an independent chemical part (e.g., hydrogen or other substituents). In some aspects, the compound includes at least one of the following: when Y is a bond, R A It is an aromatic C3 alicyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, any of which may be substituted or unsubstituted; or when Y is the chemical moiety, RA It is a C3 alicyclic ring, a 5-membered alicyclic ring, a 5-membered heterocyclic ring, a 6-membered alicyclic ring, a 6-membered heterocyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, which may be substituted or unsubstituted and may or may not have heteroatoms; or the compound comprises at least one of the following: when ring 1 is phenyl, at least one of the following: ring 2 is not furanyl; ring 3 is not imidazolyl; or ring 4 is not phenyl; when ring 2 is furanyl, at least one of the following: ring 1 is not phenyl; ring 3 is not imidazolyl; or ring 4 is not phenyl; when ring 3 is imidazolyl, at least one of the following: ring 1 is not phenyl; ring 2 is not furanyl; or ring 4 is not phenyl; or when ring 4 is phenyl, at least one of the following: ring 1 is not phenyl; ring 2 is not furanyl; or ring 3 is not imidazolyl. In some aspects, one of ring 1 or ring 4 has an o as a positive integer. In some respects, o is simply 0 when it is on a heteroaryl ring (e.g., when ring 1 or ring 4 is a heteroaryl ring).

[0582] In some respects, Y 1 Amides including those having nitrogen bonded to ring 1 and carbon bonded to ring 2.

[0583] In some embodiments, the compound comprises at least one of the following: Y 1 Including amides having a nitrogen bonded to ring 1 and a carbon bonded to ring 2; when Y is a bond, R A It is a C3 alicyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, any of which may be substituted or unsubstituted; when Y is the chemical part, R A It is a C3 alicyclic ring, a 5-membered alicyclic ring, a 5-membered heterocyclic ring, a 6-membered alicyclic ring, a 6-membered heterocyclic ring, a straight-chain aliphatic chain, or a branched aliphatic chain, which may be substituted or unsubstituted and have or not have heteroatoms; or the compound includes at least one of the following: when ring 1 is phenyl, at least one of the following: ring 2 is not furanyl; ring 3 is not imidazolyl; or ring 4 is not phenyl; when ring 2 is furanyl, at least one of the following: ring 1 is not phenyl; ring 3 is not imidazolyl; or ring 4 is not phenyl; when ring 3 is imidazolyl, at least one of the following: ring 1 is not phenyl; ring 2 is not furanyl; or ring 4 is not phenyl; or when ring 4 is phenyl, at least one of the following: ring 1 is not phenyl; ring 2 is not furanyl; or ring 3 is not imidazolyl.

[0584] In some embodiments, the compound comprises: ring 1 being phenyl, pyridyl, or pyrimidinyl; ring 2 being a 5- or 6-membered heteroaromatic ring; ring 3 comprising a 5-membered heteroaromatic ring or a 5-membered heteroaromatic ring fused to a 6-membered heteroaromatic ring, wherein the 6-membered heteroaromatic ring is fused to a 5-membered alicyclic ring, wherein the bond to Y is through the 5-membered heteroaromatic ring; ring 4 being phenyl, pyridyl, pyrimidinyl, or triazine; Y being a bond or an aliphatic linker; and wherein when Y is a bond, RA It is not a 5-membered alicyclic ring.

[0585] In some embodiments, the compound comprises: ring 1 being phenyl, pyridyl, or pyrimidinyl, wherein when ring 1 is pyridyl or pyrimidinyl, nitrogen is located at the para, meta, or ortho position in the ring; ring 2 being furanyl, thiophene, pyrroloyl, oxacyclopentaneyl, thiazolyl, imidazolyl, triazolyl, or pyridinyl; ring 3 being imidazolyl, triazolyl, or cyclopentadienylpyrrolopyridinyl fused ring; or cyclopentadienylfuranopyridinyl; ring 4 being phenyl, pyridyl, pyrimidinyl, or triazine, wherein when ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; when ring 4 is pyrimidinyl, the nitrogen atom is located at the meta or ortho position in the ring; and Y is a bond or a C1-C6 aliphatic atom.

[0586] In some implementations, when Y is a C1-C6 aliphatic connector, R A It is a C3-C6 alicyclic ring, a C5-C6 heterocyclic ring, an aromatic ring, or a C1-C6 alicyclic ring. 12 Linear aliphatic or C1-C 12 Branched aliphatic chains, which may be substituted or unsubstituted, any with or without heteroatoms, or when Y is a bond, R A It is not a C6-C6 alicyclic ring.

[0587] In some implementation schemes, R 1 R 6 R 11 and R 12 Each of these groups independently represents hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0588] In some implementation schemes, R 11 and R 12 Each is either hydrogen or does not exist, and R1 or R 6 Each of these groups independently represents hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0589] In some implementations, each R 1 Independently, it is hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethoxy, or a combination thereof.

[0590] In some implementation schemes, R 11 and R 12 It is either hydrogen or absent, and each R 6Independently, it is hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, heptaylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0591] In some implementation schemes, Y 1 It is an amide, hydrazide, carbazide, hydroxy-substituted amide, alkyl-substituted amide, carboxyoximamide, or iminosulfonamide.

[0592] In some implementation schemes, R A Derived from hydrogen, cyclopentyl, tetrahydrofuranyl, pyrrolyl, piperidinyl, pyridyl, pyrimidinyl, dicycloheptyl, dicyclooctyl, dicyclo[3.1.1]heptyl-3-yl, dicyclo[2.2.2]octyl-2-yl, dicyclo[3.2.1]octane-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxacyclobutyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, phenyl, or combinations thereof.

[0593] In some embodiments, ring 1 is phenyl or pyridyl, and when ring 1 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; ring 2 is furanyl, thiophene, pyrroloyl, oxazoloyl, thiazolyl; imidazolyl, triazolyl, or pyridyl; ring 3 is imidazolyl, triazolyl, or cyclopentadienylpyrrolopyridyl fused ring group; or cyclopentadienylfuranolpyridyl; ring 4 is phenyl, pyridyl, pyrimidinyl, or triazine, and when ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position in the ring; when ring 4 is pyrimidinyl, nitrogen is located at the meta or ortho position in the ring; Y is a bond or C1-C6 aliphatic; Y 1 It is an amide connector; and when Y is a C1-C6 aliphatic connector, R AIt is a C3-C6 alicyclic ring, a C5-C6 heterocyclic ring; C1-C 12 Linear aliphatic or C1-C 12 Branched aliphatic chains, which may be substituted or unsubstituted, either having or not having heteroatoms, or when Y is a bond, R A It is not a C6-C6 alicyclic ring.

[0594] In some implementation schemes, R 1 R 6 Each of these groups independently comprises hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, acetyl (i.e., CH3C=O), propionyl, butyryl, acetamide (i.e., acetamido), propionamide, butyrylamide, pentamide, hexamide, heptamide, octylamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, heptyl ester, octyl ester, methyl thioalkyl (i.e., thiomethyl), ethyl thioalkyl, propyl thioalkyl, butyl thioalkyl, pentyl thioalkyl, hexyl thioalkyl, heptyl thioalkyl, or octyl thioalkyl. In some aspects, R 11 and R 12 It is hydrogen or it does not exist.

