Kinase inhibitor

Abstract

The TNIK and / or MAP4K4 kinase inhibitor is represented by the formula A TIFF2022523358000101.tif4990 (Ring 1 is an aromatic ring with or without heteroatoms; Ring 2 is an aromatic heterocycle; Ring 3 contains at least one aromatic heterocycle and optionally at least one alicyclic ring fused with at least one aromatic heterocycle; Ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or a linker; Y 1 is a linker; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; and each R 1 , R 6 , R 11 and R 12 are independently substituents; R A is a ring structure, an aliphatic straight chain, or an aliphatic branched chain, which may be substituted or unsubstituted, and may optionally contain or not contain heteroatoms), its derivatives, prodrugs, salts, stereoisomers, tautomeric polymorphs, or solvates, or those with chirality at any chiral center.

Description

Technical Field

[0001] Cross-reference This patent application claims priority to U.S. Provisional Patent Application No. 62 / 809,413, filed Feb. 22, 2019, which is specifically incorporated herein by reference in its entirety.

Background Art

[0002] Biologically active enzymes known as protein kinases that interact with TRAF2 and NCK are generally known in humans as TNIK kinase and are enzymes encoded by the TNIK gene. TNIK kinase is involved in various biological processes common to serine / threonine kinases, such as acting as an activator of the Wnt signaling pathway. TNIK kinase may be recruited to the promoter of Wnt target genes and may be required to activate their expression. TNIK kinase may act by phosphorylating TCF4 / TCF7L2. TNIK kinase appears to act upstream of the JUN N-terminal pathway. TNIK kinase may play a role in the response to environmental stress. Also, TNIK kinase is part of a signaling complex composed of NEDD4, RAP2A, and TNIK and controls the outgrowth and branching of dendritic protrusions of developing neurons. More generally, TNIK may play a role in cytoskeletal remodeling and may control cell spreading. Also, TNIK kinase phosphorylates Thr-322 of SMAD1.

[0003] Also, TNIK kinase is regarded as germinal center kinase (GCK) and may be characterized by an N-terminal kinase domain and a C-terminal GCK domain that perform regulatory functions.

[0004] Activation of TNIK kinase in Wnt signaling plays an important role in carcinogenesis and embryonic development. Mutations in this gene are associated with an autosomal recessive form of cognitive impairment.

[0005] Furthermore, TNIK kinase is involved in colorectal cancer and possibly other cancers as well. As such, TNIK kinase is recognized as an attractive drug candidate for targeting colorectal cancer.

[0006] Current data indicate that TNIK kinase is a potential target for the generation of small molecule inhibitors to specifically block the Wnt pathway in conditions such as colorectal cancer or autosomal recessive genetic forms of cognitive impairment.

[0007] It is also known that TGF-β-activated EMT can be inhibited by attenuation of Smad and non-Smad signaling pathways (including the Wnt, NF-κB, FAK-Src-paxillin-related focal adhesion, and MAP kinase (ERK and JNK) signaling pathways). As such, therapeutic targets related to EMT (such as TNIK being a target for inhibition) can be used for the treatment and / or prevention of EMT-based disorders (such as cancer metastasis and fibrosis).

[0008] Therefore, it would be advantageous to have a TNIK inhibitor that can inhibit TNIK activity. It would also be advantageous to have a specific TNIK inhibitor that selectively inhibits TNIK. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0009] SUMMARY In some embodiments, a method of inhibiting TNIK kinase and / or MAP4K4 kinase can include contacting TNIK kinase with a compound having the structure of Formula A CHEMICAL STRUCTURE or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomeric polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center.

[0010] In some embodiments, ring 1 is an aromatic ring, which may or may not contain a heteroatom; ring 2 is an aromatic heterocyclic ring; ring 3 contains at least one aromatic heterocyclic ring and optionally at least one alicyclic ring fused to at least one aromatic heterocyclic ring; ring 4 is an aromatic ring, which may or may not contain a heteroatom; Y is a bond or a linker; Y 1 is a linker; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; each R 1 , R 6 , R 11 , and R 12 are independently substituents; R A is a ring structure, an aliphatic straight chain, or an aliphatic branched chain, which may be substituted or unsubstituted and may or may not contain a heteroatom. In some embodiments, R 11 and R 12 are absent or are hydrogen. In some embodiments, at least one o of ring 1 or ring 4 is at least 1.

[0011] In some embodiments, ring 1 is a phenyl group or a pyridyl group; ring 2 is a 5-membered or 6-membered aromatic heterocyclic ring, or a combination thereof; ring 3 contains a 5-membered aromatic heterocyclic ring, or a 5-membered aromatic heterocyclic ring fused to a 6-membered aromatic heterocyclic ring, which is fused to a 5-membered alicyclic ring (where the bond to Y is through the aforementioned 5-membered aromatic heterocyclic ring), or a combination thereof; ring 4 is a phenyl group, a pyridyl group, a pyrimidinyl group, or a triazinyl group, or a combination thereof; Y is a bond or an aliphatic linker; Y 1 is an amide linker; R A is an alicyclic ring, an alicyclic heterocyclic ring, an aliphatic straight chain, or an aliphatic branched chain (which may be substituted or unsubstituted and may or may not contain a heteroatom), or a combination thereof.

[0012] In some embodiments, ring 1 is a phenyl group or a pyridyl group. When ring 1 is pyridyl, nitrogen is located at the para, meta, or ortho position within the ring; ring 2 is a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a triazolyl group, or a pyridyl group; ring 3 is an imidazolyl group, a triazolyl group, or a cyclopenta - pyrrolo - pyridinyl fused - ring group; or a cyclopenta - furo - pyridinyl group; ring 4 is a phenyl group, a pyridyl group, a pyrimidyl group, or a triazinyl group. When ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position within the aforementioned ring; when ring 4 is a pyrimidyl group, nitrogen is located at the meta or ortho position within the aforementioned ring; Y is a bond or a C1 - C6 aliphatic chain; Y 1 is a substituted or unsubstituted amide, a sulfonimide amide, a ketone, a carboxamide linker, or a combination thereof; R A is a C3 - C6 cycloaliphatic ring, a C5 - C6 cycloaliphatic heterocyclic ring; a C1 - C12 aliphatic straight chain, or a C1 - C12 aliphatic branched chain, any of which can be substituted or unsubstituted, and any aliphatic chain can contain or not contain heteroatoms.

[0013] In some embodiments, each R 1 、R 6 、R 11 、and R 12is, independently, 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, octoxy, acetyl (i.e., CH3C=O), propionyl, butyryl, acetamide (i.e., acetylamino), propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl. In some embodiments, R 11 and R 12 is hydrogen or does not exist.

[0014] In some embodiments, a method of inhibiting TNIK kinase and / or MAP4K4 kinase can include contacting TNIK kinase and / or MAP4K4 kinase with a compound having a structure of formula A1 or formula A2, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center. [Chemical formula]

[0015] In some embodiments, R A is a ring structure, an aliphatic straight chain, or an aliphatic branched chain, any of which can be substituted or unsubstituted and can optionally contain or not contain heteroatoms; ring D is a ring structure having one or more rings linked together; X 1 , X2 , X 3 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 are each independently a carbon atom or a heteroatom, with or without substituents; each 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 are independently substituents; Y is a bond or a linker; Y 1 is a linker; m is 1, 2, or 3; n is 0, 1, or 2. In some embodiments, when the X group is N within an aromatic ring, there is no R group attached to the X group. In some embodiments, n is 0, and R 11 and / or R 12 are each absent. R 11 and / or R 12 , if present, may have suitable ring atoms on any ring. When n is 0, the bond and R 11 and / or R 12 are absent. In some embodiments, the R A ring is directly linked to X 1 via a covalent bond (i.e., Y), etc. When R A is a ring, R A can be any alicyclic ring or alicyclic heterocycle or a combination thereof.

[0016] In some embodiments, the method can include administering a compound having a structure of Formula 1A, 2A, 3A, 4A, or 5A, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center.

Chemical formula

[0017] In some aspects, in Formula 1A, A is a ring structure that may or may not contain a heteroatom, and may be substituted or unsubstituted; in Formula 3A, B is a ring structure having at least one heteroatom and is optionally substituted or unsubstituted; in Formula 4A, R 13 is an aliphatic straight chain or an aliphatic branched chain that may be substituted or unsubstituted and may or may not optionally contain a heteroatom.

[0018] In some embodiments, ring A is an alicyclic ring or an alicyclic heterocyclic ring, or a combination thereof, which may be substituted with an R group or may be unsubstituted. In some aspects, ring B may be only an alicyclic heterocyclic ring. In some aspects, R 13 is independently a substituent (such as the substituents described for R 11 ). X 1 and / or X 2 is CH or N. X 3 is CH 2 , NH, O, or S. X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and / or X 13 is CH or N. X 14 is O or NH. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R8 and R 9 and R 10 and R 11 and R 12 are each independently hydrogen, halogen, hydroxyl, alkoxy, aliphatic straight chain, aliphatic branched chain, cycloaliphatic, substituted aliphatic, unsubstituted aliphatic, saturated aliphatic, unsaturated aliphatic, aromatic, polycyclic aromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, aliphatic amine, carbonyl, carboxyl, amide, ester, amino acid, its derivative, optionally substituted or unsubstituted, or a combination thereof.

[0019] In some embodiments, ring A is an alicyclic ring having 3 to 12 ring atoms, an alicyclic heterocycle having 3 to 12 ring atoms, or a combination thereof, which can be substituted or unsubstituted; ring B is an alicyclic heterocycle having 3 to 12 ring atoms, which can be substituted or unsubstituted; ring D is a polycycle having at least one aromatic ring fused to a cycloaliphatic; X 1 and / or X 2 is CH or N; X 3 is CH 2 , NH, O, or S; X 6 X 7 X 8 X 9 X 10 X 11 X 11 X 12 and / or X 13 is CH or N; X 6 X 7 X 8 X 9 X 10 X 11 X 11 X 12 and / or X 13 is CH or N or O; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R9 , R 10 , R 11 , and R 12 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, halo, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, acyl, alkylcarbonyl, arylcarbonyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, halocarbonyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, mono(alkyl)-substituted carbamoyl, di(alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azide, formyl, thioformyl, amino, mono- and di(alkyl)-substituted amino, mono- and di(aryl)-substituted amino, alkylamide, arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, optionally containing or not containing heteroatoms, derivatives thereof, optionally substituted or unsubstituted, and combinations thereof. In some embodiments, R 13 is a C1-C24 aliphatic straight or branched chain that can be substituted or unsubstituted and can optionally contain or not contain heteroatoms.

[0020] In some embodiments, ring A is an alicyclic ring having 3 to 6 ring atoms, an alicyclic heterocyclic ring having 3 to 6 ring atoms, or a combination thereof, which can be substituted or unsubstituted; ring B is an alicyclic heterocyclic ring having 3 to 6 ring atoms, which can be substituted or unsubstituted; ring D is cyclopentapyridine; X 1 and X 2 is N; X 3 is O or NH; X 4 is NH; X 5 is O; X 6 , X7 , X 8 , X 9 , X 10 , X 11 , and / or X 12 is CH or N; X 13 is N; X 14 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 are each independently hydrogen, C 1 ~C 24 alkyl, C 2 ~C 24 alkenyl, C 2 ~C 24 alkynyl, C 5 ~C 20 aryl, C 6 ~C 24 alkaryl, C 6 ~C 24 aralkyl, halo, hydroxyl, sulfhydryl, C 1 ~C 24 alkoxy, C 2 ~C 24 alkenyloxy, C 2 ~C 24 alkynyloxy, C 5 ~C 20 aryloxy, acyl, acyloxy, C 2 ~C 24 alkoxycarbonyl, C 6 ~C 20 aryloxycarbonyl, halocarbonyl, C 2 ~C 24 alkylcarbonato, C 6 ~C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C 1 ~C 24 alkyl)substituted carbamoyl, di-(C 1 ~C 24(alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, di-substituted arylcarbamoyl, thiocarbamoyl, mono-(C 1 ~C 24 (alkyl)-substituted thiocarbamoyl, di-(C 1 ~C 24 (alkyl)-substituted thiocarbamoyl, mono-substituted arylthiocarbamoyl, di-substituted arylthiocarbamoyl, carbamide, mono-(C 1 ~C 24 (alkyl)-substituted carbamide, di-(C 1 ~C 24 (alkyl)-substituted carbamide, mono-substituted arylcarbamide, di-substituted arylcarbamide, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azide, formyl, thioformyl, amino, mono- and di-(C 1 ~C 24 (alkyl)-substituted amino, mono- and di-(C 5 ~C 20 (aryl)-substituted amino, C 2 ~C 24 alkylamide, C 6 ~C 20 arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfonic acid, sulfonate, C 1 ~C 24 alkylsulfanyl, C 5 ~C 20 arylsulfanyl, C 1 ~C 24 alkylsulfinyl, C 5 ~C 20 arylsulfinyl, C 1 ~C 24 alkylsulfonyl, C 5 ~C 20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, optionally containing or not containing heteroatoms, optionally substituted or unsubstituted, derivatives thereof, and any one or more of the substituents selected from the group of combinations thereof; R 13 is substituted or unsubstituted and can optionally contain or not contain heteroatoms, a C 1 ~C 12It is an aliphatic straight chain or an aliphatic branched chain.

[0021] In some embodiments, 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 are each 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, hexyloxy, heptyloxy, octyloxy, acetyl (i.e., acetyl, CH3C=O), propionyl, butyryl, acetamide (i.e., acetylamino), propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl.

[0022] In some embodiments, inhibiting TNIK can inhibit certain TNIK-related biological pathways. In some aspects, inhibiting TNIK inhibits the Wnt pathway. In some aspects, inhibiting TNIK inhibits cytoskeletal reorganization. In some aspects, inhibiting TNIK inhibits carcinogenesis. In some aspects, inhibiting TNIK inhibits embryonic development. In some aspects, inhibiting TNIK inhibits colorectal cancer. In some aspects, inhibiting TNIK inhibits TGFβ signaling. In some aspects, inhibiting TNIK inhibits glycosaminoglycan formation. In some aspects, inhibiting TNIK inhibits collagen formation. In some aspects, inhibiting TNIK inhibits fibrosis.

[0023] In some embodiments, inhibiting MAP4K4 kinase can inhibit certain MAP4K4 pathways. MAP4K4 is involved in diverse physiological processes including cell migration, proliferation, and adhesion, and thus inhibiting MAP4K4 can inhibit these processes. As such, compounds that function as MAP4K4 inhibitors can have inhibitory activity against systemic inflammation, metabolic disorders, cardiovascular diseases, and cancer.

