Kinase inhibitors

Abstract

To provide kinase inhibitors.SOLUTION: A TNIK and / or MAP4K4 kinase inhibitor can include a formula A, or a derivative, prodrug, salt, stereoisomer, tautomer polymorph or solvate thereof, or that having chirality at any chiral center. In the formula A: ring 1 is an aromatic ring with or without heteroatoms; ring 2 is a heteroaromatic ring; ring 3 includes at least one heteroaromatic ring and optionally at least one cycloaliphatic ring fused with the at least one heteroaromatic ring; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or a linker; Y1 is a linker; each n is independently 0, 1, or 2; each o is independently 0, 1, 2, 3, 4, or 5; each of R1, R6, R11 and R12 is independently a substituent; and RA is a ring structure or a straight or branched aliphatic chain, which can be substituted or unsubstituted and with or without heteroatoms.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] A biologically active enzyme known as a protein kinase that interacts with TRAF2 and NCK is commonly known as TNIK kinase in humans and is an enzyme encoded by the TNIK gene. TNIK kinase participates in a variety of biological processes common to serine / threonine kinases, such as acting as an activator of the Wnt signaling pathway. TNIK kinase may be required to recruit to the promoter of Wnt target genes and 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 responses to environmental stress. TNIK kinase is also part of a signaling complex composed of NEDD4, RAP2A, and TNIK, which controls the extension and branching of dendrites in developing neurons. More generally, TNIK may play a role in cytoskeletal reorganization and control cell spreading. TNIK kinase also phosphorylates Thr-322 of SMAD1.

[0003] TNIK kinases are also considered germinal center kinases (GCKs) and can be characterized by an N-terminal kinase domain and a C-terminal GCK domain that serve a regulatory function.

[0004] TNIK kinase activation of 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 disease conditions such as colorectal cancer or autosomal recessive forms of cognitive impairment.

[0007] It is also known that TGF-β-activated EMT can be inhibited by attenuating Smad and non-Smad signaling pathways, including Wnt, NF-κB, FAK-Src-paxillin-associated 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 therapeutically to treat and / or prevent 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] overview In some embodiments, the method of inhibiting TNIK kinase and / or MAP4K4 kinase comprises the compound of formula A [ka] or a derivative, prodrug, salt, stereoisomer, tautomeric polymorph, or solvate thereof, or a structure having any chirality at any chiral center.

[0010] In some embodiments, ring 1 is an aromatic ring with or without heteroatoms; ring 2 is an aromatic heterocycle; ring 3 comprises at least one aromatic heterocycle and at least one alicyclic ring optionally fused to at least one aromatic heterocycle; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or a linker; and 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, any of which may or may not contain heteroatoms. 11 and R 12 is absent or hydrogen. In some embodiments, at least one o in 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 heterocycle, or a combination thereof; ring 3 includes a 5-membered aromatic heterocycle, or a 5-membered aromatic heterocycle fused with a 6-membered aromatic heterocycle, which is fused with a 5-membered alicyclic ring (wherein the bond to Y is through said 5-membered aromatic heterocycle), or a combination thereof; ring 4 is a phenyl group, a pyridyl group, a pyrimidyl 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 optionally contain or not contain heteroatoms, or a combination thereof.

[0012] In some embodiments, ring 1 is a phenyl group or a pyridyl group, and when ring 1 is pyridyl, the nitrogen is located at the para, meta, or ortho position in 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, the nitrogen is located at the para, meta, or ortho position in said ring; when ring 4 is a pyrimidyl group, the nitrogen is located at the meta or ortho position in said ring; Y is a bond or a 1- to 6-membered aliphatic chain; Y 1 R is a substituted or unsubstituted amide, sulfonimide amide, ketone, carboxamide linker, or combinations thereof; A is a 3- to 6-membered alicyclic ring, a 5- to 6-membered alicyclic heterocycle; a 1- to 12-membered aliphatic straight chain, or a 1- to 12-membered aliphatic branched chain, any of which may be substituted or unsubstituted, and any aliphatic chain may or may not contain heteroatoms.

[0013] In some embodiments, each R 1 , R 6 , R 11 , and R 12are 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., CHC=O), propionyl, butyryl, acetamido (i.e., acetylamino), propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 absent.

[0014] In some embodiments, a method for 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. [ka]

[0015] In some embodiments, R A is a ring structure, an aliphatic straight chain, or an aliphatic branched chain, any of which may be substituted or unsubstituted and may 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 a substituent; 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 a substituent; Y is a bond or a linker; Y 1 is a linker; m is 1, 2, or 3; and n is 0, 1, or 2. In some embodiments, when the X group is an N in 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 does not exist. 11 and / or R 12 When present, may be present on any suitable ring atom. When n is 0, both the bond and R 11 and / or R 12 is not present. In some embodiments, R A The ring is connected to X via a covalent bond (i.e., Y) 1 It is directly connected to R A If is a ring, then R A can be any alicyclic or heteroalicyclic ring or combinations 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 aliphatic branched chain that may be substituted or unsubstituted and may or may not contain a heteroatom optionally.