[0595] In some embodiments, the kinase inhibitor (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) is a compound having the structure of formula A1 or A2, or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph, or its solvate, or any chirality having any chiral center. In some aspects of formula A1 or A2: ring D is a ring structure having one or more rings fused together; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is an independent chemical component;

[0596] X 1 X 2 X 3 X 6 X 7 X 8 X 9 X 10 X11 X 12 X 13 X 14 and X 20 Each is independently carbon or a heteroatom with or without substituents; Y is a bond or linker; Y 1 For connectors; m is 1, 2, or 3; n is 0, 1, or 2; when Y is a key, R A It is hydrogen, aromatic alicyclic, straight-chain alicyclic, or branched-chain alicyclic, any substituted or unsubstituted, any having or not having a heteroatom; when Y is a linker, R A It is aromatic, alicyclic, straight-chain aliphatic, or branched-chain aliphatic, with or without substitution, and with or without heteroatoms; wherein, when the X group in the aromatic ring is N, the R group bonded to it is absent; when the dashed line forms a double bond, X 12 For example, the oxygen in a double bond to a ketone.

[0597] In some respects: R A It is a C3 alicyclic, C4-C12 heterocyclic, straight alicyclic, or branched alicyclic chain, with or without substitution, wherein the C3 ring structure, straight alicyclic, or branched alicyclic structure has or does not have heteroatoms; ring D is a ring structure in which one or more rings are fused together; R 1 R 2 R 3 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is an independent substituent; X 1 X 2 X 3 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 and X 14 Each is independently carbon or a heteroatom with or without substituents; Y is a bond or linker; Y 1 It is a connector; m is 1, 2, or 3; and n is 0, 1, or 2. In some aspects, when the X group in the aromatic ring is N, the R group bonded to it is not present. These variables may be the same as those defined herein. In some aspects, the R group substitution patterns of some exemplary compounds may be applied to these formulas. In some aspects, the X group patterns of exemplary compounds may be applied to these formulas.

[0598] In some embodiments, the kinase inhibitor (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) may comprise a structure of one of formulas 4A-4K or 5A-5K, or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph, or its solvate, or any chirality having any chiral center. In some aspects: R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is an independent part of chemistry; X 1 X 2 X 3 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 and X 20 Each is independently carbon or a heteroatom with or without substituents; Y 1 For the linker; m is 1, 2, or 3; and n is 0, 1, or 2; wherein when the X group in the aromatic ring is N, the R group bound to it does not exist; R 13 Independently selected from hydrogen, straight-chain aliphatic, branched-chain aliphatic, -Y-ring A; ring B; or -YR A In which rings A and B are either substituted or unsubstituted, and either have or do not have heteroatoms, wherein: Y is a bond or linker; ring A is alicyclic or heterocyclic alicyclic, or a combination thereof, either substituted or unsubstituted; and ring B is heterocyclic. In some cases, R 13 It is an aromatic compound, such as phenyl, pyridyl, pyrimidinyl, etc.

[0599] In some implementation schemes, X 4 It is C (e.g., CH, CH2) or N (e.g., N, NH, NR). 1 NOR 1 ), any group with or without substituents (e.g.,

[0600] R 1 ); and X 5 It is O or N (e.g., NH, NR)1 NOR 1 ). Here, R 1 As defined herein, H, OH, methyl, ethyl, and trifluoromethyl are examples. X 4 It can be C, NH, or NOH, or NOR. 1 X 5 Is it O or NR? 1 , or NOR 1 In some respects, X 4 It is C, CH, CH2, CR 1 C(R) 1 )2 or N, NH, NR 1 NOH, any substance with or without substituents.

[0601] In some embodiments, the compound may include at least one of the following: Y is a chemical particulate connector; Y 1 An amide connector that connects in any direction; X 3 Is it S or NH; X 6 X 7 X 8 X 9 X 10 X 11 X 12 or X 13 At least one of them is N; or X 14 It is O or NH. X 5 Is it O or NH, NR1, NOR? 1 .

[0602] In some implementations, connector Y 1 It is an amide, hydrazide, carbazide, hydroxy-substituted amide, alkyl-substituted amide, carboxyoximamide, or iminosulfonamide.

[0603] In some implementation schemes, Y 1 It could be:

[0604]

[0605] Where X 4 X 5 and X 6 It is a heteroatom. In some respects, X 4 For N and X 5 For O and R 1 It is as defined in this article. In some respects, X 4 For N and X 5 For N and R 1 It is, as defined in this article, for example, hydrogen. In some respects, X 4 For N and X 5 For O and R1 It is an amine that is hydrogen-containing, methyl, hydroxyl-containing, has substituents such as alkyl (e.g., methyl), or does not have substituents. In some aspects, X 4 Let N, X 5 For NH and X 6 It is O. In some respects, X 4 For C (e.g., CH, CH) 2 ) or N (e.g., N, NH, NR) 1 NOR 1 ), any group with or without substituents (e.g., R 1 ); and X 5 For O or N (e.g., NH, NR) 1 NOR 1 ). Here, R 1 As defined herein, H, OH, methyl, ethyl, and trifluoromethyl are examples. X 4 It can be C, NH, or NOH, or NOR. 1 X 5 Is it O or NR? 1 , or NOR 1 .

[0606] In some implementation schemes, Y 1 It could be:

[0607]

[0608] In some embodiments, the kinase inhibitor (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) may comprise a structure of formula 1K, formula 1L, formula 1M, formula 1N, formula 1O, formula 1P or formula 1Q or a derivative thereof, its prodrug, its salt, its stereoisomer, its tautomer, its polymorph or its solvate, or any chirality having any chiral center. In some aspects, Y is a chemical part connector; Y 1 For chemical component connectors; X 4 It is NH; and X 5 It is O. In some respects, X 4 It is C (e.g., CH, CH2) or N (e.g., N, NH, NR). 1 NOR 1 ), any group with or without substituents (e.g., R 1 ); and X 5 For O or N (e.g., NH, NR) 1 NOR 1 ). Here, R 1 As defined herein, H, OH, methyl, ethyl, and trifluoromethyl are examples. X 4 It can be C, NH, or NOH, or NOR.1 X 5 Is it O or NR? 1 , or NOR 1 .

[0609]

[0610]

[0611] Wherein; Y is the chemical connector; Y 1 For the chemistry section; X 4 For NR 1 And X 5 It can be O or N. In some respects, X 4 It is C (e.g., CH, CH2) or N (e.g., N, NH, NR). 1 NOR 1 ), any group with or without substituents (e.g., R 1 ); and X 5 For O or N (e.g., NH, NR) 1 NOR 1 ). Here, R 1 As defined herein, H, OH, methyl, ethyl, and trifluoromethyl are examples. X 4 It can be C, NH, or NOH, or NOR. 1 X 5 Is it O or NR? 1 , or NOR 1 .