[0024] In some embodiments, the TNIK kinase and / or MAP4K4 kinase compounds can include: a structure of Formula A, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center.

[0025] In some aspects, Ring 1 is an aromatic ring with or without heteroatoms; Ring 2 is an aromatic heterocyclic ring; Ring 3 includes at least one aromatic heterocyclic ring and optionally at least one alicyclic ring fused to at least one aromatic heterocyclic ring; Ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or a linker; Y 1is a linker; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; each R 1 、R 6 、R 11 、and R 12 is independently a substituent. In some embodiments, the compound comprises at least one of the following conditions: Y 1 is an amide having a nitrogen bonded to Ring 1 and a carbon bonded to Ring 2; the compound comprises at least one of the following conditions for Y: when Y is a bond, R A is a C 3 alicyclic ring, 5-membered alicyclic heterocycle, 6-membered alicyclic heterocycle, aliphatic straight chain, or aliphatic branched chain, any of which can be substituted or unsubstituted; or when Y is a chemical moiety, R A is a C 3 alicyclic ring, 5-membered alicyclic ring, 5-membered alicyclic heterocycle, 6-membered alicyclic ring, 6-membered alicyclic heterocycle, aliphatic straight chain, or aliphatic branched chain, which are substituted or unsubstituted and can or cannot contain heteroatoms; or the compound comprises at least one of the following: when Ring 1 is a phenyl group, at least one of the following: Ring 2 is not a furanyl group; Ring 3 is not an imidazolyl group; or Ring 4 is not a phenyl group; when Ring 2 is a furanyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 3 is not an imidazolyl group, or Ring 4 is not a phenyl group; when Ring 3 is an imidazolyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 2 is not a furanyl group; or Ring 4 is not a phenyl group; or when Ring 4 is a phenyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 2 is not a furanyl group; or Ring 3 is not an imidazolyl group.

[0026] In some embodiments, ring 1 is a phenyl group or a pyridyl group; ring 2 is a 5-membered or 6-membered aromatic heterocyclic ring; ring 3 includes a 5-membered aromatic heterocyclic ring or a 5-membered aromatic heterocyclic ring fused to a 6-membered aromatic heterocyclic ring, which is fused to a 5-membered alicyclic ring (where the bond to Y is through the aforementioned 5-membered aromatic heterocyclic ring); ring 4 is a phenyl group, a pyridyl group, a pyrimidyl group, or a triazinyl group; Y is a bond or an aliphatic linker; Y 1 is an amide linker; R A is an alicyclic ring, an alicyclic heterocyclic ring; an aliphatic straight chain, or an aliphatic branched chain, which may be substituted or unsubstituted and may optionally contain or not contain heteroatoms, where when Y is a bond, R A is not a 5-membered alicyclic ring.

[0027] In some embodiments, ring 1 is a phenyl group or a pyridyl group, and when ring 1 is pyridyl, nitrogen is located at the para, meta, or ortho position within the ring; ring 2 is a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a triazolyl group, or a pyridyl group; ring 3 is an imidazolyl group, a triazolyl group, or a cyclopenta - pyrrolo - pyridinyl fused ring group; or a cyclopenta - furo - pyridinyl group; ring 4 is a phenyl group, a pyridyl group, a pyrimidyl group, or a triazinyl group, and when ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position within the aforementioned ring; when ring 4 is a pyrimidyl group, nitrogen is located at the meta or ortho position within the aforementioned ring; Y is a bond or a C1 - C6 aliphatic chain; when Y is a C1 - C6 (e.g., C 1 ~C 6 ) aliphatic linker, R A is not a 5-membered alicyclic ring, Y 1 is an amide linker; R A is a C3 - C6 (e.g., C 3 ~C 6 ) alicyclic ring, a C5 - C6 (e.g., C 5 ~C 6 ) alicyclic heterocyclic ring; a C1 - C12 (e.g., C 1 ~C 12)An aliphatic straight chain, or C 1 ~C 12 is an aliphatic branched chain, which can be substituted or unsubstituted, and can optionally contain or not contain heteroatoms, or when Y is a bond, R A is not a 5- or 6-membered (e.g., C 6 ~C 6 ) alicyclic ring that is not.

[0028] In some embodiments, each of R 1 , R 6 , R 11 , and R 12 is independently 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, octoxy, acetyl (i.e., CH 3 C=O), propionyl, butyryl, acetamide (i.e., acetylamino), propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl. In some aspects, R 11 and R 12 are hydrogen or do not exist.

[0029] In some embodiments, the TNIK kinase and / or the MAP4K4 kinase can be a compound comprising: a structure of formula A1 or formula A2, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center.

Chemical formula

[0030] In some embodiments, R A is an optionally substituted or unsubstituted C 3 alicyclic ring, a 4- to 12-membered (e.g., C 4 -C 12 ) alicyclic heterocyclic ring, an aliphatic straight chain, or an aliphatic branched chain, where the C 3 alicyclic ring, aliphatic straight chain, or aliphatic branched chain may or may not contain a heteroatom; ring D is a ring structure having one or more rings fused together; each R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is, independently of each other, a 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 is, independently of each other, a carbon atom or a heteroatom with or without a substituent; Y is a bond or a linker; Y 1 is a linker; m is 1, 2, or 3; n is 0, 1, or 2. In some embodiments, when the X group is N in an aromatic ring, there is no R group attached to the X group.

[0031] The foregoing summary is for illustrative purposes only and is not intended to be limiting. In addition to the above exemplary aspects, embodiments, and features, further aspects, embodiments, and features will become apparent with reference to the drawings and the following detailed description. In an embodiment of the present invention, for example, the following items are provided. (Item 1) A compound of formula A:

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Best Mode for Carrying Out the Invention

[0032] In the following detailed description, reference is made to the accompanying drawings which form a part hereof. Unless the context dictates otherwise, in the drawings, like reference numerals typically identify like components. The exemplary embodiments described in the detailed description, the drawings, and the 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 presented herein. The aspects of the disclosure generally described and illustrated in chemical structures herein can be arranged, substituted, combined, separated, and designed in a variety of different configurations, and all of these configurations are clearly intended herein as will be readily understood.

[0033] Generally, the present invention relates to at least one molecule that functions as a kinase inhibitor such as TNIK kinase and / or MAP4K4 kinase. As such, the molecules described herein can be used in methods related to the inhibition of TNIK to inhibit the biological activity of TNIK and thereby inhibit biological pathways associated with TNIK activation. As a result, the molecules described herein can be used in therapeutic methods that can provide treatment to a subject administered the molecule by inhibiting TNIK. Thus, each of the molecules described herein can be referred to as a TNIK kinase inhibitor, and some may be broad-spectrum inhibitors of a number of kinases, while others may be specific inhibitors that inhibit a particular kinase (such as TNIK kinase and / or MAP4K4 kinase).

[0034] Method

[0035] Thus, TNIK kinase inhibitors can be used to inhibit biological pathways downstream from TNIK inhibition. In some embodiments, the TNIK inhibitor can inhibit fibrillar collagen, thereby inhibiting biological activities related to the control of the extracellular matrix and the control of extracellular matrix remodeling. The TNIK inhibitor can inhibit the control of cell growth, differentiation, cell migration, proliferation, and metabolism.

[0036] In some embodiments, inhibiting TNIK can inhibit a particular TNIK-related biological pathway. In some embodiments, inhibiting TNIK inhibits the Wnt pathway.

[0037] In some embodiments, inhibiting TNIK inhibits cytoskeletal reorganization. Inhibiting TNIK can inhibit the c-Jun N-terminal kinase pathway. Inhibiting TNIK can inhibit the phosphorylation of gelsolin. Inhibiting TNIK can inhibit the control of the cytoskeleton (such as cytoskeletal reorganization).

[0038] In some embodiments, inhibition of TNIK inhibits carcinogenesis. In some aspects, administration of a TNIK inhibitor comprises a therapeutically effective amount of a compound sufficient to inhibit cancer cell growth; inhibit cancer cell migration; inhibit cancer cell proliferation; or treat cancer by inhibiting cancer cell migration. In some aspects, the cancer is colorectal cancer.

[0039] In some embodiments, inhibition of TNIK inhibits embryonic development. As such, a TNIK inhibitor can inhibit the progression of pregnancy and thereby can be used for abortion.

[0040] In some embodiments, inhibition of TNIK inhibits TGFβ signaling. The TGFβ signaling pathway is involved in various processes, and thus, inhibition of the TGFβ signaling pathway can inhibit these processes (some of which are described herein). This inhibition can include the inhibition of embryonic development described herein for inhibiting the progression of pregnancy. This inhibition can include inhibition of cell growth and cell differentiation that can be used for inhibiting the progression of pregnancy and inhibiting cancer.

[0041] In some embodiments, inhibition of TGFβ signaling can be used to inhibit the formation of the extracellular matrix or the excessive formation of the extracellular matrix and related problems (e.g., fibrosis). In some aspects, inhibition of TGFβ signaling by inhibition of TNIK inhibits glycosaminoglycan formation. In some aspects, inhibition of TGFβ by inhibition of TNIK inhibits collagen formation. In some aspects, inhibition of TNIK inhibits fibrosis. In some aspects, the fibrosis to be inhibited is selected from pulmonary fibrosis (e.g., idiopathic or radiation-induced), cystic fibrosis, hepatic fibrosis (e.g., cirrhosis), myocardial fibrosis (e.g., atrial fibrosis, endomyocardial fibrosis, old myocardial infarction), renal fibrosis, cerebral fibrosis (e.g., glial scar), arterial fibrosis, articular fibrosis (e.g., knee, shoulder, other joints), intestinal fibrosis (e.g., Crohn's disease), Dupuytren contracture fibrosis (e.g., hand, finger), keloid fibrosis (e.g., skin), mediastinal fibrosis (e.g., mediastinal soft tissue), myelofibrosis (e.g., bone marrow), Peyronie's disease fibrosis (e.g., penis), progressive massive fibrosis (e.g., lung, complication of coal worker's pneumoconiosis), retroperitoneal fibrosis (e.g., retroperitoneal soft tissue), scleroderma, sclerosis, fibrosis (e.g., skin, lung), fibrosis of adhesive synovitis (e.g., shoulder), or a combination thereof.

[0042] In some embodiments, a TNIK inhibitor can be used to inhibit the epithelial-to-mesenchymal transition of cancer cells and / or the development of fibrosis. In some aspects, this can include inhibition of the Smad signaling pathway. In some aspects, this can include inhibition of non-Smad signaling pathways. In some aspects, this can include inhibition of the signaling pathways of Wnt, NF-κB, FAK-Src-paxillin-related focal adhesions, and MAP kinases (e.g., ERK and JNK).

[0043] The therapeutic treatments provided herein can be used for prevention to inhibit the occurrence, onset, or progression of a medical condition. As such, a TNIK inhibitor can be used for the prevention or treatment of the listed medical conditions.

[0044] In some embodiments, the TNIK inhibitor, as shown herein, has the structure of any of the formulas provided herein, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, one having any chirality at any chiral center, or a tautomer, polymorph, solvate, or combination thereof. In some examples, the compound can be a pharmaceutically acceptable salt. In cases such as these formulas, the R substituents can be any substituents. For example, the R substituents can be one or more of the substituents listed herein or a combination thereof.

[0045] Similarly, inhibition of the MAP4K4 kinase can inhibit its related biological functions.

[0046] Summary In some embodiments, a method of inhibiting a kinase (e.g., TNIK kinase and / or MAP4K4 kinase) can include contacting the kinase with a compound having the structure of Formula A

Chemical formula

[0047] In some aspects, Ring 1 is an aromatic ring, with or without heteroatoms; Ring 2 is an aromatic heterocyclic ring; Ring 3 includes at least one aromatic heterocyclic ring and, optionally, at least one alicyclic ring fused to at least one aromatic heterocyclic ring; Ring 4 is an aromatic ring, with or without heteroatoms; Y is a bond or a linker; Y 1 is a linker; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; each R 1 、R 6 、R 11 、and R 12 are independently substituents; R Ais a ring structure, an aliphatic straight chain, or an aliphatic branched chain, which may be substituted or unsubstituted and either may or may not contain a heteroatom.

[0048] In some embodiments, Ring 1 is a phenyl group, a pyridyl group or a pyrimidinyl group; Ring 2 is a 5-membered or 6-membered aromatic heterocyclic ring; Ring 3 includes a 5-membered aromatic heterocyclic ring, or a 5-membered aromatic heterocyclic ring fused with a 6-membered aromatic heterocyclic ring, which is fused with a 5-membered alicyclic ring (where the bond to Y is through the aforementioned 5-membered aromatic heterocyclic ring); Ring 4 is a phenyl group, a pyridyl group, a pyrimidinyl group, or a triazinyl group; Y is a bond or an aliphatic linker; Y 1 is an amide linker; R A is an aromatic ring, an aromatic heterocyclic ring, an alicyclic ring, an alicyclic heterocyclic ring, an aliphatic straight chain, or an aliphatic branched chain (which may be substituted or unsubstituted and optionally may or may not contain a heteroatom).

[0049] In some embodiments, Ring 1 is a phenyl group, a pyridyl group or a pyrimidinyl group. When Ring 1 is pyridyl or pyrimidinyl, nitrogen is located at the para-position, meta-position, or ortho-position within the ring; Ring 2 is a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a triazolyl group, or a pyridyl group; Ring 3 is an imidazolyl group, a triazolyl group, or a cyclopenta-pyrrolo-pyridinyl fused ring group; or a cyclopenta-furo-pyridinyl group; Ring 4 is a phenyl group, a pyridyl group, a pyrimidinyl group, or a triazinyl group. When Ring 4 is pyridyl, nitrogen is located at the para-position, meta-position, or ortho-position within the aforementioned ring; when Ring 4 is a pyrimidinyl group, nitrogen is located at the meta-position or ortho-position within the aforementioned ring; Y is a bond or a C1-C6 (for example, C 1 -C 6 ) aliphatic chain; Y 1 is an amide linker; R A is an aromatic ring, an aromatic heterocyclic ring, a C1-C6 (for example, C 3 -C 6alicyclic ring, 5- to 6-membered alicyclic heterocycle; 1- to 12-membered (e.g., C 1 ~C 12 ) aliphatic straight chain, or 1- to 12-membered (e.g., C 1 ~C 12 ) aliphatic branched chain, and these can be either substituted or unsubstituted and can optionally contain or not contain heteroatoms.

[0050] In some embodiments, each R 1 , R 6 , R 11 , and R 12 is independently F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, acetyl (i.e., CH3C=O), propionyl, butyryl, acetamide (i.e., acetylamino), propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl. In some aspects, R 11 and R 12 are hydrogen or do not exist.