[0612] In some embodiments, the kinase inhibitor may include a structure of formula 1R, formula 1S, formula 1T, formula 1U, formula 1V, formula 1W, formula 1X, formula 1Y or formula 1Z, its derivatives, its prodrugs, its salts, its stereoisomers, its tautomers, its polymorphs, or its solvates, or any chirality having any chiral center.

[0613]

[0614]

[0615] Among them, X 4 For NR 1 And X 5 It can be O or N. In some respects, X 4 It is C (e.g., CH, CH2) or N (e.g., N, NH, NR). 1 NOR 1 ), any group with or without substituents (e.g., R 1 ); and X 5 For O or N (e.g., NH, NR)1 NOR 1 ). Here, R 1 As defined herein, H, OH, methyl, ethyl, and trifluoromethyl are examples. X 4 It can be C, NH, or NOH, or NOR. 1 X 5 Is it O or NR? 1 , or NOR 1 .

[0616] In some embodiments, the kinase inhibitor may include the structure of formula 5K1 or formula 5L1, its derivatives, its prodrugs, its salts, its stereoisomers, its tautomers, its polymorphs, or its solvates, or any chirality having any chiral center.

[0617]

[0618] In the formula provided herein, the compound comprises at least one of the following: R as a substituent 3 ; R for substituents 6 / R 10 ; R for substituents 7 / R 9 ; and R for substituents 8 Other R groups may be hydrogen or absent. In some aspects, the compound includes at least one of the following: R that is F or methyl. 3 R is F, Br, Cl, methoxy, or methyl ester. 6 / R 10 R is F or methoxy 7 / R 9 ; or R is F, methoxy or methyl 8 In some respects, the compound comprises: R being F or methyl. 3 ; and R for H 1 R 2 R 4 and R 5 In some respects, the compound includes one of the following: R having a substituent. 6 and R 9 And R for H 7 R 8 and R 10 R with substituents 6 And R for H 7 R 8 R 9 and R 10 R with substituents 8 And R for H 6 R 7 R 9and R 10 ; or R with substituents 6 and R 8 And R for H 7 R 9 and R 10 In some respects, the compound comprises: R being F or methyl. 3 ; for H of R 1 R 2 R 4 and R 5 R is F, Br, Cl, methoxy, or methyl ester. 6 R is F or methoxy 9 ; and R for H 7 R 8 and R 10 In some respects, the compound comprises: R being F or methyl. 3 ; for H of R 1 R 2 R 4 and R 5 R is F, Br, Cl, methoxy, or methyl ester. 6 ; and R for H 7 R 8 R 9 and R 10 In some respects, the compound comprises: R being F or methyl. 3 ; for H of R 1 R 2 R 4 and R 5 ; R is F, methoxy or methyl 8 ; and R for H 6 R 7 R 9 and R 10 In some respects, the compound comprises: R being F or methyl. 3 ; for H of R 1 R 2 R 4 and R 5 R is F, Br, Cl, methoxy, or methyl ester. 6 ; R is F-methoxy or methyl 8 ; and R for H 7 R 9 and R 10 .

[0619] In some implementation schemes, R 1 R 2 R 3 R 4 R 5R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each is independently a halogen, alkyl, branched alkyl, alkoxy, alkyl ester, alkylthioalkyl (i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy, trifluoroalkyl, or acetamide (i.e., acetamido). In some respects, R 3 R 6 R 7 R 8 R 9 or R 10 Each group is independently a halogen, alkyl, branched alkyl, alkoxy, alkyl ester, alkylthioalkyl (i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy, trifluoroalkyl, acetamide (i.e., acetamido), and the remaining R groups are hydrogen or absent. In some respects, n is 0 and R 11 and R 12 It does not exist.

[0620] In some implementation schemes, R 1 R 2 R 3 R 4 and R 5 Each of the following is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethoxy, or a combination thereof.

[0621] In some implementation schemes, R 6 R 7 R 8 R 9 or R 10Each of these groups independently represents hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazine, piperazine, hydroxyethylpiperazine, bis(2-hydroxyethyl)amino, morpholino, or combinations thereof.

[0622] In some implementation schemes, R 11 and R 12 Each is either hydrogen or does not exist.

[0623] In some implementation schemes: X 1 X 2 X 6 X 7 X 8 X 9 X 12 X 13 and X 20 Independently CH or N; X 3 For NH, O, or S; X 10 and X 11 Independently CH or N; and X 14 It can be NH or O independently.

[0624] In some implementation schemes, R 13 Independently a C1-C6 alkyl group or coupled with at least one of the following: hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, any substituted or unsubstituted, or a combination thereof.

[0625] In some implementation schemes, R 13Independently a bond coupled to at least one of the following or a C1-C6 alkyl group: hydrogen, cyclopentyl, tetrahydrofuran, fluorotetrahydrofuran, difluorotetrahydrofuran, pyrrolyl, piperidinyl, phenyl, pyridinyl, pyrimidinyl, dicycloheptyl, dicyclooctyl, dicyclo[3.1.1]heptyl-3-yl, dicyclo[2.2.2]octyl-2-yl, dicyclo[3.2.1]octane-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, phenyl, or combinations thereof.

[0626] In some embodiments, the compound is one of the following compounds 80-106:

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633] In some embodiments, the R group substitution patterns and substituents of compounds 1-79 can be applied to any of compounds 80-106. Therefore, data from compounds 1-79 can provide indications of the corresponding compounds 80-106. In some respects, the substitution modes and substituents of the following compounds are applied to the core structures of compounds 80-106: 2-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide; 3-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide; 13-N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide; 14-N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide; 18-5 -(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide; compound 24-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide; compound 27-2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide Methyl H-imidazol-5-yl)furan-2-carboxamido)benzoate; compound 47-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide; or compound 50-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide.

[0634] In some embodiments, the compound has one of the following structures from compound A-1 to compound A-63:

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645] In some embodiments, the compound has one of the following structures from compound B-1 to compound B-79:

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661] In some embodiments, the compound has one of the following structures from compound C-1 to compound C-59:

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675] In some implementations, the core structure of compounds 80-106, which are TNIK kinase inhibitors, may be without the substitution patterns and substituents of compounds 1-79, which are not specifically listed in this paragraph.

[0676] In some embodiments, said compound is one of the following (compounds 80-106): 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound 80); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 81); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidine-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound 82); 5-(1-cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide Compound 83: N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide; Compound 84: N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidine-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide; Compound 85: N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide; Compound 86: N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)carboxamide); Compound 85: N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)carboxamide); Compound 86: N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)carboxamide); Compound 87: N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)carboxamide); Compound 88: N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)carboxamide); Compound 89 ... 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 87); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 88); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 89); 5-(1-cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound 90); 5-(1-cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-( 2-Fluorophenyl)furan-2-carboxamide (Compound 91); 5-(1-cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 92); 5-(1-cyclopentyl-4-(6-fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 93); 5-(1-cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound 94); N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide (Compound 95);5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide (Compound 96); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide (Compound 97); 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-5-carboxamide (Compound 98); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-2-carboxamide (Compound 99); 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiazole-5-carboxamide (Compound 100); 3'-Cyclopentyl-N-(2-fluorophenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (Compound 101) ); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazol-3-carboxamide (compound 102); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound 103); 6-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)pyridine Formamide (compound 104); N-(5-fluoro-2-methoxyphenyl)-5-(2-phenyl-3,6,7,8-tetrahydrocyclopentadien[d]pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide (compound 105); or N-(4-fluoro-2-methoxyphenyl)-5-(2-phenyl-7,8-dihydro-6H-cyclopentyl[d]furan[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide (compound 106).

[0677] In some embodiments, said compound is one of the following (compounds A-1 to A-63): 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-1); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-2); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidine-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-3); 5-(1-cyclopropyl-4 -(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-4); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide (compound A-5); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidine-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-6); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-8); N-(2-fluorophenyl)-5-( 4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-9); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidine-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-10); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-11); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A) -12); 5-(1-cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-13); 5-(1-cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-14); 5-(1-cyclopentyl-4-(6-fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-15); 5-(1-cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-16);N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide (compound A-17); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide (compound A-18); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide (compound A-19); 2-(1-cyclopentyl-4-(4-fluorophenyl)-;

[0678] 1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-5-carboxamide (compound A-20); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-2-carboxamide (compound A-21); 2-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)triazol-5-carboxamide (compound A-22); 3'-cyclopentyl-N-(2-fluorophenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound A-23); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-( 2-Fluorophenyl)-4H-1,2,4-triazol-3-carboxamide (Compound A-24); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound A-25); 6-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)pyridineamide (Compound A-26); 5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound A-36); 5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide 5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-37); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-38); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-39); 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-39); A-40); 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-5-hydroxypyridin-4-yl)furan-2-carboxamide (Compound A-41); 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (Compound A-42); 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(5-fluoro-2-methylpyridin-4-yl)furan-2-carboxamide (Compound A-43);5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-44); N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-45); 5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-46); 5-(4-(4-fluorophenyl)-1- (oxetane-3-yl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)furan-2-carboxamide (compound A-47); N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-48); 5-(4-(4-fluorophenyl)-1-methyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-49); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-aminosulfonyl) (Phenyl)furan-2-carboxamide (Compound A-50); N-(2-fluoro-4-aminosulfonylphenyl)-5-(4-(4-fluorophenyl)-1-(1-hydroxypropane-2-yl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-51); 4-(4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)-3-fluorophenyl)-1-methylpiperazin-1-onium (Compound A-52); 5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound A-50) A-53); rac-5-(4-(4-fluorophenyl)-1-((3R,4S)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-54); 5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-55); N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-56);rac-5-(4-(4-fluorophenyl)-1-((4R)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-57); N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-58); rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-6) 0); rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-61); rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-62); or rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-63).

[0679] In some embodiments, said compound is one of the following (compounds B-1 to B-79): 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide (compound B-1); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide (compound B-2); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide (compound B-3); 5-(1-cyclohexyl-4-(p-tolyl ...79). 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide (Compound B-4); 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (Compound B-6); 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound B-7); 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan- 2-Formamide (Compound B-8); N-(4-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound B-9); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound B-10); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide (Compound B-11); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide Amine (compound B-12); N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-13); N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-14); N-(4-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-15); N-(4-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-16);N-(5-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-17); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide (compound B-18); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (compound B-19); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-xylyl)furan-2-carboxamide (Compound B-20); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-xylyl)furan-2-carboxamide (Compound B-21); 3-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)ethyl benzoate (Compound B-22); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethylphenyl)furan-2-carboxamide (Compound B-23); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound B-23); -24); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide (compound B-25); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide (compound B-26); 2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide)methyl benzoate (compound B-27); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide (compound B-28); 5 -(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide (compound B-29); N-(3-chloro-4-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-30); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-xylyl)furan-2-carboxamide (compound B-31); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-xylyl)furan-2-carboxamide (compound B-32);4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)ethyl benzoate (compound B-33); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-isopropylidene acetone furan-2-carboxamide (compound B-34); N-(3-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-35); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide (compound B-36); 5-(1- Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethyl-6-methylphenyl)furan-2-carboxamide (compound B-37); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide (compound B-38); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide (compound B-39); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-4-methylphenyl)furan-2-carboxamide (compound B-40); 5-( 1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (compound B-41); N-(4-chloro-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-42); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluoro-2-methylphenyl)furan-2-carboxamide (compound B-43); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)furan-2-carboxamide (compound B) -44); N-(3-chloro-4-methoxyphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-45); N-(4-acetamidophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-46); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide (compound B-47); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(m-tolyl)furan-2-carboxamide (compound B-48);N-(4-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-49); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide (compound B-50); N-(4-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-51); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide (compound B-52); 5-(1-cyclohexyl-4-( 4-Fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (compound B-53); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide (compound B-54); N-(2-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-55); N-(4-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-56); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)- N-(2,4-difluorophenyl)furan-2-carboxamide (compound B-57); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (compound B-58); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-xylyl)furan-2-carboxamide (compound B-59); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-xylyl)furan-2-carboxamide (compound B-60); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethylyl)furan-2-carboxamide 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound B-62); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide (compound B-63); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide (compound B-64); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide (compound B-65);N-(3-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-66); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-xylyl)furan-2-carboxamide (compound B-67); N-(2-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-68); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-isopropylidene acetone furan-2-carboxamide (compound B-70); N-(3-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-71); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide (compound B-72); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide (compound B-73); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (compound B-74); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (compound B-75); N-(4-chloro-2-fluorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1 H-Imidazol-5-yl)furan-2-carboxamide (compound B-76); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-methylphenyl)furan-2-carboxamide (compound B-77); N-(4-acetamidophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound B-78); or 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide (compound B-79).