[0051] In some embodiments, when Y is a C 1 ~C 6 aliphatic linker, R A is a C 3 ~C 6 alicyclic ring, C 5 ~C 6 alicyclic heterocycle, aromatic ring, C 1 ~C12 Linear alicyclic, or C 1 ~C 12 branched alicyclic, which may be substituted or unsubstituted and may optionally contain or not contain heteroatoms, or when Y is a bond, R A is C 6 ~C 6 is not an alicyclic ring.

[0052] In some embodiments, each R 1 , R 6 , R 11 , and R 12 is, independently, hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl, acetamide, methylacetamide, ethylacetamide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino, morpholino, or a combination thereof.

[0053] In some embodiments, R 11 and R 12 are hydrogen or do not exist, and each R 1 or R 6 is, independently, hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl, acetamide, methylacetamide, ethylacetamide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino, morpholino, or a combination thereof.

[0054] In some embodiments, each R 1is, independently, 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, trifluoromethyloxy, or a combination thereof.

[0055] In some embodiments, R 11 and R 12 are hydrogen or absent, and each R 6 is, independently, hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl, acetamide, methyl acetamide, ethyl acetamide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino, morpholino, or a combination thereof.

[0056] In some embodiments, Y 1 is an amide, hydrazide, carbohydrazide, hydroxy-substituted amide, alkyl-substituted amide, carboxyimide amide, or sulfonimide amide.

[0057] In some embodiments, R A is independently hydrogen, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyridinyl, pyrimidinyl, bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[3.2.1]octan-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetanyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, phenyl, or a combination thereof.

[0058] In some embodiments, a method of inhibiting a kinase (e.g., TNIK kinase and / or MAP4K4 kinase) can include contacting the kinase with a compound having a structure of one of Formula A1 or Formula A2, a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center.

Chemical formula

[0059] Here, R A is a ring structure, an aliphatic straight chain, or an aliphatic branched chain, which can be substituted or unsubstituted and can optionally contain or not contain heteroatoms; ring D is a ring structure having one or more rings linked together; X1 , X 2 , X 3 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , and X 14 are each, independently, a carbon atom or a heteroatom, with or without substituents; each 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 are, independently, substituents; Y is a bond or a linker; Y 1 is a linker; m is 1, 2, or 3; n is 0, 1, or 2. In some embodiments, when the X group is N within an aromatic ring, there is no R group attached to the X group. In some embodiments, n is 0, and R 11 and / or R 12 are each absent. R 11 and / or R 12 may, if present, have suitable ring atoms on any ring. When n is 0, the bond and R 11 and / or R 12 are absent. In some embodiments, the R A ring is directly linked to X 1 via a covalent bond (i.e., Y), etc. When R A is a ring, R A can be any alicyclic ring or alicyclic heterocycle or a combination thereof.

[0060] In some embodiments, Y 1 is

[0061] [Chemical formula] can be, which is [Chemical formula] or other linkers for Y etc., or X 4 and / or X 5 can be as defined herein. In some embodiments, X 4 is C (e.g., CH, CH 2 ) or N (e.g., N, NH, NR 1 , NOR 1 ), which may or may not contain substituents (e.g., R 1 ); X 5 is O or N (e.g., NH, NR 1 , NOR 1 ). Here, R 1 is as defined herein, and examples include H, OH, methyl, ethyl, trifluoromethyl. X 4 can be C, NH or NOH, or NOR 1 . X 5 is O or NR 1 , or NOR 1 .

[0062] In some embodiments, the method may include administering a compound having a structure of one of Formulas 4A - 4K or 5A - 5K, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center. [Chemical formula] Here, R 13 is selected from hydrogen, an aliphatic straight chain, an aliphatic branched chain, [Chemical formula] or -Y-R A (any of these can be substituted or unsubstituted, and can optionally contain or not contain heteroatoms).

[0063] In some embodiments, in Formula 1A, A is an optionally substituted or unsubstituted ring structure, which may or may not contain a heteroatom; in Formula 3A, B is an optionally substituted or unsubstituted ring structure containing at least one heteroatom; in Formula 4A, R 13 is an aliphatic straight chain, an aliphatic branched chain, an alicyclic ring, a cyclopropane, an aryl, a polyaryl, -Y-R A , R B , a fused ring D (e.g., fused with X 1 and X 6 ), a fused ring E (e.g., an example of the fused ring D), or a combination thereof, and any of these may be substituted or unsubstituted and may or may not contain a heteroatom.

[0064] In some embodiments, ring A is an alicyclic ring or an alicyclic heterocyclic ring, or a combination thereof, which may or may not be substituted with an R group. In some embodiments, ring B may be only an alicyclic heterocyclic ring. In some embodiments, R 13 is independently a substituent (such as the substituents described for R 11 ). X 1 and / or X 2 is CH or N. X 3 is CH 2 , NH, O, or S. X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , and / or X 13 is CH or N. X 14 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 12Each is independently hydrogen, halogen, hydroxyl, alkoxy, aliphatic straight chain, aliphatic branched chain, cycloaliphatic, substituted aliphatic, unsubstituted aliphatic, saturated aliphatic, unsaturated aliphatic, aromatic, polycyclic aromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, aliphatic amine, carbonyl, carboxyl, amide, ester, amino acid, its derivative, optionally substituted or unsubstituted, or a combination thereof.

[0065] In some embodiments, ring A is an alicyclic ring having 3 to 12 ring atoms, an alicyclic heterocyclic ring having 3 to 12 ring atoms, or a combination thereof, which can be substituted or unsubstituted; ring B is an alicyclic heterocyclic ring having 3 to 12 ring atoms, which can be substituted or unsubstituted; ring D is a polycycle having at least one aromatic ring fused to a cycloaliphatic; X 1 and / or X 2 is CH or N; X 3 is CH 2 , NH, O, or S; X 6 X 7 X 8 X 9 X 10 X 11 X 11 X 12 and / or X 13 is CH or N; X 6 X 7 X 8 X 9 X 10 X 11 X 11 X 12 and / or X 13 is CH or N or O; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12is, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, halo, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, acyl, alkylcarbonyl, arylcarbonyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, halocarbonyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, mono(alkyl)-substituted carbamoyl, di(alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamide, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azide, formyl, thioformyl, amino, mono- and di(alkyl)-substituted amino, mono- and di(aryl)-substituted amino, alkylamide, arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, optionally containing or not containing heteroatoms, derivatives thereof, optionally substituted or unsubstituted, and combinations thereof; R 13 is substituted or unsubstituted and can optionally contain or not contain heteroatoms, and is a monocyclic to 24-membered (e.g., C 1 ~C 24 ) aliphatic straight chain or aliphatic branched chain.

[0066] In some embodiments, ring A is an alicyclic ring having 3 to 6 ring atoms, an alicyclic heterocyclic ring having 3 to 6 ring atoms, or a combination thereof, which can be substituted or unsubstituted; ring B is an alicyclic heterocyclic ring having 3 to 6 ring atoms, which can be substituted or unsubstituted; ring D is cyclopentapyridine; X 1 and X 2 are N; X 3 is O or NH; X 4 is NH, CH 2 , O or S; X 5 is O or S; X 6 , X 7, X 8 , X 9 , X 10 , X 11 , and / or X 12 is CH or N; X 13 is N; X 14 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 independently is hydrogen, C 1 ~C 24 alkyl, C 2 ~C 24 alkenyl, C 2 ~C 24 alkynyl, C 5 ~C 20 aryl, C 6 ~C 24 alkaryl, C 6 ~C 24 aralkyl, halo, hydroxyl, sulfhydryl, C 1 ~C 24 alkoxy, C 2 ~C 24 alkenyloxy, C 2 ~C 24 alkynyloxy, C 5 ~C 20 aryloxy, acyl, acyloxy, C 2 ~C 24 alkoxycarbonyl, C 6 ~C 20 aryloxycarbonyl, halocarbonyl, C 2 ~C 24 alkylcarbonato, C 6 ~C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C 1 ~C 24 alkyl)substituted carbamoyl, di-(C 1 ~C 24(alkyl)-substituted carbamoyl, monosubstituted arylcarbamoyl, disubstituted arylcarbamoyl, thiocarbamoyl, mono(C 1 ~C 24 (alkyl)-substituted thiocarbamoyl, di(C 1 ~C 24 (alkyl)-substituted thiocarbamoyl, monosubstituted arylthiocarbamoyl, disubstituted arylthiocarbamoyl, carbamide, mono(C 1 ~C 24 (alkyl)-substituted carbamide, di(C 1 ~C 24 (alkyl)-substituted carbamide, monosubstituted arylcarbamide, disubstituted arylcarbamide, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azide, formyl, thioformyl, amino, mono- and di(C 1 ~C 24 (alkyl)-substituted amino, mono- and di(C 5 ~C 20 (aryl)-substituted amino, C 2 ~C 24 alkylamide, C 6 ~C 20 arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfonic acid, sulfonate, C 1 ~C 24 alkylsulfanyl, C 5 ~C 20 arylsulfanyl, C 1 ~C 24 alkylsulfinyl, C 5 ~C 20 arylsulfinyl, C 1 ~C 24 alkylsulfonyl, C 5 ~C 20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, optionally containing or not containing heteroatoms, optionally substituted or unsubstituted, derivatives thereof, and any one or more of the substituents selected from the group of combinations thereof; R 13 is substituted or unsubstituted and can optionally contain or not contain heteroatoms, a 1-member to 12-member (e.g., C 1 ~C 12)It is an aliphatic straight chain or an aliphatic branched chain.

[0067] In some embodiments, 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 are each 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, hexyloxy, heptyloxy, octyloxy, acetyl (i.e., acetyl, CH 3 C=O), propionyl, butyryl, acetamide (i.e., acetylamino), propionamide, butyramide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl.

[0068] In some embodiments, R 13 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, or -C(R 14 ) 2 , where each R 14 is independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decanyl, undecanyl, or dodecanyl.

[0069] In these formulas and other formulas provided herein, X 4 is a carbon atom or a heteroatom, with or without substituents; X 5 is a heteroatom. In some embodiments, X 4 is C (e.g., CH, CH 2 ), or N (e.g., N, NH, NR 1 , NOR 1 ), which may or may not optionally contain substituents (e.g., R 1 ); X 5 is O or N (e.g., NH, NR 1 , NOR 1 ). Here, R 1 is as defined herein, and by way of example, includes H, OH, methyl, ethyl, trifluoromethyl. X 4 can be C, NH or NOH, or NOR 1 . X 5 is O or NR 1 , or NOR 1 .

[0070] In some embodiments, the kinase inhibitor (e.g., TNIK kinase and / or MAP4K4 kinase) can include the structure of one of Formulas 4B - 4K or 5B - 5K, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center.

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0071] In some embodiments, ring A can be any ring structure having a single ring or two or more fused rings, which can be an alicyclic ring, an alicyclic heterocyclic ring, an aryl, a heteroaryl, a polyaryl, a polyheteroaryl, or a combination thereof having 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms. When containing heteroatoms, the atoms of ring A can be C, O, N, or S depending on the valence, and any ring A can contain 1, 2, 3, 4, 5, 6, or more heteroatoms. Ring A can be substituted with one or more R groups, and the R groups can be the same as those defined for any other R group. The number of R substituents on ring A can be determined by the number of atoms in the ring when the single ring is n - 1 (where n is the number of ring atoms). Each R substituent on the ring can be different from the others.

[0072] In some embodiments, ring A represents a 5- or 6-membered alicyclic ring or alicyclic heterocyclic ring, or a combination thereof, which may be substituted or unsubstituted. This can include cyclopentyl or cyclohexyl, which may be substituted or unsubstituted.

[0073] In some embodiments, the X ring atom can be a carbon (C) or a heteroatom (such as O, N, or S), or other atoms. As described, when it is carbon, the X ring atom may or may not contain substituents such as those shown by R 11 and R 12 etc., and the substituents can be present on any atom of each ring (such as on the X ring atom), and when present, X 1 、X 2 、X 3 、X 6 、X 10 、and X 11 etc. As such, X 1 can be C (e.g., CH) or N having a suitable hydrogen atom. X 2 can be C (e.g., CH) or N having a suitable hydrogen atom. X 3 can be C (e.g., CH 2 ) or NH, O, or S. X 4 can be C (e.g., CH2 ) or can be NH, O or S. X 5 can be O or S. In some embodiments, Y 1 can be a linker Y. In some embodiments, X 4 is C (e.g., CH, CH 2 ) or N (e.g., N, NH, NR 1 , NOR 1 ), which may or may not contain a substituent (e.g., R 1 ); X 5 is O or N (e.g., NH, NR 1 , NOR 1 ). Here, R 1 is as defined herein, and by way of example, includes H, OH, methyl, ethyl, trifluoromethyl. X 4 is C, NH or NOH, or NOR 1 can be. X 5 is O or NR 1 , or NOR 1 .

[0074] In some embodiments, Y 1 If it is a chemical moiety beyond just a bond, it can be a linker Y, and Y can be any linker (such as a chemical moiety or a bond). In some examples, Y is a bond, but in most cases, it is a chemical moiety. If Y is one chain atom or more than one chain atom, at least one R 13 may be present on one or more chain atoms, and R 13 can be any R group as defined herein. The linker can be O, S, CH 2 , NH, or a hydrocarbon chain, with or without heteroatoms (such as the heteroatoms listed herein for X ring atoms). The linker can be O, S, CH 2, NH, aliphatic straight chain, aliphatic branched chain, cycloaliphatic, substituted aliphatic, unsubstituted aliphatic, saturated aliphatic, unsaturated aliphatic, aromatic, polycyclic aromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, aliphatic amine, carbonyl, carboxyl, amide, ester, amino acid, its derivative (substituted or unsubstituted), or a combination thereof may be included. In some embodiments, the linker includes C 1 ~C 24 alkyl, C 2 ~C 24 alkenyl, C 2 ~C 24 alkynyl, C 6 ~C 20 aryl, C 7 ~C 24 alkaryl, C 7 ~C 24 aralkyl, amino, mono- and di-(alkyl)substituted amino, mono- and di-(aryl)substituted amino, alkylamide, arylamide, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, optionally containing heteroatoms or not, optionally substituted or unsubstituted, its derivatives, and combinations thereof may be included. In some examples, Y is a linker substituted with at least one R 13 (which may be a substituent described herein).