[0680] In some embodiments, said compound is one of the following (compounds C-1 to C-59): 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamido)-3-fluoropyridine 1-oxide (compound C-1); 3'-(tert-butyl)-N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-2); 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-methoxybenzoic acid (compound C-3); 3-( 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-fluorophenyl)propionic acid (compound C-4); 3'-(tert-butyl)-N-(2-chloro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-5); 3'-(tert-butyl)-5'-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-6); N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl) -3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-7); 3-chloro-4-(5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)pyridine 1-oxide (compound C-8); 5'-(4-fluorophenyl)-N-(4-(2-hydroxyethyl)-2-methoxyphenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-9); 3-fluoro-4-(5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (amino)benzoic acid (compound C-10); 3-(3-chloro-4-(5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)phenyl)propionic acid (compound C-11); 5'-(4-fluorophenyl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-12); N-(2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-13);N-(4-(bis(2-hydroxyethyl)amino)-2-chlorophenyl)-5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-14); 4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-methoxypyridine 1-oxide (compound C-15); N-(2-fluoro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-16); 3-chloro-4-(5'-( 4-Fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamido)benzoic acid (compound C-17); 3-(4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-methoxyphenyl)propionic acid (compound C-18); N-(2-fluoro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-19); N-(2-chloro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5'-(4- 3-(4-(bis(2-hydroxyethyl)amino)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-20); N-(4-(bis(2-hydroxyethyl)amino)-2-methoxyphenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-21); 3-fluoro-4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide)pyridine 1-oxide (compound C-22); N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide)-1-oxide 'H-[2,4'-biimidazole]-5-carboxamide (compound C-23); 4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-methoxybenzoic acid (compound C-24); 3-(3-fluoro-4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamido)phenyl)propionic acid (compound C-25); N-(2-chloro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-26);5'-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-27); N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-28); 5-(4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-29); 4-(5-(1-cyclopentyl-4-(4-fluorophenyl) 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-31); 5-(1-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-32); 5-(4-(4-fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-33); 5 -(4-(4-fluorophenyl)-1-(1-methylcyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-34); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-(piperazin-1-yl)phenyl)furan-2-carboxamide (compound C-35); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-morpholinophenyl)furan-2-carboxamide (compound C-36); N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-5-(1-cyclopentyl-4-yl)-2-fluorophenyl)-5-(1-cyclopentyl-4-yl)-2-fluorophenyl)-5-(1-cyclopentyl-4-yl)-5-(4-fluorophenyl ... 5-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound C-37); 5-(1-benzyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-38); 5-(4-(4-fluorophenyl)-1-(pyridin-4-ylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-39); 5-(4-(4-fluorophenyl)-1-(pyrimidin-4-ylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-40);5-(1-(bicyclo[3.2.1]octane-3-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-41); 5-(1-(bicyclo[2.2.2]octane-2-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-42); 5-(1-(bicyclo[3.1.1]heptane-3-ylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-43); 5-( 4-(4-chlorophenyl)-1-cyclopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-44); 5-(1-cyclopentyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-45); 5-(1-cyclopentyl-4-(2,4-difluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-46); 5-(1-cyclopentyl-4-(4-isopropylphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound C-47); 5-(1-cyclopentyl-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound C-48); 5-(4-(4-chlorophenyl)-1-(cyclopentylmethyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound C-49); 5-(1-(cyclopentylmethyl)-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound C-50); 5-(1-(cyclopentylmethyl)-4-(4-isopropylphenyl)-1H-imidazol-5-yl) 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N-methylfuran-2-carboxamide (compound C-52); 5'-(4-fluorophenyl)-N-(3-fluoropyridin-4-yl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-iminosulfonamide (compound C-56); 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxyoxime amide (compound C-57);5'-(4-fluorophenyl)-N-(3-fluoropyridin-4-yl)-N-hydroxy-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound C-58); or 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N'-methylfuran-2-carbazide (compound C-59).

[0681] In some embodiments, the compound is contained in a pharmaceutical composition comprising: a TNIK kinase inhibitor compound; and a pharmaceutically acceptable carrier containing the compound.

[0682] In some respects, the core structure of compounds 80-106 (e.g., the claimed compounds) as TNIK kinase inhibitors may be without the substitution patterns and substituents of compounds 1-79 not specifically listed in this paragraph.

[0683] In some embodiments, the claimed compound is not one of compounds 1-79. However, these compounds 1-79 can be used in the methods described herein.

[0684] In some embodiments, the claimed compound is not one of compounds A-1 to A-63. However, these compounds A-1 to A-63 can be used in the methods described herein.

[0685] In some embodiments, the claimed compound is not one of compounds B-1 to B-79. However, these compounds B-1 to B-79 can be used in the methods described herein.

[0686] In some embodiments, the claimed compound is not one of compounds C-1 to C-59. However, these compounds C-1 to C-59 can be used in the methods described herein.

[0687] In some embodiments, the claimed compound is not a compound of formula B or B1, but has a ring C as defined herein, such as a C5-C6 ring structure with or without heteroatoms (e.g., alicyclic). However, compounds of formula B or B1 may be used in the methods described herein.

[0688] In some embodiments, the claimed compound is not a compound of formula 7, 8, 9, 10, 11, 12, 13 or 14 having a ring A as defined herein; however, such compounds may be used in the methods described herein.

[0689] In vitro assay protocol

[0690] MAP4K4(h) was incubated with 8 mM MOPS at pH 7.0, 0.2 mM EDTA, 250 μM, 10 mM magnesium acetate, and [γ-33P-ATP] (specific activity and concentration as needed). The reaction was initiated by adding a Mg / ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding 0.5% phosphoric acid. 10 μL of the reaction solution was then spotted onto a P30 filter pad and washed four times in 0.425% phosphoric acid for 4 min each, followed by one wash in methanol before drying and scintillation counting.

[0691] LX-2 fibrosis determination.

[0692] Human hepatic stellate cells (LX-2) were grown in DMEM (Invitrogen, 11960) supplied with 1% MEM non-essential amino acids (Invitrogen, 11140-050), 2% fetal bovine serum (Hyclone, SV30087.03), penicillin (100 U / mL)-streptomycin (100 μg / mL) (Millipore, TMS-AB2-C), and 2 mM L-glutamine (Invitrogen, 25030-001). After culturing the cells in 12-well plates for 24 hours, the cell culture medium was replaced with the same medium as described above, except that 0.4% fetal bovine serum was used. After growing in the reduced serum medium for 20 hours, the cells were treated with the specified dose of the compound for 30 minutes. Subsequently, the cells were stimulated with 4 ng / mL TGF-β (R&D Systems, 240-B-002) for 48 hours. Cells were washed twice with DPBS and then harvested at 4°C with 100 μL of RIPA buffer (Sigma, R0278) supplemented with a protease inhibitor mixture (Roche, 04693132001). The cells were then analyzed using a BCA protein assay kit (Pierce). TM Total protein in each sample was quantified, and an equal amount of total protein in each sample was subjected to Western blot analysis. The antibodies used were mouse anti-α-actin (SPM332) (sc-365970), mouse anti-CTGF (E5) (sc-365970), and mouse anti-collagen α1 (3G3) (sc-293182) from Santa Cruz Biotechnologies; and mouse anti-GAPDH (6C5) (EMD Millipore, MAB374).

[0693] Table – TNIK, MAP4K4, Collagen Production Data:

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700] definition

[0701] As used herein, the term "alkyl" or "aliphatic" refers to a branched or unbranched saturated hydrocarbon group that typically, but not necessarily, contains 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, octyl, decyl, etc., and cycloalkyl such as cyclopentyl, cyclohexyl, etc. Typically, though not necessarily, alkyl as used herein contains 1 to 18 carbon atoms, or 1 to 12 carbon atoms. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Substituents identified as "C1-C6 alkyl" or "lower alkyl" contain 1 to 3 carbon atoms, and such substituents contain 1 or 2 carbon atoms (i.e., methyl and ethyl). "Substituted alkyl" refers to an alkyl group substituted by one or more substituents, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl groups in which at least one carbon atom is substituted by a heteroatom, as described in further detail below. Unless otherwise specified, the terms "alkyl" and "lower alkyl" respectively include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, etc. Alkyl groups may be substituted or unsubstituted. Exemplary substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substituted phenethyl, etc.