[0075] In some embodiments, each 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 is independently hydrogen, C 1 ~C 24 alkyl, C 2 ~C24 Alkenyl, C 2 ~C 24 Alkynyl, C 5 ~C 20 Aryl, C 6 ~C 24 Alkaryl, C 6 ~C 24 Aralkyl, halo, hydroxyl, sulfhydryl, C 1 ~C 24 Alkoxy, C 2 ~C 24 Alkenyloxy, C 2 ~C 24 Alkynyloxy, C 5 ~C 20 Aryloxy, acyl (C 2 ~C 24 Alkylcarbonyl (-CO-alkyl) and C 6 ~C 20 Arylcarbonyl (-CO-aryl) is included), acyloxy (-O-acyl), C 2 ~C 24 Alkoxycarbonyl (-(CO)-O-alkyl), C 6 ~C 20 Aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-(CO)-X, where X is halo), C 2 ~C 24 Alkylcarbonato (-(O-(CO)-O-alkyl)), C 6 ~C 20 Arylcarbonato (-(O-(CO)-O-aryl)), carboxy (-(COOH)), carboxylato (-(COO - ), carbamoyl (-(CO)-NH 2 ), mono-(C 1 ~C 24 Alkyl) substituted carbamoyl (-(CO)-NH(C 1 ~C 24 Alkyl)), di-(C 1 ~C 24 Alkyl) substituted carbamoyl (-(CO)-N(C 1 ~C 24 Alkyl) 2), a substituted arylcarbamoyl (-(CO)-NH-aryl), a disubstituted arylcarbamoyl (-(CO)-NH-aryl) 2 , a thiocarbamoyl (-(CS)-NH 2 ), a mono(C 1 ~C 24 alkyl)substituted thiocarbamoyl (-(CS)-NH(C 1 ~C 24 alkyl)), a di(C 1 ~C 24 alkyl)substituted thiocarbamoyl (-(CS)-N(C 1 ~C 24 alkyl) 2 ), a mono-substituted arylthiocarbamoyl (-(CS)-NH-aryl), a disubstituted arylthiocarbamoyl (-(CS)-NH-aryl) 2 , a carbamide (-NH-(CO)-NH 2 ), a mono(C 1 ~C 24 alkyl)substituted carbamide (-NH-(CO)-NH(C 1 ~C 24 alkyl)), a di(C 1 ~C 24 alkyl)substituted carbamide (-NH-(CO)-N(C 1 ~C 24 alkyl) 2 ), a mono-substituted arylcarbamide (-NH-(CO)-NH-aryl), a disubstituted arylcarbamide (-NH-(CO)-N-(aryl) 2 ), cyano (-C≡N), isocyano (-N + ≡C - ), cyanato (-O-C≡N), isocyanato (-O-N + ≡C - ), thiocyanato (-S-C≡N), isothiocyanato (-S-N + ≡C - ), azide (-N=N + =N - ), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH 2 ), mono- and di(C 1 ~C 24 alkyl)substituted amino, mono- and di(C 6 ~C20 aryl) - substituted amino, C 2 ~C 24 alkylamide (-NH-(CO)-alkyl), C 5 ~C 20 arylamide (-NH-(CO)-aryl), imino (-CR=NH (wherein R is hydrogen, C 1 ~C 24 alkyl, C 5 ~C 20 aryl, C 6 ~C 24 alkaryl, C 6 ~C 24 aralkyl, etc.), alkylimino (-CR=N(alkyl) (wherein R = hydrogen, C 1 ~C 24 alkyl, aryl, alkaryl, aralkyl, etc.)), arylimino (-CR=N(aryl) (wherein R = hydrogen, alkyl, aryl, alkaryl, etc.)), nitro (-NO 2 ), nitroso (-NO), sulfonic acid (-SO 2 -OH), sulfonato (-SO 2 -O - ), C 1 ~C 24 alkylsulfanyl (-S-alkyl; also called "alkylthio"), C 5 ~C 20 arylsulfanyl (-S-aryl; also called "arylthio"), C 1 ~C 24 alkylsulfinyl (-(SO)-alkyl), C 5 ~C 20 arylsulfinyl (-(SO)-aryl), C 1 ~C 24 alkylsulfonyl (-SO 2 -alkyl), C 5 ~C 20 arylsulfonyl (-SO 2 -aryl), phosphono (-P(O)(OH) 2 ), phosphonato (-P(O)(O - )) 2 ), phosphinato (-P(O)(O-)), phospho (-PO 2 ), phosphino (-PH2 )(optionally containing or not containing a heteroatom (e.g., N, O, S, or others), where the heteroatom can be substituted for carbon (e.g., a heteroatom substituted for carbon within a chain or a ring), added to carbon (e.g., a heteroatom added to a carbon chain or a carbon ring), exchanged, optionally containing a straight chain, optionally containing a branched chain, optionally deriving a ring, and optionally being substituted or unsubstituted), any one or more of the substituents selected from the group consisting of its derivatives and combinations thereof.

[0076] In some embodiments, the method uses a compound under formula B or formula B1, where ring C is as defined herein (a C (optionally containing a heteroatom or not containing a heteroatom) 5 ~C 6 ring structure (e.g., an alicyclic ring), etc.). [Chemical formula]

[0077] In some aspects, ring C is a C that does not contain a heteroatom 5 ~C 6 alicyclic structure; each R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is, independently, a substituent; n is 0, 1, or 2. In some aspects, ring C is a C that does not contain a heteroatom 5 ~C 6 alicyclic structure; each R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is, independently, a substituent having R 11 , R 12is either absent or is hydrogen.

[0078] In some embodiments, the compound has the structure of Formula 7, 8, 9, 10, 11, 12, 13, or 14, a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center. [Chemical formula]

[0079] In some embodiments, in any formula, 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 substituents are each 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, octoxy, acetyl (i.e., acetyl, CH 3 C=O), propionyl, butyryl, acetamide (i.e., acetylamino), propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl.

[0080] In some embodiments, 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 are each independently halogen, alkyl, branched alkyl, alkoxy, alkyl ester, alkylsulfanyl (i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy, trifluoroalkyl, or acetamide (i.e., acetylamino).

[0081] In some embodiments, the compound comprises at least one of the following: R 3 is a substituent; R 6 is a substituent; R 7 is a substituent; R 8 is a substituent; R 9 is a substituent; and / or R 10 is a substituent. The remainder of the R group can be hydrogen or can be absent. This can be applied to all of the formulas recited herein.

[0082] In some embodiments, the compound comprises at least one of the following: R 3 is F; R 6 is F, Br, Cl, methoxy, or methyl ester; R 7 is F or methoxy; R 8 is F, methoxy, or methyl; R 9 is F or methoxy; and / or R 10 is F, Br, Cl, methoxy, or methyl ester. The remainder of the R group can be hydrogen or can be absent. This can be applied to all of the formulas recited herein.

[0083] In some embodiments, the compound comprises: R 3 is F; R 1 , R 2 , R 4 , and R 5 is H. The remainder of the R groups can be hydrogen or can be absent. This can be applied to all of the formulas recited herein.

[0084] In some embodiments, the compound comprises at least one of the following: R 6 and R 9 has a substituent, and R 7 , R 8 , and R 10 are H; R 7 and R 10 has a substituent, and R 6 , R 8 , and R 9 are H; R 6 has a substituent, and R 7 , R 8 , R 9 , and R 10 are H; R 8 has a substituent, and R 6 , R 7 , R 9 , and R 10 are H; R 10 has a substituent, and R 6 , R 7 , R 8 , and R 9 are H; R 6 and R 8 has a substituent, and R 7 , R 9 , and R 10 are H; or R 8 and R 10 has a substituent, and R 6 , R 7 , and R 9 are H. The remainder of the R groups can be hydrogen or can be absent. This can be applied to all of the formulas recited herein.

[0085] In some embodiments, the compound comprises: R3 is F; R 1 , R 2 , R 4 , and R 5 is H; R 6 is F, Br, Cl, methoxy, or methyl ester; R 9 is F or methoxy; and R 7 , R 8 , and R 10 is H. The remainder of the R group can be hydrogen or can be absent. This can be applied to all the formulas listed in this specification.

[0086] In some embodiments, the compound comprises: R 3 is F; R 1 , R 2 , R 4 , and R 5 is H; R 6 is F, Br, Cl, methoxy, or methyl ester; and R 7 , R 8 , R 9 , and R 10 is H. The remainder of the R group can be hydrogen or can be absent. This can be applied to all the formulas listed in this specification.

[0087] In some embodiments, the compound comprises: R 3 is F; R 1 , R 2 , R 4 , and R 5 is H; R 8 is F, methoxy, or methyl; and R 6 , R 7 , R 9 , and R 10 is H. The remainder of the R group can be hydrogen or can be absent. This can be applied to all the formulas listed in this specification.

[0088] In some embodiments, the compound comprises: R 3 is F; R 1 , R2 , R 4 , and R 5 is H; R 10 is F, Br, Cl, methoxy, or methyl ester, and R 6 , R 7 , R 8 , and R 9 is H. The remainder of the R group can be hydrogen or can be absent. This can be applied to all of the formulas recited herein.

[0089] In some embodiments, the compound comprises: R 3 is F; R 1 , R 2 , R 4 , and R 5 is H; R 6 is F, Br, Cl, methoxy, or methyl ester; R 8 is F, methoxy, or methyl; and R 7 , R 9 , and R 10 is H. The remainder of the R group can be hydrogen or can be absent. This can be applied to all of the formulas recited herein.

[0090] In some embodiments, the inhibitor compound used in the method (e.g., TNIK kinase inhibitor and / or MAP4K4 kinase inhibitor) can be one of the following:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0091] In some embodiments, the compound used in the 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; methyl 2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide)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.

[0092] In some embodiments, the substitution pattern and substituents of the R group shown in the structures of Compounds 17-87 can be applied to any of the formulas provided herein.

[0093] In some embodiments, the compound is included in a pharmaceutical composition, and the aforementioned pharmaceutical composition includes the compound; and a pharmaceutically acceptable carrier containing the compound.

[0094] The kinase inhibitor can be formulated for experimental or therapeutic use. The formulation is prepared by combining the purified kinase inhibitor of the present invention with a pharmaceutically acceptable vehicle (e.g., carrier, excipient) for storage and use (Remington, The Science and Practice of Pharmacy 20th Edition Mack Publishing, 2000). Suitable pharmaceutically acceptable vehicles include non-toxic buffers (such as buffers of phosphoric acid, citric acid, and other organic acids); salts (such as sodium chloride); antioxidants (including ascorbic acid and methionine); preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens (such as methyl paraben or propyl paraben); catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (e.g., less than about 10 amino acid residues); proteins (such as serum albumin, gelatin, or immunoglobulins); hydrophilic polymers (such as polyvinyl pyrrolidone); 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., Zn-protein complexes); and non-ionic surfactants (such as TWEEN® or polyethylene glycol (PEG)), but are not limited thereto.

[0095] The pharmaceutical composition of the present invention can be administered by any method of topical or systemic treatment. Administration can be topical (such as administration to mucous membranes including vaginal delivery and rectal delivery) (such as transdermal patches, ointments, lotions, creams, gels, instillations, suppositories, sprays, solutions, and powders); pulmonary administration (such as by inhalation or insufflation of powders or aerosols (including nebulizers, intratracheal, intranasal, epithelial, and transdermal)); oral administration; or parenteral administration (including injection or infusion into veins, arteries, subcutaneous, intraperitoneal or intramuscular); intratumoral administration, or intracranial administration (such as intrathecal or intraventricular).

[0096] The therapeutic agent can be in unit dosage form. 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 administration by inhalation. In solid compositions such as tablets, the active ingredient is mixed with a pharmaceutical carrier. Components for conventional tableting include corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dibasic calcium phosphate, or gums, and other diluents (such as water) to form a solid preliminary formulation composition containing a homogeneous mixture of the compound of the present invention or its pharmaceutically acceptable non-toxic salts. The solid preliminary formulation composition is then subdivided into unit dosage forms of the above types. Tablets, pills, etc. of the novel composition can be coated or otherwise formulated so as to obtain a dosage form having the advantage of sustained action. For example, a tablet or pill can contain an internal composition coated with an external component. Further, the two components can be separated by an enteric layer that resists disintegration and allows the internal component to pass through the stomach unchanged or serves to delay release. Various materials can be used for such enteric layers or enteric coatings, and such materials include several polymeric acids as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0097] In some embodiments, the pharmaceutical formulation can include the kinase inhibitor of the present invention that forms a complex with liposomes (Epstein, et al., 1985, Proc. Natl. Acad. Sci. USA 82:3688; 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 improved circulation times are disclosed in U.S. Patent No. 5,013,556. Some liposomes can be produced by the reverse phase evaporation method using a lipid composition containing phosphatidylcholine, cholesterol, and a PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with a defined pore size to obtain liposomes having a desired diameter.

[0098] Also, the kinase inhibitor can be entrapped within microcapsules. Such microcapsules can be prepared, for example, by coacervation techniques or interfacial polymerization, for example, hydroxy methylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in a colloidal drug delivery system (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or a macroemulsion, as described in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000).

[0099] Furthermore, sustained release preparations can be prepared. Suitable examples of sustained release preparations include a semipermeable matrix of a solid hydrophobic polymer containing a kinase inhibitor, where the matrix is in the form of a shaped article (e.g., a thin film or microcapsule). Examples of sustained release matrices include polyesters, hydrogels (such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT™ (injectable microspheres composed of a lactic acid-glycolic acid copolymer and leuprolide acetate)), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0100] In some embodiments, the treatment relates to the combined administration of a TNIK inhibitor of the present invention and a chemotherapeutic agent or a cocktail of multiple different chemotherapeutic agents. Combinatorial therapies often use agents that act by different mechanisms of action. Combinatorial therapies using agents with different mechanisms of action often result in additive or synergistic effects. The combinatorial therapy can reduce the dose of each agent compared to the dose used in monotherapy, thereby reducing toxic side effects. The combinatorial therapy can reduce the likelihood of the development of resistant cancer cells. In some embodiments, the combinatorial therapy includes a kinase inhibitor that binds to a kinase (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) and a chemotherapeutic agent.

[0101] The pharmaceutical composition may include, but is not limited to, freeze-dried powder or aqueous or non-aqueous sterile injection solutions or suspensions, which may further include antioxidants, buffers, bacteriostatic agents, and solutes that substantially conform to the tissues or blood of the intended recipient of the composition. Other components that may be present in such compositions include, for example, water, surfactants (e.g., Tween®), alcohols, polyols, glycerin, and vegetable oils. Injectable solutions or suspensions for immediate preparation may be prepared from sterile powders, granules, tablets, or concentrated solutions or suspensions. The composition may be supplied, for example, but not limited to, as a freeze-dried powder reconstituted with sterile water or saline before administration to a patient.