[0702] As used herein, the term "alkenyl" refers to a straight-chain, branched, or cyclic hydrocarbon group containing 2 to 24 carbon atoms and at least one double bond, such as vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosene, 24-carbonenyl, etc. Generally, though not strictly necessary, alkenyl groups herein contain 2 to 18 carbon atoms, or 2 to 12 carbon atoms. The term "lower alkenyl" refers to an alkenyl group with 2 to 6 carbon atoms, and the specific term "cycloalkenyl" refers to a cyclic alkenyl group, or one having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to an alkenyl group substituted by one or more substituents, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl groups in which at least one carbon atom is substituted by a heteroatom. Unless otherwise specified, the terms "alkenyl" and "lower alkenyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and lower alkenyl groups, respectively.

[0703] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 24 carbon atoms, such as ethynyl, n-propynyl, etc. Typically, though not strictly necessary, an alkynyl group as used herein contains 2 to approximately 18 carbon atoms, or 2 to 12 carbon atoms. The term "lower alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms. The term "substituted alkynyl" refers to an alkynyl group substituted by one or more substituents, and the terms "heteroatom-containing alkynyl" and "heteroatom-containing alkynyl" refer to alkynyl groups in which at least one carbon atom is substituted by a heteroatom. Unless otherwise specified, the terms "alkynyl" and "lower alkynyl" respectively include straight-chain, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl groups.

[0704] As used herein, the term "alkoxy" refers to an alkyl group linked by a single terminal ether bond; that is, "alkoxy" can be represented as -O-alkyl, where the alkyl group is as defined above. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, etc. Substituents labeled "C1-C6 alkoxy" or "lower alkoxy" herein contain 1 to 3 carbon atoms, and such substituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

[0705] As used herein, unless otherwise stated, the term "aryl" refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings fused together, directly or indirectly linked (such that different aromatic rings are bonded to a common group, such as a methylene or ethylene moiety). Examples of aryl groups contain 5 to 20 carbon atoms, and aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, such as phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone, etc. "Substituted aryl" refers to an aryl moiety substituted with one or more substituents, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl substituents in which at least one carbon atom is substituted with a heteroatom, as will be described in further detail below. Unless otherwise stated, the term "aryl" includes unsubstituted, substituted, and / or heteroatom-containing aromatic substituents.

[0706] As used herein, the term "aryloxy group" refers to an aryl group bonded by a single terminal ether bond, wherein "aryl" is as defined above. An "aryloxy group" may be represented as -O-aryl, wherein "aryl" is as defined above. Examples of aryloxy groups contain 5 to 20 carbon atoms, and aryloxy groups contain 5 to 14 carbon atoms. Examples of aryloxy groups include, but are not limited to, phenoxy, o-halo-phenoxy, m-halo-phenoxy, p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy-phenoxy, 2,4-dimethoxy-phenoxy, 3,4,5-trimethoxy-phenoxy, etc.

[0707] The term "alkylaryl" refers to an aryl group with an alkyl substituent, and the term "aralkyl group" refers to an alkyl group with an aryl substituent, wherein "aryl" and "alkyl" are as defined above. Examples of aralkyl groups contain 6 to 24 carbon atoms, and aralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, etc. Alkylaryl groups include, for example, p-methylphenyl, 2,4-xylylene, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl, 3-ethyl-cyclopent-1,4-diene, etc.

[0708] The term "cyclic" refers to an alicyclic or aromatic substituent that may or may not be substituted and / or contains heteroatoms, and that can be monocyclic, bicyclic, or polycyclic.

[0709] The terms “halogenated” and “halogen” are used in the conventional sense to refer to chlorine, bromine, and fluorine or iodine substituents.

[0710] The term "heteroatom-containing" as in "heteroatom-containing alkyl" (also known as "heteroalkyl") or "heteroatom-containing aryl" (also known as "heteroaryl") or "other uses of heteroatom" refers to a molecule, bond, or substituent in which one or more carbon atoms are substituted by non-carbon atoms, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur. Similarly, the term "heteroalkyl" refers to an alkyl substituent containing a heteroatom, and the term "heterocyclic" refers to a cyclic substituent containing a heteroatom. "Aryl" and "heteroaromatic" refer to "aryl" and "aromatic" substituents containing heteroatoms, respectively. Examples of heteroalkyl groups include alkoxyaryl, alkylthioalkyl-substituted alkyl groups, and N-alkylated aminoalkyl groups. Examples of heteroaryl substituents include pyrrolithyl, pyrrolithyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazoleyl, 1,2,4-triazolyl, and tetrazolyl, and examples of alicyclic groups containing heteroatoms include pyrrolithyl, morpholinyl, piperazine, and piperidinyl.

[0711] The term "hydrocarbon group" refers to a monovalent hydrocarbon group containing 1 to about 30 carbon atoms, or 1 to about 24 carbon atoms, or 1 to about 18 carbon atoms, or about 1 to 12 carbon atoms, including straight-chain, branched, cyclic, saturated and unsaturated species, such as alkyl, alkenyl, aryl, etc. "Substituted hydrocarbon group" refers to a hydrocarbon group substituted by one or more substituents, and the term "heteroatom-containing hydrocarbon group" refers to a hydrocarbon group in which at least one carbon atom is substituted by a heteroatom. Unless otherwise stated, the term "hydrocarbon group" should be interpreted as including substituted and / or heteroatom-containing hydrocarbon groups.

[0712] The term "substituted" in "substituted alkyl", "substituted aryl", etc., as mentioned in some of the above definitions, means that in an alkyl, aryl or other moiety, at least one hydrogen atom bonded to a carbon (or other) atom is substituted by one or more non-hydrogen substituents.

[0713] Furthermore, if permitted by specific groups, the aforementioned functional groups may be further substituted with one or more additional functional groups or one or more hydrocarbon moieties, such as those specifically listed above. Similarly, the aforementioned hydrocarbon moieties may be further substituted with one or more functional groups or other hydrocarbon moieties, such as those specifically listed above.

[0714] When the term “substituted” appears before a list of possible substituted groups or refers to possible substituted groups, it is intended that the term applies to each member of that group. For example, the phrase “substituted alkyl, alkenyl, and aryl” should be interpreted as “substituted alkyl, substituted alkenyl, and substituted aryl.” Similarly, when the term “heteroatom-containing” appears before a list of possible heteroatom-containing groups, it is intended that the term applies to each member of that group. For example, the phrase “heteroatom-containing alkyl, alkenyl, and aryl” should be interpreted as “heteroatom-containing alkyl, heteroatom-containing alkenyl, and heteroatom-containing aryl.”