[0102] Suitable pharmaceutically acceptable carriers include compositions that are essentially chemically inert and non-toxic and do not interfere with the effectiveness of the biological activity of the pharmaceutical composition. Examples of suitable pharmaceutical carriers include, but are not limited to, water, saline solution, glycerol solution, ethanol, N-(1(2,3-dioleyloxy)propyl)N,N,N-trimethylammonium chloride (DOTMA), dioleoyl-phosphatidyl-ethanolamine (DOPE), and liposomes. Such compositions should contain a therapeutically effective amount of the compound together with an appropriate amount of carrier for providing a form for direct administration to a patient.

[0103] The compositions described herein can be administered, for example, by parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, intraocular, intraventricular, intracapsular, intraspinal, intrasinus, intraperitoneal, intranasal, aerosol, or oral administration. Common carriers or excipients can be used for the preparation of pharmaceutical compositions designed for such routes of administration.

[0104] For the treatment of a disease, the appropriate dosage of the kinase inhibitor of the present invention depends on the type of disease to be treated, the severity and course of the disease, the responsiveness of the disease, whether the kinase inhibitor administration is for a therapeutic or prophylactic purpose, the treatment history, and the patient's clinical history, at the discretion of the attending physician. The kinase inhibitor can be administered as a single dose, over a series of treatments lasting from several days to several months, or until cured or until symptom relief is achieved (e.g., reduction in tumor size). The optimal dosing schedule can be calculated from measurements of drug accumulation in the patient's body, and this dosing schedule will vary depending on the relative potency of the individual kinase inhibitor. The administering physician can readily determine the optimal dosage, administration method, and number of repetitions. Generally, the dosage is from 0.01 μg to 100 mg / kg body weight and can be administered once or multiple times per day, per week, per month, or per year. The treating physician can estimate the number of repetitions of administration based on measurements of the residence time and concentration of the drug in body fluids or tissues.

[0105] The present invention provides a kit comprising a kinase inhibitor described herein that can be used to carry out the methods described herein. In certain embodiments, the kit comprises at least one purified kinase inhibitor in one or more containers. In some embodiments, the kit comprises all of the components necessary and / or sufficient to perform a detection assay (including controls, instructions for performing the assay, and any software necessary for analysis and display of results). One of ordinary skill in the art will readily recognize that the disclosed kinase inhibitors of the present invention can be easily incorporated into one of the established kit formats well known in the art.

[0106] In some embodiments, the compound can have an IC50 value of 1 μM or less (when determined using any scientifically acceptable kinase inhibition assay), preferably an IC50 of 500 nM or less, preferably an IC50 value of 250 nM or less, preferably an IC50 value of 100 nM or less, preferably an IC50 value of 50 nM or less, preferably an IC50 value of 25 nM or less, preferably an IC50 value of 10 nM or less, for wild-type or mutant (especially clinically relevant mutations) kinases, and can have inhibitory activity against them.

[0107] In some embodiments, the compound can have an IC50 value measured in the TNIK enzyme assay provided in Table 1 below, and this compound can be used to inhibit TNIK so as to obtain therapeutic advantages and the like described herein.

Table 1-1

Table 1-2

Table 1-3

[0108] In addition, the compounds of the present invention are useful as standards and reagents for the characterization of various kinases (especially, but not limited to, TNIK kinase and / or MAP4K4 kinase), and the study of the role of such kinases in biological and pathological phenomena; the study of intracellular signaling pathways mediated by such kinases, the comparative evaluation of new kinase inhibitors; and the study of various cancers in cell lines and animal models.

[0109]

Example

[0110] TNIK Inhibition

[0111] The compound was studied for its function as a TNIK inhibitor and the data in Table 1 was generated. The compound was incubated with 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 250 μM TNIK control peptide, 10 mM magnesium acetate, and 33 [γ-

[0112] Fibrosis assay

[0113] Cell culture

[0114] The HDF / TERT166 working lot cells were thawed from liquid nitrogen and can be expanded and grown under standard conditions (medium: DMEM / Ham's F12 basal medium supplemented with 1× GlutaMax-I and 10% FBS and without antibiotics; 37 °C, 5% CO 2 ₂). For the implementation of the treatment, the cells were seeded at 7500 cells / cm² in a 12-well plate on the day before the first treatment 2It can be seeded at the cell density of. Cells can be seeded in a starvation medium (DMEM / Ham's F12 basal medium supplemented with 1×GlutaMax-I and 0.5% FBS and without antibiotics). Approximately 24 hours after seeding, the substance can be dissolved in DMSO (stock: 10 mM) and diluted to a final concentration of 10 μM in the starvation medium. Half of this working dilution can capture 100 pg / mL TGFβ. For each substance, two wells can be treated with the substance at a concentration of 10 μM and the substance at a concentration of 10 μM supplemented with 100 pg / mL of TGF-β. In parallel, the cells can be treated with 100 pg / mL TGF-β only. The cells in the starvation medium can serve as a control. For all cells, they can be treated by medium replacement. 24 hours after the first treatment (48 hours after seeding), the treatment can be repeated using fresh dilutions. 24 hours after the second treatment (72 hours after seeding), the medium can be removed, the cells can be washed once with PBS, and the cells can be directly lysed using 1 mL of Tri-reagent (Sigma Aldrich) per well. The lysate can be collected in a 1.5 mL tube and stored at -80 °C until RNA isolation.

[0115] qPCR analysis

[0116] RNA isolation

[0117] RNA can be extracted 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 further precipitated and purified using the miRNeasy Mini Kit (Qiagen) on a QIAcube liquid handling robot. To 500 μL, 150 μL of nuclease-free water and 7 μL of glycogen can be added and precipitation can be carried out using 750 μL of 100% ethanol. The column can be washed with RWT buffer and RPE buffer, and the circular RNA can be eluted in 30 μL of nuclease-free water in one round and stored at -80°C. The RNA concentration can be determined by spectroscopic analysis using a Nanodrop device.

[0118] qPCR quantification of mRNA

[0119] cDNA can be synthesized from the isolated total RNA using the GrandScript cDNA synthesis kit. Reverse transcription reactions can be performed using 200 ng of total RNA in a 20 μL reaction (if possible, 10 μL of RNA can be used for low-concentration samples). For each sample, qPCR reactions can be performed in duplicate in a 10 μL reaction using an 8 μL qPCR Mix consisting of 2 μL of 1:2 diluted cDNA, 5 μL of SYBR Grandmaster Mix, 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 device. The following thermocycling conditions can be used: 45 cycles of 30 seconds at 95°C, 5 seconds at 95°C, 15 seconds at 63°C, and 10 seconds at 72°C, followed by analysis using a melting curve. The Cq value can be calculated using the second derivative maximum method within the LC480 II software.

[0120] TNIK is associated with fibrosis and cancer metastasis

[0121] A collagen production assay was performed on a known TNIK inhibitor (5-(4-acetamidobenzamide)-2-(phenylamino)-1,3-thiazole-4-carboxamide). The data show that this TNIK inhibitor decreased the mRNA expression of type I collagen α1 chain (COL1A1). Also, this TNIK inhibitor inhibited the effect of TGF-β treatment on COL1A1 mRNA expression. COL1A1 expression is involved in fibrosis, and when COL1A1 is upregulated, fibrosis in the subject can increase. Therefore, reducing COL1A1 mRNA expression, especially in the early stage of overexpression, can treat or inhibit fibrosis in the subject. An increase in TGF-β expression in the affected organ and subsequent deregulation of TGF-β function are known to correlate with the abnormal accumulation of connective tissue observed during the onset of fibrotic diseases. By inhibiting the effect of TGF-β treatment on COL1A1 mRNA expression, fibrosis can be treated and alleviated. It is known that TGF-β-activated EMT can be inhibited by attenuation of the Smad and non-Smad signaling pathways (including the Wnt, NF-κB, FAK-Src-paxillin-related focal adhesions, and MAP kinase (ERK and JNK) signaling pathways), so there is evidence that the TNIK inhibitor can be used for TGF-β-activated EMT inhibition. As such, TNIK is an inhibitory target for the treatment of disorders (such as cancer metastasis and fibrosis) caused by EMT and / or prevention. As such, the foregoing evidence shows that the TNIK inhibitor described herein can be used in a method for treating disorders (such as cancer metastasis and fibrosis) caused by EMT.

[0122] TNIK is associated with lung cancer

[0123] Furthermore, TGF-β is known to mediate the epithelial-mesenchymal transition of cancer cells (such as lung cancer). It is known that inhibiting TNIK can inhibit TGF-β activity, and thereby inhibit the onset or progression of cancers such as lung cancer. Therefore, inhibition of TNIK using the TNIK inhibitor described herein can be used in a method for treating cancers such as lung cancer.

[0124] Furthermore, the TNIK inhibitor can be administered to a human who is susceptible to or suspected of being susceptible to the diseases or conditions described herein, before, during, or after the onset of the disease or condition. Specifically, the TNIK inhibitor can be used to inhibit, prevent, or delay the onset or adverse effects of diseases or conditions such as cancer and fibrosis.

[0125] Therefore, the TNIK inhibitor described herein can be used in a method for inhibiting TNIK to inhibit a disease or condition associated with TNIK activity or an increase in TNIK activity, or an upregulation or increase in downstream activity.

[0126] Compound

[0127] In some embodiments, the invention includes novel compounds that are kinase inhibitors (e.g., TNIK kinase inhibitors and / or MAP4K4 kinase inhibitors). For example, the compounds listed in this section can be novel compounds.

[0128] Summary In some embodiments, the kinase inhibitor compound (e.g., TNIK kinase inhibitor and / or MAP4K4 kinase inhibitor) has the structure of Formula A

Chemical formula

[0129] In some embodiments, ring 1 is an aromatic ring, which may or may not contain heteroatoms; ring 2 is an aromatic heterocyclic ring; ring 3 contains at least one aromatic heterocyclic ring and optionally at least one alicyclic ring fused to at least one aromatic heterocyclic ring; ring 4 is an aromatic ring, which may or may not contain heteroatoms; Y is a bond or a linker; Y 1 is a linker; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; each R 1 、R 6 、R 11 、and R 12 is independently a chemical moiety (e.g., hydrogen or other substituents). In some embodiments, the compound comprises at least one of the following conditions: when Y is a bond, R A is an aromatic C 3 alicyclic ring, a 5-membered alicyclic heterocyclic ring, a 6-membered alicyclic heterocyclic ring, an aliphatic straight chain, or an aliphatic branched chain, any of which can be substituted or unsubstituted; or when Y is a chemical moiety, R A is C 3It is an alicyclic ring, a 5-membered alicyclic ring, a 5-membered alicyclic heterocyclic ring, a 6-membered alicyclic ring, a 6-membered alicyclic heterocyclic ring, an aliphatic straight chain, or an aliphatic branched chain, which can be substituted or unsubstituted and can contain or not contain heteroatoms; or the compound contains at least one of the following: when Ring 1 is a phenyl group, at least one of the following: Ring 2 is not a furanyl group; Ring 3 is not an imidazolyl group; or Ring 4 is not a phenyl group; when Ring 2 is a furanyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 3 is not an imidazolyl group, or Ring 4 is not a phenyl group; when Ring 3 is an imidazolyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 2 is not a furanyl group; or Ring 4 is not a phenyl group; or when Ring 4 is a phenyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 2 is not a furanyl group; or Ring 3 is not an imidazolyl group. In some embodiments, one of Ring 1 or Ring 4 has o as a positive integer. In some embodiments, in the case of an aromatic heterocyclic ring (for example, when Ring 1 or Ring 4 is an aromatic heterocyclic ring), o is only 0.

[0130] In some embodiments, Y 1 contains an amide having a nitrogen bonded to Ring 1 and a carbon bonded to Ring 2.

[0131] In some embodiments, the compound contains at least one of the following: Y 1 contains an amide having a nitrogen bonded to Ring 1 and a carbon bonded to Ring 2; when Y is a bond, R A is C 3 is an alicyclic ring, a 5-membered alicyclic heterocyclic ring, a 6-membered alicyclic heterocyclic ring, an aliphatic straight chain, or an aliphatic branched chain, and any of these can be substituted or unsubstituted; or when Y is a chemical moiety, R A is C 3It is an alicyclic ring, a 5-membered alicyclic ring, a 5-membered alicyclic heterocyclic ring, a 6-membered alicyclic ring, a 6-membered alicyclic heterocyclic ring, an aliphatic straight chain, or an aliphatic branched chain, which can be substituted or unsubstituted and can contain or not contain heteroatoms; or the compound contains at least one of the following: when Ring 1 is a phenyl group, at least one of the following: Ring 2 is not a furanyl group; Ring 3 is not an imidazolyl group; or Ring 4 is not a phenyl group; when Ring 2 is a furanyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 3 is not an imidazolyl group, or Ring 4 is not a phenyl group; when Ring 3 is an imidazolyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 2 is not a furanyl group; or Ring 4 is not a phenyl group; or when Ring 4 is a phenyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 2 is not a furanyl group; or Ring 3 is not an imidazolyl group.

[0132] In some embodiments, the compound contains the following: Ring 1 is a phenyl group, a pyridyl group or a pyrimidinyl group; Ring 2 is a 5-membered or 6-membered aromatic heterocyclic ring; Ring 3 contains a 5-membered aromatic heterocyclic ring, or a 5-membered aromatic heterocyclic ring condensed with a 6-membered aromatic heterocyclic ring, which is condensed with a 5-membered alicyclic ring (where the bond to Y is through the aforementioned 5-membered aromatic heterocyclic ring); Ring 4 is a phenyl group, a pyridyl group, a pyrimidinyl group, or a triazinyl group; Y is a bond or an aliphatic linker; when Y is a bond, R A is not a 5-membered alicyclic ring.

[0133] In some embodiments, the compound comprises: Ring 1 is a phenyl group, a pyridyl group or a pyrimidinyl group; when Ring 1 is pyridyl or pyrimidinyl, nitrogen is located at the para, meta or ortho position within the ring; Ring 2 is a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a triazolyl group, or a pyridyl group; Ring 3 is an imidazolyl group, a triazolyl group, or a cyclopenta - pyrrolo - pyridinyl fused ring group; or a cyclopenta - furo - pyridinyl group; Ring 4 is a phenyl group, a pyridyl group, a pyrimidinyl group, or a triazinyl group; when Ring 4 is pyridyl, nitrogen is located at the para, meta or ortho position within the aforementioned ring; when Ring 4 is a pyrimidinyl group, nitrogen is located at the meta or ortho position within the aforementioned ring; Y is a bond or, for example, C 1 ~C 6 is an aliphatic chain.

[0134] In some embodiments, when Y is C 1 ~C 6 and is an aliphatic linker, R A is C 3 ~C 6 a cycloaliphatic ring, C 5 ~C 6 a cycloaliphatic heterocyclic ring, an aromatic ring, C 1 ~C 12 a straight-chain cycloaliphatic, or C 1 ~C 12 a branched-chain cycloaliphatic, which may be substituted or unsubstituted and may optionally contain heteroatoms, or when Y is a bond, R A is not a C 6 ~C 6 cycloaliphatic ring.

[0135] In some embodiments, each R 1 、R 6 、R 11 、and R 12is, independently, hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl, acetamide, methyl acetamide, ethyl acetamide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino, morpholino, or a combination thereof.

[0136] In some embodiments, R 11 and R 12 are hydrogen or absent, each R 1 or R 6is, independently, hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl, acetamide, methyl acetamide, ethyl acetamide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino, morpholino, or a combination thereof.

[0137] In some embodiments, each R 1 is, independently, 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, trifluoromethyloxy, or a combination thereof.

[0138] In some embodiments, R 11and R 12 is hydrogen or absent, and each R 6 is, independently, hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl, acetamide, methyl acetamide, ethyl acetamide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino, morpholino, or a combination thereof.

[0139] In some embodiments, Y 1 is an amide, hydrazide, carbohydrazide, hydroxy-substituted amide, alkyl-substituted amide, carboxyimide amide, or sulfonimide amide.

[0140] In some embodiments, R Ais independently hydrogen, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyridinyl, pyrimidinyl, bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[3.2.1]octan-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetanyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, phenyl, or a combination thereof.

[0141] In some embodiments, Ring 1 is a phenyl group or a pyridyl group, and when Ring 1 is pyridyl, nitrogen is located at the para, meta, or ortho position within the ring; Ring 2 is a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a triazolyl group, or a pyridyl group; Ring 3 is an imidazolyl group, a triazolyl group, or a cyclopenta-pyrrolo-pyridinyl fused ring group; or a cyclopenta-furo-pyridinyl group; Ring 4 is a phenyl group, a pyridyl group, a pyrimidinyl group, or a triazinyl group, and when Ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position within the aforementioned ring; when Ring 4 is a pyrimidinyl group, nitrogen is located at the meta or ortho position within the aforementioned ring; Y is a bond or C 1 ~C 6 aliphatic chain; Y 1 is an amide linker; when Y is C 1 ~C 6 aliphatic linker, R A is C 3 ~C 6 alicyclic ring, C 5 ~C 6 alicyclic heterocycle; C 1 ~C 12 aliphatic straight chain, or C 1 ~C 12They are aliphatic branched chains, which can be substituted or unsubstituted, and can optionally contain or not contain heteroatoms, or when Y is a bond, R A is C 6 ~C 6 is not an alicyclic ring.

[0142] In some embodiments, each R 1 , R 6 is independently 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, octoxy, acetyl (i.e., CH3C=O), propionyl, butyryl, acetamide (i.e., acetylamino), propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl (i.e., thiomethyl), ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, or octylsulfanyl. In some aspects, R 11 and R 12 are hydrogen or do not exist.

[0143] In some embodiments, the kinase inhibitor (e.g., TNIK kinase inhibitor and / or MAP4K4 kinase inhibitor) is a compound having a structure of formula A1 or formula A2, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center. In some aspects of formula A1 or A2, ring D is a ring structure having 1 or more rings fused together; each R 1 , R 2 , R3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are, independently, chemical moieties; 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 are each independently a carbon atom or a heteroatom, either with or without substituents; Y is a bond or a linker; Y 1 is a linker; m is 1, 2, or 3; n is 0, 1, or 2; when Y is a bond, R A is hydrogen, an aromatic ring, an alicyclic ring, an aliphatic straight chain, or an aliphatic branched chain, optionally substituted or unsubstituted, and optionally containing or not containing heteroatoms; when Y is a linker, R A is an aromatic ring, an alicyclic ring, an aliphatic straight chain, or an aliphatic branched chain, optionally substituted or unsubstituted, and optionally containing or not containing heteroatoms; provided that when the X group is N within an aromatic ring, there is no R group attached to the X group; when the dashed line forms a double bond, X 12 is N (e.g., for the double bond to oxygen in a ketone).

[0144] In some embodiments, R A is an optionally substituted or unsubstituted C 3 alicyclic ring, a C4 - C12 alicyclic heterocyclic ring, an aliphatic straight chain, or an aliphatic branched chain, where the C 3 ring structure, aliphatic straight chain, or aliphatic branched chain contains or does not contain heteroatoms; ring D is a ring structure having 1 or more rings fused together; each R 1 , R 2 , R 3 , R5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are, independently, substituents; 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 are each independently a carbon atom or a heteroatom that may or may not contain a substituent; Y is a bond or a linker; Y 1 is a linker; m is 1, 2, or 3; n is 0, 1, or 2. In some embodiments, when the X group is N within an aromatic ring, there is no R group attached to the X group. These variables can be as defined herein. In some embodiments, the substitution pattern of the R groups of some compound examples can be applied to these formulas. In some embodiments, the pattern of the X groups of compound examples can be applied to these formulas.

[0145] In some embodiments, a kinase inhibitor (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) can comprise a structure of one of Formulas 4A - 4K or 5A - 5K, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center. In some embodiments, each 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 are, independently, chemical moieties; X1 , 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 is, independently of each other, a carbon atom or a heteroatom which may or may not contain a substituent; Y 1 is a linker; m is 1, 2, or 3; n is 0, 1, or 2; provided that when the X group is N within an aromatic ring, there is no R group attached to the X group; R 13 is selected independently from hydrogen, an aliphatic straight chain, an aliphatic branched chain, -Y-ring A; ring B; or -Y-R A and any of these may be substituted or unsubstituted and may optionally contain or not contain a heteroatom, where Y is a bond or a linker; ring A is an optionally substituted or unsubstituted alicyclic ring or alicyclic heterocyclic ring, or a combination thereof; ring B is an alicyclic heterocyclic ring. In some examples, R 13 is an aromatic ring such as phenyl, pyridinyl, or pyrimidinyl.

[0146] In some embodiments, X 4 is C (e.g., CH, CH 2 ), or N (e.g., N, NH, NR 1 , NOR 1 ), which may or may not optionally contain a substituent (e.g., R 1 ); X 5 is O or N (e.g., NH, NR 1 , NOR 1 ). Here, R 1 is as defined herein, and by way of example, includes H, OH, methyl, ethyl, trifluoromethyl. X 4 can be C, NH or NOH, or NOR 1 . X 5 is O or NR 1 , or NOR 1 . In some aspects, X4 is C, CH, CH 2 , CR 1 , C(R 1 ) 2 or N, NH, NR 1 , NOH, which may or may not optionally contain substituents.

[0147] In some embodiments, the compound can comprise at least one of the following: Y is a linker of a chemical moiety; Y 1 is an amide linker linked in either direction; X 3 is S or NH; X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , or X 13 of which at least one is N; or X 14 is O or NH. X 5 is O or NH, NR 1 , NOR 1 .

[0148] In some embodiments, the linker Y 1 is an amide, hydrazide, carbohydrazide, hydroxy-substituted amide, alkyl-substituted amide, carboxyimide amide, or sulfonimide amide.

[0149] In some embodiments, Y 1 is

Chemical formula

[0150] and may be, where X 4 , X 5 , and X 6 are heteroatoms. In some aspects, X 4 is N, X 5 is O, and R 1 is as defined herein. In some aspects, X 4is N, and X 5 is N, and R 1 is as defined herein (such as hydrogen). In some embodiments, X 4 is N, and X 5 is O, and R 1 is hydrogen, methyl, hydroxyl, amine, which may or may not contain substituents such as alkyl (e.g., methyl). In some embodiments, X 4 is N, and X 5 is NH, and X 6 is O. In some embodiments, X 4 is C (e.g., CH, CH 2 ) or N (e.g., N, NH, NR 1 , NOR 1 ), which may or may not optionally contain substituents (e.g., R 1 ); X 5 is O or N (e.g., NH, NR 1 , NOR 1 ). Here, R 1 is as defined herein, and examples include H, OH, methyl, ethyl, trifluoromethyl. X 4 can be C, NH or NOH, or NOR 1 . X 5 is O or NR 1 , or NOR 1 .

[0151] In some embodiments, Y 1 is

[0152]

Chemical formula

[0153] In some embodiments, the kinase inhibitor (e.g., TNIK kinase inhibitor and / or MAP4K4 kinase inhibitor) can include a structure of Formula 1K, 1L, 1M, 1N, 1O, 1P, or 1Q, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center. In some aspects, Y is a linker of chemical moieties; Y 1 is a linker of chemical moieties; X 4 is NH; X 5 is O. In some aspects, X 4 is C (e.g., CH, CH 2 ), or N (e.g., N, NH, NR 1 , NOR 1 ), which optionally includes a substituent (e.g., R 1 ); X 5 is O or N (e.g., NH, NR 1 , NOR 1 ). Here, R 1 is as defined herein, and by way of example, includes H, OH, methyl, ethyl, trifluoromethyl. X 4 can be C, NH, or NOH, or NOR 1 . X 5 is O or NR 1 , or NOR 1 . [Chemical Formula] [Chemical Formula] Here, Y is a linker of chemical moieties; Y 1 is a chemical moiety; X 4 is NR 1 ; X 5 is O or N. In some aspects, X 4 is C (e.g., CH, CH 2 ), or N (e.g., N, NH, NR 1 , NOR 1 ), which optionally includes a substituent (e.g., R1 either contains or does not contain; X 5 is O or N (e.g., NH, NR 1 , NOR 1 ). Here, R 1 is as defined herein, and by way of example, includes H, OH, methyl, ethyl, trifluoromethyl. X 4 is C, NH or NOH, or NOR 1 and can be. X 5 is O or NR 1 , or NOR 1 and is.

[0154] In some embodiments, the kinase inhibitor can include a structure of Formula 1R, 1S, 1T, 1U, 1V, 1W, 1X, 1Y, or 1Z, a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center.

Chemical formula

Chemical formula

Chemical formula

[0155] In some embodiments, the kinase inhibitor can comprise a structure of Formula 5K1, or 5L1, or a derivative thereof, a prodrug thereof, a salt thereof, a stereoisomer thereof, a tautomer thereof, a polymorph thereof, or a solvate thereof, or a structure having any chirality at any chiral center.

Chemical formula

[0156] In the formulas provided herein, the compound comprises at least one of the following: R 3 is a substituent; R 6 / R 10 is a substituent; R 7 / R 9 is a substituent; and R 8 is a substituent. Other R groups can be hydrogen or absent. In some aspects, the compound comprises at least one of the following: R 3 is F or methyl; R 6 / R 10 is F, Br, Cl, methoxy, or methyl ester; R 7 / R 9 is F or methoxy; or R 8 is F, methoxy, or methyl. In some aspects, the compound comprises: R 3 is F or methyl; and R 1 R 2 R 4 and R 5 is H. In some aspects, the compound comprises at least one of the following: R 6 and R 9 have substituents, R 7 R 8 and R 10 are H; R 6 has a substituent, R7 and R 8 and R 9 and R 10 is H; R 8 has a substituent, R 6 and R 7 and R 9 and R 10 is H; or R 6 and R 8 has a substituent, R 7 and R 9 and R 10 is H. In some embodiments, the compound comprises: R 3 is F or methyl; R 1 and R 2 and R 4 and R 5 is H; R 6 is F, Br, Cl, methoxy, or methyl ester; R 9 is F or methoxy; and R 7 and R 8 and R 10 is H. In some embodiments, the compound comprises: R 3 is F or methyl; R 1 and R 2 and R 4 and R 5 is H; R 6 is F, Br, Cl, methoxy, or methyl ester; and R 7 and R 8 and R 9 and R 10 is H. In some embodiments, the compound comprises: R 3 is F or methyl; R 1 and R 2 and R 4 and R 5 is H; R 8 is F, methoxy, or methyl; and R 6 and R 7 and R 9 and R 10 is H. In some embodiments, the compound comprises: R 3 is F or methyl; R 1, R 2 , R 4 , and R 5 is H; R 6 is F, Br, Cl, methoxy, or methyl ester; R 8 is F, methoxy, or methyl; and R 7 , R 9 , and R 10 is H.

[0157] In some embodiments, 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 are each independently halogen, alkyl, branched alkyl, alkoxy, alkyl ester, alkylsulfanyl (i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy, trifluoroalkyl, or acetamide (i.e., acetylamino). In some aspects, R 3 , R 6 , R 7 , R 8 , R 9 , or R 10 are each independently halogen, alkyl, branched alkyl, alkoxy, alkyl ester, alkylsulfanyl (i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy, trifluoroalkyl, acetamide (i.e., acetylamino), and the remainder of the R groups is hydrogen or does not exist. In some aspects, n is 0 and R 11 and R 12 do not exist.

[0158] In some embodiments, each R 1 , R 2 , R 3 , R 4 , and R 5is independently 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, trifluoromethyloxy, or a combination thereof;

[0159] In some embodiments, each R 6 , R 7 , R 8 , R 9 , or R 10 is independently hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl, acetamide, methyl acetamide, ethyl acetamide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinium, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino, morpholino, or a combination thereof.

[0160] In some embodiments, each R 11 and R 12 is hydrogen or absent.

[0161] In some embodiments, X 1 , X 2 , X 6 , X 7 , X 8 , X 9 , X 12 , X 13 , and X 20 is independently CH or N; X 3 is NH, O, or S; X 10 and X 11 is independently CH or N; X 14 is independently NH or O.

[0162] In some embodiments, R 13 is independently a bond coupled to at least one of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy (optionally substituted or unsubstituted) or a combination thereof or C 1 ~C 6 alkyl.

[0163] In some embodiments, R 13is independently coupled to at least one of hydrogen, cyclopentyl, tetrahydrofuran, fluorotetrahydrofuran, difluorotetrahydrofuran, pyrrolidinyl, piperidinyl, phenyl, pyridinyl, pyrimidinyl, bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[3.2.1]octan-3-yl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, oxetanyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, phenyl, or a combination thereof, or a C 1 ~C 6 alkyl.

[0164] In some embodiments, the compound is one of Compounds 80-106 below:

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0165] In some embodiments, the substitution patterns of the R groups of Compounds 1-79 and their substituents can be applied to any of Compounds 80-106. As such, data from Compounds 1-79 may indicate the corresponding Compounds 80-106. In some aspects, the substitution patterns and their substituents of the following compounds are applied to the core structure of Compounds 80-106: Compound 2 - 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide; Compound 3 - 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide; Compound 13 - N-(2-Bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide; Compound 14 - N-(2-Chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide; Compound 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 - Methyl 2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide)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.