[0715] All other chemical terms are defined as known in the art.

[0716] As used herein, the term “subject” refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that will become the recipient of a particular treatment. Generally, the terms “subject” and “patient” are used interchangeably in this document for the purpose of referring to human subjects.

[0717] "Pharmaceutical acceptable" means approved or permitted for use in animals, including humans, by federal or state regulatory agencies or listed in the United States Pharmacopeia or other recognized pharmacopoeias.

[0718] "Pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the expected pharmacological activity of the parent compound.

[0719] "Pharmaceutically acceptable excipients, carriers or adjuvants" means excipients, carriers or adjuvants that can be administered to a subject together with at least one TNIK inhibitor of the present disclosure, without destroying its pharmacological activity and being non-toxic when administered at a dose sufficient to deliver a therapeutic amount of the TNIK inhibitor.

[0720] "Pharmaceutically acceptable mediator" means a diluent, adjuvant, excipient or carrier that is administered with at least one TNIK inhibitor disclosed herein.

[0721] The terms "effective dose," "therapeutic effective dose," or "therapeutic effect" refer to the amount of a TNIK inhibitor, peptide, polynucleotide, small organic molecule, or other drug that effectively "treats" a disease or condition in a subject or mammal. In the case of cancer, a therapeutically effective dose of a drug has a therapeutic effect and may therefore reduce the number of cancer cells; reduce tumorigenicity, frequency, or capacity for tumorigenesis; reduce the number or frequency of cancer stem cells; reduce tumor size; inhibit or prevent cancer cell infiltration into peripheral organs, including, for example, cancer spread to soft tissues and bones; inhibit and prevent tumor metastasis; inhibit and prevent tumor growth; alleviate one or more cancer-related symptoms to some extent; reduce morbidity and mortality; improve quality of life; or a combination of these effects.

[0722] Terms such as “treatment” or “management” or “to treat” or “to alleviate” or “to alleviate” refer to 1) therapeutic measures that cure, alleviate, or reduce the symptoms of a diagnosed pathological condition or symptom and / or prevent its progression, and 2) preventive or preventative measures that prevent and / or slow the development of a target pathological condition or symptom. Therefore, those who need treatment include those who already have the condition; those who are susceptible to the condition; and those who need to prevent the condition.

[0723] Those skilled in the art will understand that the functions performed in the processes and methods disclosed herein can be implemented in different orders. Furthermore, the steps and operations outlined are provided by way of example only, and some steps and operations may be optional, combined into fewer steps and operations, or extended to other steps and operations without departing from the spirit of the disclosed embodiments.

[0724] This disclosure is not limited to the specific embodiments described in this application, but is intended as illustrative of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. In addition to those listed herein, functionally equivalent methods and apparatus within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terms of the appended claims and the full scope of their equivalents. It should be understood that this disclosure is not limited to specific methods, reagents, compound compositions, or biological systems, which, of course, can vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0725] Regarding the use of virtually any plural and / or singular terms in this document, those skilled in the art can convert plural to singular and / or singular to plural depending on the context and / or application. For clarity, various singular / plural substitutions may be explicitly stated herein.

[0726] Those skilled in the art will understand that, generally, the terms used herein, particularly in the appended claims (e.g., the body of the appended claims), are intended to be “open-ended” terms (e.g., the term “comprising” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “including” should be interpreted as “including but not limited to,” etc.). Those skilled in the art will further understand that if a particular number of claim statements are intended to be introduced, such intention will be explicitly stated in the claims, and without such statements, there is no such intention. For example, to aid understanding, the appended claims may include the use of the introductory phrases “at least one” and “one or more” to introduce claim statements. However, the use of such phrases should not be construed as implying that a claim statement introduced by the indefinite article “a” or “an” will limit any particular claim containing such an introduced claim statement to an embodiment containing only one such statement, even when the same claim includes the introductory phrases “one or more” or “at least one” along with indefinite articles such as “a,” “,” or “an” (e.g., “a” and / or “an” should be interpreted as meaning “at least one” or “one or more”); the same applies to the use of definite articles used to introduce claim statements. Furthermore, even when a specific number of introduced claims are explicitly stated, those skilled in the art will recognize that such a statement should be interpreted as meaning at least the number stated (e.g., a bare statement of "two statements" without other modifiers means at least two statements, or two or more statements). Additionally, in cases where conventions such as "at least one of A, B, and C" are used, such a construction generally implies that those skilled in the art will understand the meaning of the convention (e.g., "a system having at least one of A, B, and C" will include, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In cases where conventions such as "at least one of A, B, or C" are used, such a construction generally implies that those skilled in the art will understand the meaning of the convention (e.g., "a system having at least one of A, B, or C" will include, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Those skilled in the art will further understand that, in practice, any extractive terms and / or phrases presenting two or more alternative terms, whether in the specification or the claims, should be understood to include those terms.

[0727] 1. The possibility of either or both of these terms. For example, the phrase "A or B" would be understood as including the possibility of "A" or "B" or "A and B".

[0728] Furthermore, when features or aspects of this disclosure are described in accordance with the Markush Group, those skilled in the art will recognize that this disclosure is also described in accordance with any single member or subgroup of the Markush Group.

[0729] As those skilled in the art will understand, for any and all purposes, such as for providing written description, all scopes disclosed herein also cover any and all possible subscopes and combinations thereof. Any listed scope can be readily identified as sufficiently descriptive, and the same scope can be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily decomposed into a lower third, a middle third, and an upper third. As those skilled in the art will also understand, all language, such as “up to,” “at least,” etc., includes the listed numbers and refers to a scope that can subsequently be decomposed into subscopes as discussed above. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1-3 cells means a group having 1, 2, or 3 cells. Similarly, a group having 1-5 cells means a group having 1, 2, 3, 4, or 5 cells, etc.

[0730] Based on the foregoing, it will be understood that various embodiments of this disclosure have been described herein for illustrative purposes, and various modifications may be made without departing from the scope and spirit of this disclosure. Therefore, the various embodiments disclosed herein are not intended to be limiting, and the true scope and spirit are indicated by the appended claims.

[0731] The full content of all references cited in this article is incorporated into the article by specifically referencing everything they teach.

Claims

1. A compound of formula A or a salt or solvate thereof, in: Ring 1 is phenyl, pyridinyl, or pyrimidinyl; Ring 2 is a 5-membered heteroaromatic ring, wherein the heteroatom is selected from N, O and S; Ring 3 is an imidazole group; Ring 4 is a phenyl group; Y is a key; Y 1 It is an amide joint where nitrogen is bonded to ring 1 and carbon is bonded to ring 2; Each n is independently 0, 1, or 2; Each 'o' can be 0, 1, 2, 3, 4, or 5 independently; R 1 R 6 R 11 and R 12 Each of these groups independently represents F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, oxygen, oxide, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, methylcarboxylic acid, ethylcarboxylic acid, propionyl, butyryl, ethyl Amides, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, heptaylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazinyl, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino or morpholino; R A Alicyclic rings, 5- or 6-membered heterocyclic rings, C1-C 12 Straight-chain fatty acid chain or C3-C 12 Branched fatty chains, any of which are independently substituted or unsubstituted; The compound said compound satisfies at least one of the following conditions a) or b): a) When ring 1 is phenyl, ring 2 is not furanyl; or b) When ring 2 is furanyl, ring 1 is not phenyl.