[0166] In some embodiments, the compound has one of the structures of the following Compounds A-1 to A-63:

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

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Chem.

Chem.

[0167] In some embodiments, the compound has one of the structures of Compounds B-1 to B-79 below:

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0168] In some embodiments, the compound has one of the structures of Compounds C-1 to C-59 below: [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry]

Chem.

Chem.

Chem.

Chem.

[0169] In some embodiments, the core structures of Compounds 80-106, which are TNIK kinase inhibitors, may lack the substitution patterns and substituents of Compounds 1-79 that are not specifically described in this paragraph.

[0170] In some embodiments, the 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-(pyrrolidin-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound 82); 5-(1-Cyclopropyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)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-(pyrrolidin-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)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound 87); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazol-5-yl)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); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-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)oxazole-5-carboxamide (Compound 98); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-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-triazole-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)picolylamide (Compound 104); N-(5-fluoro-2-methoxyphenyl)-5-(2-phenyl-3,6,7,8-tetrahydrocyclopenta[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-cyclopenta[d]furo[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide (Compound 106).;

[0171] In some embodiments, the compound is one of the following (Compound 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-(pyrrolidin-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-(pyrrolidin-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-(pyrrolidin-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)oxazole-5-carboxamide (Compound A-20); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)oxazole-2-carboxamide (Compound A-21); 2-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)thiazole-5-carboxamide (Compound A-22); 3’-Cyclopentyl-N-(2-fluorophenyl)-5’-(4-fluorophenyl)-1H,3’H-[2,4’-biiimidazole]-5-carboxamide (Compound A-23);5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)-4H-1,2,4-triazole-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)picolylamide (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-(oxetan-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-(oxetan-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-45); 5-(4-(4-Fluorophenyl)-1-(oxetan-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-(oxetan-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-(oxetan-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-sulfamoylphenyl)furan-2-carboxamide (Compound A-50); N-(2-Fluoro-4-sulfamoylphenyl)-5-(4-(4-fluorophenyl)-1-(1-hydroxypropan-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-carboxamide)-3-fluorophenyl)-1-methylpiperazin-1-ium (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-hydroxylcyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound A-60); rac-5-(4-(4-Fluorophenyl)-1-((1R,2R)-2-hydroxylcyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound A-61); rac-5-(4-(4-Fluorophenyl)-1-((1R,3S)-3-hydroxylcyclopentyl)-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);

[0172] In some embodiments, the compound is one of the following (Compound B-1 to B-79): 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-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)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide; Compound B-4); 5-(1-Cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide (Compound B-5); 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-carboxamide (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 (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-dimethylphenyl)furan-2-carboxamide (Compound B-20); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide (Compound B-21); Ethyl 3-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide)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-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); Methyl 2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide)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-dimethylphenyl)furan-2-carboxamide (Compound B-31); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide (Compound B-32); Ethyl 4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide)benzoate (Compound B-33); 5-(1-Cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-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-dimethylphenyl)furan-2-carboxamide (Compound B-59);5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide (Compound B-60); 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethylphenyl)furan-2-carboxamide (Compound B-61); 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound B-62); 5-(1-Cyclohexyl-4-(4-fluorop; 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-dimethylphenyl)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)-N-(3,4-dimethylphenyl)furan-2-carboxamide (Compound B-69); 5-(1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-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-ethylphenyl)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)-1H-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).;

[0173] In some embodiments, the 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-carboxamide)-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-carboxamide)-3-methoxybenzoic acid (Compound C-3); 3-(4-(3'-(tert-Butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide)-3-fluorophenyl)propanoic 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-carboxamide)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’-bimidazole]-5-carboxamide)benzoic acid (Compound C-10); 3-(3-chloro-4-(5’-(4-fluorophenyl)-3’-(trifluoromethyl)-1H,3’H-[2,4’-bimidazole]-5-carboxamide)phenyl)propanoic acid (Compound C-11); 5’-(4-fluorophenyl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-3’-(trifluoromethyl)-1H,3’H-[2,4’-bimidazole]-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’-bimidazole]-5-carboxamide (Compound C-13); N-(4-(bis(2-hydroxyethyl)amino)-2-chlorophenyl)-5’-(4-fluorophenyl)-3’-(trifluoromethyl)-1H,3’H-[2,4’-bimidazole]-5-carboxamide (Compound C-14); 4-(5’-(4-fluorophenyl)-3’-methoxy-1H,3’H-[2,4’-bimidazole]-5-carboxamide)-3-methoxypyridine 1-oxide (Compound C-15); N-(2-fluoro-4-(2-hydroxyethyl)phenyl)-5’-(4-fluorophenyl)-3’-methoxy-1H,3’H-[2,4’-bimidazole]-5-carboxamide (Compound C-16); 3-chloro-4-(5’-(4-fluorophenyl)-3’-methoxy-1H,3’H-[2,4’-bimidazole]-5-carboxamide)benzoic acid (Compound C-17); 3-(4-(5’-(4-fluorophenyl)-3’-methoxy-1H,3’H-[2,4’-bimidazole]-5-carboxamide)-3-methoxyphenyl)propanoic acid (Compound C-18); N-(2-fluoro-4-(piperazin-1-yl)phenyl)-5’-(4-fluorophenyl)-3’-methoxy-1H,3’H-[2,4’-bimidazole]-5-carboxamide (Compound C-19);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); 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 (Compound C-23); 4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide)-3-methoxybenzoic acid (Compound C-24); 3-(3-fluoro-4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide)phenyl)propanoic 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)-1H-imidazol-5-yl)furan-2-carboxamide)-3-fluoropyridine 1-oxide (Compound C-30); 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-(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]octan-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]octan-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]heptan-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)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound C-51); 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'-bimidazole]-4-sulfonimide amide (Compound C-56); 5-(4-(4-Fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboximidamide (Compound C-57); 5'-(4-Fluorophenyl)-N-(3-fluoropyridin-4-yl)-N-hydroxy-3'-isopropyl-1H,3'H-[2,4'-bimidazole]-4-carboxamide (Compound C-58); or 5-(4-(4-Fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N'-methylfuran-2-carbohydrazide (Compound C-59). In some embodiments, the compound is included in a pharmaceutical composition, and the aforementioned pharmaceutical composition includes a compound that is a TNIK kinase inhibitor; and a pharmaceutically acceptable carrier having the aforementioned compound.

[0174] In some aspects, the core structure of Compounds 80-106 (for example, the compounds recited in the claims), which are TNIK kinase inhibitors, may lack the substitution patterns and substituents of Compounds 1-79 that are not specifically listed in this paragraph.

[0175]

[0176] ​In some embodiments, the compound recited in the claims is not one of Compounds 1 to 79. However, these Compounds 1 to 79 can be used in the methods described herein.

[0177] In some embodiments, the compound recited in the claims 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.

[0178] In some embodiments, the compound recited in the claims 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.

[0179] In some embodiments, the compound recited in the claims 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.

[0180] In some embodiments, the compound recited in the claims is not a compound under Formula B or Formula B1, where ring C is as defined herein (a C (with or without heteroatoms) 5 ~C 6 ring structure (e.g., an alicyclic ring), etc.). However, the compounds of Formula B or Formula B1 can be used in the methods described herein.

[0181] In some embodiments, the compound recited in the claims is not a compound under Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12, Formula 13, or Formula 14, where ring A is as defined herein; however, these compounds can be used in the methods described herein.

[0182] Protocol for in vitro assay

[0183] Incubate MAP4K4(h) with 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 250 μM, 10 mM magnesium acetate, and [gamma-33P-ATP] (specific activity and radioactivity concentration as required). Start the reaction by adding the Mg / ATP mix. After incubation at room temperature for 40 minutes, stop the reaction by adding phosphoric acid to a concentration of 0.5%. Then spot 10 μl of the reaction onto a P30 filter mat, wash 4 times in 0.425% phosphoric acid for 4 minutes and once in methanol, dry, and perform scintillation measurement.

[0184] LX-2 fibrosis assay.

[0185] Human hepatic stellate cells LX-2 were grown in DMEM (Invitrogen, 11960) supplemented 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 the cells were grown in a 12-well plate for 24 hours, the cell culture medium was replaced with the same medium as above except using 0.4% fetal bovine serum. After growing in the serum-reduced medium for 20 hours, the cells were treated with the indicated doses of the compound for 30 minutes. Thereafter, the cells were stimulated with 4 ng / mL TGF-β (R&D Systems, 240-B-002) for 48 hours. After the cells were rinsed twice with DPBS, they were harvested at 4°C using 100 μL of RIPA buffer (Sigma, R0278) supplemented with a protease inhibitor cocktail (Roche, 04693132001). The total protein in each sample was quantified using a BCA protein assay kit (Pierce™, 23227), and an equal amount of total protein from 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) (Santa Cruz Biotechnologies); and mouse anti-GAPDH (6C5) (EMD Millipore, MAB374).

Table 2-1

Table 2-2

Table 2-3

[0186] Definition

[0187] As used herein, the term "alkyl" or "aliphatic", although not essential, typically refers to a branched or unbranched saturated hydrocarbon group containing from 1 to about 24 carbon atoms, and includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, and decyl, as well as cycloalkyl groups (such as cyclopentyl and cyclohexyl). Generally, although this is also not essential, alkyl groups herein contain from 1 to about 18 carbon atoms, or from 1 to about 12 carbon atoms. The term "lower alkyl" is intended to mean an alkyl group having 1 to 6 carbon atoms. " 1 ~C 6 alkyl" or substituents designated "lower alkyl" contain from 1 to 3 carbon atoms, and such substituents contain 1 or 2 carbon atoms (i.e., methyl and ethyl). "Substituted alkyl" refers to alkyl substituted with one or more substituents, and the terms "alkyl containing a heteroatom" and "heteroalkyl" refer to alkyl in which at least one carbon atom is substituted with a heteroatom, as will be described in more detail below. Unless otherwise indicated, the terms "alkyl" and "lower alkyl" each include linear, branched, cyclic, unsubstituted, substituted, and / or alkyl or lower alkyl containing a heteroatom. Examples of alkyl 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 may be either substituted or unsubstituted. Examples of 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.

[0188] As used herein, the term "alkenyl" refers to a straight-chain, branched-chain, or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond (such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, icosenyl, and tetracosenyl). Generally, although not necessarily, alkenyl groups herein contain 2 to about 18 carbon atoms, or 2 to 12 carbon atoms. The term "lower alkenyl" is intended to mean an alkenyl group of 2 to 6 carbon atoms, and the specific term "cycloalkenyl" is intended to mean a cyclic alkenyl group or one having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to an alkenyl substituted with one or more substituents, and the terms "alkenyl containing a heteroatom" and "heteroalkenyl" refer to an alkenyl in which at least one carbon atom is substituted with a heteroatom. Unless otherwise indicated, the terms "alkenyl" and "lower alkenyl" each include straight-chain, branched-chain, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and lower alkenyl.

[0189] As used herein, the term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond (such as ethynyl and n-propynyl). Generally, although not necessarily, alkynyl groups herein contain 2 to about 18 carbon atoms, or 2 to 12 carbon atoms. The term "lower alkynyl" is intended to mean an alkynyl group of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to an alkynyl substituted with one or more substituents, and the terms "alkynyl containing a heteroatom" and "heteroalkynyl" refer to an alkynyl in which at least one carbon atom is substituted with a heteroatom. Unless otherwise indicated, the terms "alkynyl" and "lower alkynyl" each include straight-chain, branched-chain, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl.

[0190] As used herein, the term "alkoxy" is intended to mean an alkyl group attached via a single terminal ether linkage; that is, an "alkoxy" group can be represented as -O-alkyl, where alkyl is as defined above. A "lower alkoxy" group is intended to mean an alkoxy group containing from 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, and the like. As used herein, a substituent designated as "C 1 ~C 6 alkoxy" or "lower alkoxy" contains from 1 to 3 carbon atoms, and such a substituent contains 1 or 2 carbon atoms (i.e., methoxy and ethoxy).

[0191] As used herein, the term "aryl" refers to an aromatic substituent that, unless otherwise specified, contains a single aromatic ring or multiple aromatic rings that are fused to each other, directly linked, or indirectly linked (such that different aromatic rings are attached to a common group such as a methylene or ethylene moiety). Examples of aryl groups contain from 5 to 20 carbon atoms, and aryl groups contain from 5 to 14 carbon atoms. Examples of aryl groups include those containing one aromatic ring or two fused or linked aromatic rings (e.g., phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, and benzophenone, among others). "Substituted aryl" refers to an aryl moiety substituted with one or more substituents, and the terms "aryl containing a heteroatom" and "heteroaryl" refer to aryl substituents in which at least one carbon atom is replaced by a heteroatom, as further detailed below. Unless otherwise indicated, the term "aryl" includes unsubstituted, substituted, and / or aromatic substituents containing a heteroatom.

[0192] As used herein, the term "aryloxy" refers to an aryl group bonded through a single terminal ether linkage, where "aryl" is as defined above. The "aryloxy" group may be represented as -O-aryl, where aryl is as defined above. Examples of aryloxy groups contain from 5 to 20 carbon atoms, and aryloxy groups contain from 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, and 3,4,5-trimethoxy-phenoxy.

[0193] The term "alkaryl" refers to an aryl group having an alkyl substituent, and the term "aralkyl" refers to an alkyl group having an aryl substituent, where "aryl" and "alkyl" are as defined above. Examples of aralkyl groups contain from 6 to 24 carbon atoms, and aralkyl groups contain from 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, and 4-benzylcyclohexylmethyl. Examples of alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethyl(dimethyi)naphthyl, 7-cyclooctylnaphthyl, and 3-ethyl-cyclopenta-1,4-diene.

[0194] The term "cyclic" refers to an alicyclic or aromatic substituent which may or may not be substituted and / or which may or may not contain heteroatoms, and which may be monocyclic, bicyclic, or polycyclic.

[0195] The terms "halo" and "halogen" are used in their conventional sense to refer to each of the substituents chloro, bromo, and fluoro or iodo.

[0196] The term "alkyl group containing a heteroatom" (also referred to as a "heteroalkyl" group), or "aryl group containing a heteroatom" (also referred to as a "heteroaryl" group), or "heteroatom-containing" as seen in other uses of "hetero" refers to a molecule, bond, or substituent in which one or more carbon atoms are replaced by atoms other than carbon (e.g., nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur). Similarly, the term "heteroalkyl" refers to an alkyl substituent containing a heteroatom, the term "heterocyclic" refers to a cyclic substituent containing a heteroatom, and the terms "heteroaryl" and "aromatic heterocycle" refer to "aryl" and "aromatic" substituents containing a heteroatom, respectively. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, and N-alkylated aminoalkyl. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examples of alicyclic groups containing a heteroatom are pyrrolidino, morpholino, piperazino, piperidino, etc.

[0197] The term "hydrocarbyl" refers to a monovalent hydrocarbyl radical containing from 1 to about 30 carbon atoms, or from 1 to about 24 carbon atoms, or from 1 to about 18 carbon atoms, or from about 1 to 12 carbon atoms (including straight-chain, branched-chain, cyclic, saturated, and unsaturated species such as alkyl groups, alkenyl groups, and aryl groups). "Substituted hydrocarbyl" refers to a hydrocarbyl substituted with one or more substituents, and the term "hydrocarbyl containing a heteroatom" refers to a hydrocarbyl in which at least one carbon atom is replaced by a heteroatom. Unless otherwise indicated, the term "hydrocarbyl" should be interpreted to include substituted and / or heteroatom-containing hydrocarbyl moieties.

[0198] "Substituted", as seen in "substituted alkyl" and "substituted aryl", means that at least one hydrogen atom bonded to a carbon (or other) atom in an alkyl, aryl, or other moiety is replaced by one or more non-hydrogen substituents, as suggested by some of the foregoing definitions.

[0199] Furthermore, the foregoing functional groups may be further substituted with one or more additional functional groups or one or more hydrocarbyl moieties (such as those specifically enumerated), provided that the particular groups are permitted. Similarly, the above hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties (such as those specifically enumerated).

[0200] When the term "substituted" precedes a list of possible substituents or is otherwise referred to in connection with possible substituents, it is intended that this term apply to any member of the foregoing groups. For example, the phrase "substituted alkyl, alkenyl, and aryl" should be interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl". Similarly, when the term "containing a heteroatom" precedes a list of groups that may contain a heteroatom, it is intended that this term apply to any member of the foregoing groups. For example, the phrase "alkyl, alkenyl, and aryl containing a heteroatom" should be interpreted as "alkyl containing a heteroatom, alkenyl containing a heteroatom, and aryl containing a heteroatom".

[0201] All other chemical terms are defined as known in the art.

[0202] As used herein, the term "subject" refers to any animal (e.g., a mammalian animal) (including, but not limited to, humans, non-human primates, and rodents) that is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein when referring to a human subject.

[0203] "Pharmaceutically acceptable" refers to being approved or approvable by a regulatory agency of the Federal or a State government for use in animals (including humans), or being included in the United States Pharmacopeia or other generally recognized pharmacopeias.

[0204] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound.

[0205] "Pharmaceutically acceptable excipient, carrier, or adjuvant" refers to an excipient, carrier, or adjuvant that can be administered to a subject in combination with at least one TNIK inhibitor of the present disclosure, is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the TNIK inhibitor without destroying its pharmacological activity.

[0206] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier that is administered in combination with at least one TNIK inhibitor of the present disclosure.

[0207] The terms "effective amount", "therapeutically effective amount", or "therapeutic effect" refer to the amount of a TNIK inhibitor, polypeptide, polynucleotide, small organic molecule, or other drug that is effective to "treat" a disease or disorder in a subject or mammal. In the case of cancer, a therapeutically effective amount of a drug has a therapeutic effect and, as such, can reduce the number of cancer cells; can it reduce tumorigenicity, tumorigenic frequency, or tumorigenic performance; can it reduce the number or frequency of cancer stem cells; can it reduce tumor size; can it inhibit and stop the invasion of cancer cells into peripheral organs (including, for example, the metastasis of cancer to soft tissue and bone); can it inhibit and stop tumor metastasis; can it inhibit and stop tumor growth; can it somewhat alleviate one or more of the symptoms associated with cancer; can it reduce morbidity and mortality; can it improve the quality of life; and combinations of such effects are possible.

[0208] The terms "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" and the like refer to both 1) therapeutic means for curing, delaying, alleviating symptoms of, and / or arresting the progression of a diagnosed pathological condition or disorder, and 2) prophylactic or preventive means for preventing and / or delaying the onset of a targeted pathological condition or disorder. Accordingly, those in need of treatment include those already suffering from a disorder; those predisposed to suffering from a disorder, and those seeking to prevent a disorder.

[0209] One of ordinary skill in the art will recognize that the processes and other procedures and methods disclosed herein may be performed in a different order of the acts performed in the processes and methods. Further, the steps and operations outlined are provided for purposes of illustration only, and some of the steps and operations may be combined into fewer steps and operations or expanded into additional steps and operations, as necessary, without departing from the essence of the disclosed embodiments.

[0210] The present disclosure is not limited to the specific embodiments described in this application, and the specific embodiments are intended to be illustrative of various aspects. As will be apparent to those of ordinary skill in the art, many modifications and variations are possible without departing from the spirit and scope of the invention. In addition to the methods and apparatuses recited herein, functionally equivalent methods and apparatuses within the scope of the present disclosure will be apparent to those of ordinary skill in the art from the foregoing description. Such modifications and variations are intended to be within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims together with the full scope of equivalents to which such claims are entitled. It should be understood that the present disclosure is not limited to a particular method, reagent, compound, composition, or biological system and may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0211] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art can interchange from plural to singular and / or from singular to plural as appropriate to the context and / or application. For the sake of clarity, various singular / plural exchanges may be explicitly set forth herein.

[0212] Generally, it will be understood by those skilled in the art that terms used herein, particularly in the appended claims (e.g., the main body part of the appended claims), are generally to be construed as "non-limiting" terms (e.g., the term "including" should be construed as "including, but not limited to", the term "having" should be construed as "having at least", and the term "includes" should be construed as "including, but not limited to"). It will further be understood by those skilled in the art that where a specific number is intended in the claim recitations, such intent is clearly recited in the claim, and where there is no such recitation, there is no such intent. For example, for purposes of illustration, the following appended claims may introduce into the claim recitations the introductory phrases "at least one" and "one or more". However, even if such phrases are used, the fact that an indefinite article "a" or "an" is introduced into the claim recitations does not mean that any particular claim containing such claim recitations is limited to embodiments containing only one such recitation (e.g., "a" and / or "an" should be construed as meaning "at least one" or "one or more"); the same applies when a definite article is introduced into the claim recitations. Further, even where a specific number is clearly recited in the claim recitations, those skilled in the art will recognize that such recitation should be construed as meaning at least the recited number (e.g., a mere recitation of "two recitations" without other modifiers means at least two recitations, or two or more recitations).Furthermore, in examples where a conventional expression similar to "at least one of A, B, and C, etc." is used, generally, such a construction is intended to convey the meaning of the conventional expression as understood by those skilled in the art (e.g., a "system having at least one of A, B, and C" would include, but not be limited to, a system having only A, only B, only C, both A and B, both A and C, both B and C, and / or all of A, B, and C). In examples where a conventional expression similar to "at least one of A, B, or C, etc." is used, generally, such a construction is intended to convey the meaning of the conventional expression as understood by those skilled in the art (e.g., a "system having at least one of A, B, or C" would include, but not be limited to, a system having only A, only B, only C, both A and B, both A and C, both B and C, and / or all of A, B, and C). It will be further understood by those skilled in the art that any substantially disjunctive and / or disjunctive clause representing two or more selectable terms, whether in the description, claims, or drawings, should be understood to countenance the possibility of including one of those terms, any of those terms, or both of those terms. For example, the clause "A or B" would be understood to include the possibilities of "A" or "B", or "A and B".

[0213] Furthermore, when a feature or aspect of the present disclosure is described in Markush format, those skilled in the art will recognize that any individual member or subgroup of members of the Markush group is also described by the present disclosure.

[0214] As will be understood by those skilled in the art, for all purposes, for example, from the perspective of providing a specification, all ranges disclosed in this specification include all possible sub-ranges and combinations of those sub-ranges. Any recited range is sufficiently described and can be readily recognized as being divisible into at least equal halves, thirds, quarters, fifths, tenths, etc. of the aforementioned range. By way of non-limiting example, each range discussed in this specification can be readily divided into lower thirds, middle thirds, upper thirds, etc. Also, as will be understood by those skilled in the art, all expressions such as "up to" and "at least" include the recited number and refer to a range that can be divided into the sub-ranges discussed above. Finally, as will be understood by those skilled in the art, a range includes individual members. Thus, for example, a group having 1 to 3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1 to 5 cells refers to a group having 1, 2, 3, 4, or 5 cells, etc.

[0215] From the foregoing, it will be recognized that various embodiments of the present disclosure are described herein for purposes of illustration and that various modifications are possible without departing from the scope and spirit of the present disclosure. Accordingly, the various embodiments disclosed herein are not intended to limit the present invention, and the true scope and spirit are indicated by the following claims.

[0216] All references cited in this specification are hereby incorporated by reference in their entirety for all that they teach.

Claims

1. Formula A: 【Chemical Formula 25】 (wherein Ring 1 is a phenyl group, a pyridyl group, or a pyrimidinyl group; Ring 2 is a 5-membered aromatic heterocyclic ring; Ring 3 is an imidazolyl group, a triazolyl group, a cyclopenta-pyrrolo-pyridinyl condensed ring group, or a cyclopenta-furo-pyridinyl group; Ring 4 is a phenyl group, a pyridyl group, a pyrimidinyl group, or a triazinyl group; Y is a bond; Y １ is an amide linker having nitrogen bonded to ring 1 and carbon bonded to ring 2; each n is 0; each o is independently 0, 1, 2, 3, 4, or 5; each R1 or R6 is independently F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, trifluoromethyl, oxygen, oxide, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, trifluoromethyloxy, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, acetyl, carboxylic acid, alkyl carboxylic acid, methyl carboxylic acid, ethyl carboxylic acid, propionyl, butyryl, acetamide, methylacetamide, ethylacetamide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, difluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, methylsulfanyl, thiomethyl, ethylsulfanyl, propylsulfanyl, butylsulfanyl, pentylsulfanyl, hexylsulfanyl, heptylsulfanyl, octylsulfanyl, sulfamoyl, methylpiperazinyl, piperazinyl, hydroxyethylpiperazinyl, bis(2-hydroxyethyl)amino, or morpholino, R Ａ is a C ３ alicyclic ring, 5-membered alicyclic heterocyclic ring, 6-membered alicyclic heterocyclic ring, C １ to C １２ aliphatic straight chain, or C １ to C １２ aliphatic branched chain, each of which is substituted or unsubstituted; the following conditions a), b), c), and d): a) When Ring 1 is a phenyl group, at least one of the following: Ring 2 is not a furanyl group; Ring 3 is not an imidazolyl group; or Ring 4 is not a phenyl group; b) When ring 2 is a furanyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 3 is not an imidazolyl group, or Ring 4 is not a phenyl group; c) When ring 3 is an imidazolyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 2 is not a furanyl group; or Ring 4 is not a phenyl group; or d) When ring 4 is a phenyl group, at least one of the following: Ring 1 is not a phenyl group; Ring 2 is not a furanyl group; or Ring 3 is not an imidazolyl group at least one of which is applicable) A compound having the structure, its salt, or its solvate. **Claim 2** Ring 1 is a phenyl group, a pyridyl group, or a pyrimidinyl group. When ring 1 is pyridyl or pyrimidinyl, nitrogen is located at the para, meta, or ortho position within the ring; Ring 2 is a furanyl group, a thiophenyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group; an imidazolyl group, or a triazolyl group; Ring 3 is an imidazolyl group, or a triazolyl group; Ring 4 is a phenyl group, a pyridyl group, a pyrimidinyl group, or a triazinyl group. When ring 4 is pyridyl, nitrogen is located at the para, meta, or ortho position within the ring; when ring 4 is pyrimidinyl, nitrogen is located at the meta or ortho position within the ring. The compound, its salt, or its solvate according to claim 1. **Claim 3** Each R １ is independently 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 trifluoromethyloxy, the compound according to claim 1, or a salt or solvate thereof.

4. Each R ６ is independently 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 trifluoromethyloxy, the compound according to claim 1, or a salt or solvate thereof. **Claim 5** R Ａ is tetrahydrofuranyl, pyrrolidinyl, piperidinyl, fluorotetrahydrofuranyl, difluorotetrahydrofuranyl, hydroxycyclopentyl, methylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, hydroxypropyl, or trifluoromethyl, the compound according to claim 1, or a salt or solvate thereof. **Claim 6** One of the following: N-(2-Fluorophenyl)-5-(4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound 90); N-(5-Fluoro-2-methoxyphenyl)-5-(2-phenyl-3,6,7,8-tetrahydrocyclopenta[d]pyrrolo[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide (Compound 105); N-(4-Fluoro-2-methoxyphenyl)-5-(2-phenyl-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]pyridin-1-yl)-1H-pyrrole-2-carboxamide (Compound 106) 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-(pyrrolidin-3-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-3); 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-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-9); N-(2-Fluorophenyl)-5-(4-(4-fluorophenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-10); 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-(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-(oxetan-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-(oxetan-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-45); 5-(4-(4-Fluorophenyl)-1-(oxetan-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-(oxetan-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-(oxetan-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); N-(2-Fluoro-4-sulfamoylphenyl)-5-(4-(4-fluorophenyl)-1-(1-hydroxypropan-2-yl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-51); 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); 4-(3'-(tert-Butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide)-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-carboxamide)-3-methoxybenzoic acid (Compound C-3); 3-(4-(3'-(tert-Butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide)-3-fluorophenyl)propanoic 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-carboxamido)benzoic acid (Compound C-10); 3-(3-Chloro-4-(5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)phenyl)propanoic 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); 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 (Compound C-23); 4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide)-3-methoxybenzoic acid (Compound C-24); 3-(3-Fluoro-4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamide)phenyl)propanoic 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); 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-(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]octan-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]octan-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]heptan-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-(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)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (Compound C-51); 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-sulfonimide amide (Compound C-56); 5-(4-(4-Fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboximide 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-carbohydrazide (Compound C-59) A compound selected from the group consisting of, or a salt or solvate thereof.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a salt or solvate thereof, and a pharmaceutically acceptable excipient.

8. A composition for use in the treatment of fibrosis, cancer, systemic inflammation, metabolic disorders, or cardiovascular diseases, comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

9. The composition according to claim 8, wherein the fibrosis is selected from the group consisting of pulmonary fibrosis, cystic fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, cerebral fibrosis, arterial fibrosis, joint fibrosis, intestinal fibrosis, Dupuytren's contracture fibrosis, keloid fibrosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma fibrosis, and adhesive synovitis.

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