2. The compound according to claim 1, wherein: Ring 1 is pyridinyl or pyrimidinyl; Ring 2 is a furanyl group; Ring 3 is an imidazole group; and Ring 4 is a phenyl group.

3. The compound according to claim 1, wherein n is 0, and R 1 or R 6 Each of these groups independently represents F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl Acetamide, methylacetamide, ethylacetamide, propionamide, butyramide, pentamide, hexamide, heptaamide, octamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptayl ester, octyl ester, methylthioalkyl, thiomethyl, ethylthioalkyl, propylthioalkyl, butylthioalkyl, pentylthioalkyl, hexylthioalkyl, octylthioalkyl, aminosulfonyl, methylpiperazinyl, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino or morpholino.

4. The compound according to claim 3, wherein each R 1 Independently, it is F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or trifluoromethoxy.

5. The compound according to claim 4, wherein each R 6 Independently, it is F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, or trifluoromethyloxy.

6. The compound according to claim 1, wherein R A It is tetrahydrofuranyl, pyrrolylyl, piperidinyl, dicycloheptyl, dicyclooctyl, dicyclo[3.1.1]hept-3-yl, dicyclo[2.2.2]oct-2-yl, dicyclo[3.2.1]oct-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, isopropyl or tert-butyl.

7. The compound of claim 1 or a salt or solvate thereof, wherein the compound is one of the following: 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide (Compound 96); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide (Compound 97); 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-5-carboxamide (Compound 98); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-2-carboxamide (Compound 99); 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiazol-5-carboxamide (Compound 100); 3'-Cyclopentyl-N-(2-fluorophenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-Bimidazole]-5-carboxamide (Compound 101); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazol-3-carboxamide (compound 102); or 5-(1-Cyclopentyl-4-(4-Fluorophenyl)-1H-Imidazol-5-yl)-N-(3-Fluoropyridin-4-yl)furan-2-carboxamide (Compound 103).

8. A compound or its salt or solvate that is one of the following: 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-1); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-2); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-3); 5-(1-Cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-4); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxamide (compound A-5); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-6); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-8); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-9); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidone-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-10); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-1,2,3-triazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-11); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-12); 5-(1-Cyclopentyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-13); 5-(1-Cyclopentyl-4-(pyridin-3-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-14); 5-(1-Cyclopentyl-4-(6-Fluoropyridin-3-yl)-1H-imidazol-5-yl)-N-(2-Fluorophenyl)furan-2-carboxamide (Compound A-15); 5-(1-Cyclopentyl-4-(pyrimidin-5-yl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-16); N-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-yl)-2-fluorobenzamide (compound A-17); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiophene-2-carboxamide (Compound A-18); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-1H-pyrrole-2-carboxamide (compound A-19); 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-5-carboxamide (Compound A-20); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazol-2-carboxamide (compound A-21); 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiazol-5-carboxamide (compound A-22); 3'-Cyclopentyl-N-(2-fluorophenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-Bimidazole]-5-carboxamide (compound A-23); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazol-3-carboxamide (compound A-24); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound A-25); 6-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)pyridineamide (compound A-26); 5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-36); 5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-37); 5-(4-(4-fluorophenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-38); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxypyridin-4-yl)furan-2-carboxamide (compound A-39); 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-40); 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-5-hydroxypyridin-4-yl)furan-2-carboxamide (compound A-41); 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-42); 5-(1-(4,4-difluorotetrahydrofuran-3-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(5-fluoro-2-methylpyridin-4-yl)furan-2-carboxamide (compound A-43); 5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-44); N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-45); 5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-46); 5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)furan-2-carboxamide (compound A-47); N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(oxetane-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-48); 5-(4-(4-fluorophenyl)-1-methyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-49); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluoro-4-aminosulfonylphenyl)furan-2-carboxamide (Compound A-50); N-(2-fluoro-4-aminosulfonylphenyl)-5-(4-(4-fluorophenyl)-1-(1-hydroxypropane-2-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-51); 4-(4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carbamoyl)-3-fluorophenyl)-1-methylpiperazin-1-onium (compound A-52); 5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-53); rac-5-(4-(4-fluorophenyl)-1-((3R,4S)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-54); 5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-55); N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-56); rac-5-(4-(4-fluorophenyl)-1-((4R)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-57); N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-58); rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-60); rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-61); rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-62); or rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-63).

9. The compound of claim 1 or a salt or solvate thereof, wherein the compound is one of the following: 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamido)-3-fluoropyridine 1-oxide (compound C-1); 3'-(tert-butyl)-N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-2); 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carbamate)-3-methoxybenzoic acid (compound C-3); 3-(4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carbamate)-3-fluorophenyl)propionic acid (compound C-4); 3'-(tert-butyl)-N-(2-chloro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-5); 3'-(tert-butyl)-5'-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-6); N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-7); 4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)-3-fluoropyridine 1-oxide (compound C-30); 5-(1-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-32); 5-(4-(4-fluorophenyl)-1-neopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-33); 5-(4-(4-fluorophenyl)-1-(1-methylcyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-34); 5-(4-(4-chlorophenyl)-1-cyclopentyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-44); 5-(1-Cyclopentyl-4-(p-Tolyl)-1H-Imidazol-5-yl)-N-(3-Fluoropyridin-4-yl)furan-2-carboxamide (Compound C-45); 5-(1-Cyclopentyl-4-(2,4-Difluorophenyl)-1H-imidazol-5-yl)-N-(3-Fluoropyridin-4-yl)furan-2-carboxamide (compound C-46); 5-(1-Cyclopentyl-4-(4-isopropylphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-47); or 5-(1-Cyclopentyl-4-(4-methoxyphenyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound C-48).

10. A pharmaceutical composition comprising: a compound of any one of claims 1-9 or a salt or solvate thereof and a pharmaceutically acceptable excipient.

11. Use of a compound of any one of claims 1-9 or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for inhibiting a kinase in a subject, wherein said kinase is a TNIK kinase and / or a MAP4K4 kinase.

12. Use of any compound of claims 1-9 or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating a disease, wherein said disease is fibrosis, cancer, systemic inflammation, metabolic disorder, cardiovascular disease or cancer.

13. The use according to claim 12, wherein the disease is fibrosis.

14. The use of claim 13, wherein the fibrosis is selected from pulmonary fibrosis, cystic fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, cerebral fibrosis, arterial fibrosis, joint fibrosis, intestinal fibrosis, Duchenne contracture fibrosis, keloid fibrosis, mediastinal fibrosis, myelofibrosis, Peronis disease fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma fibrosis, or adhesive capsulitis fibrosis.

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