[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 , R 9 , R 10 , 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, polyaromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, aliphatic amine, carbonyl, carboxyl, amide, ester, amino acid, derivatives thereof, optionally substituted or unsubstituted, or combinations thereof.

[0019] In some embodiments, ring A is an alicyclic ring having 3-12 ring atoms, an alicyclic heterocyclic ring having 3-12 ring atoms, or a combination thereof, which can be substituted or unsubstituted; ring B is an alicyclic heterocyclic ring having 3-12 ring atoms, which can be substituted or unsubstituted; ring D is a polycyclic ring having at least one aromatic ring fused with a cycloaliphatic; and X is a cycloaliphatic ring. 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, 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 each independently represents 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, cyano, In some embodiments, R is an aryl group, optionally with or without a heteroatom, derivatives thereof ... optionally with or without a heteroatom, derivatives thereof, optionally with or without a heteroatom, optionally with or without a heteroatom, derivatives thereof, optionally with or without a heteroatom, optionally with or without a heteroatom, derivatives thereof, optionally with or without a heteroatom, optionally with or without a heteroatom, derivatives thereof, optionally with or without a heteroatom, optionally with or without a heteroatom, optionally with or without a heteroatom, derivatives thereof, optionally with or without a heteroatom, optionally with or without a heteroatom, optionally with or without a heteroatom, 13 is a C1 to C24 aliphatic straight or branched chain that may be substituted or unsubstituted and may optionally contain or not contain heteroatoms.

[0020] In some embodiments, ring A is an alicyclic ring having 3-6 ring atoms, an alicyclic heterocycle having 3-6 ring atoms, or a combination thereof, which can be substituted or unsubstituted; ring B is an alicyclic heterocycle having 3-6 ring atoms, which can be substituted or unsubstituted; ring D is cyclopentapyridine; and X is a cyclopentapyridine. 1 and X 2 is N ;X 3 is O or NH; X 4 is NH;X 5 is O;X6 , 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 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 Alkarli, 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 Alkylcarbonate, C 6 ~C 20 Arylcarbonato, carboxy, carboxylato, carbamoyl, mono(C 1 ~C 24 Alkyl) substituted carbamoyl, di(C 1 ~C24 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 carbamides, di(C 1 ~C 24 alkyl) substituted carbamides, monosubstituted aryl carbamides, disubstituted aryl carbamides, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azido, 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 any one or more of the substituents selected from the group of arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, optionally with or without heteroatoms, optionally substituted or unsubstituted, derivatives thereof, and combinations thereof; R 13 is a C which may be substituted or unsubstituted and may or may not optionally contain heteroatoms; 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, hexoxy, heptoxy, octoxy, 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 cytoskeleton rearrangement. 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 a variety of 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 the inhibitory activity of systemic inflammation, metabolic disorders, cardiovascular disease, and cancer.

[0024] In some embodiments, the TNIK kinase and / or MAP4K4 kinase compound 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 embodiments, ring 1 is an aromatic ring with or without heteroatoms; ring 2 is an aromatic heterocycle; ring 3 comprises at least one aromatic heterocycle and at least one alicyclic ring optionally fused to at least one aromatic heterocycle; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or a linker; and 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 are independently substituents. In some embodiments, the compounds include 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 includes at least one of the following provisions for Y: if Y is a bond, then R A is C 3 or when Y is a chemical moiety, R A is 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 may be substituted or unsubstituted and may or may not contain heteroatoms; or the compound includes at least one of the following: if ring 1 is a phenyl group, then 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; if ring 2 is a furanyl group, then 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; if ring 3 is an imidazolyl group, then 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 if ring 4 is a phenyl group, then 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 or pyridyl group; ring 2 is a 5- or 6-membered aromatic heterocycle; ring 3 includes a 5-membered aromatic heterocycle or a 5-membered aromatic heterocycle fused with a 6-membered aromatic heterocycle, which is fused with a 5-membered alicyclic ring (wherein the bond to Y is through said 5-membered aromatic heterocycle); ring 4 is a phenyl, pyridyl, pyrimidyl, or triazinyl group; Y is a bond or an aliphatic linker; Y is a phenyl, pyridyl, pyrimidyl, or triazinyl group; 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 heteroatoms, where when Y is a bond, R A is not a five-membered alicyclic ring.

[0027] In some embodiments, ring 1 is a phenyl group or a pyridyl group, and when ring 1 is pyridyl, the nitrogen is located at the para, meta, or ortho position in 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, the nitrogen is located at the para, meta, or ortho position in said ring; when ring 4 is a pyrimidyl group, the nitrogen is located at the meta or ortho position in said ring; Y is a bond or a 1- to 6-membered aliphatic chain; Y is a 1- to 6-membered (e.g., 1 ~C 6 ) if R is an aliphatic linker, A is not a 5-membered alicyclic ring, Y 1 is an amide linker; R A is a 3- to 6-membered (e.g., C 3 ~C 6 ) alicyclic ring, 5- to 6-membered (e.g., C 5 ~C 6 ) alicyclic heterocycles; 1- to 12-membered (e.g., C 1 ~C 12) Aliphatic straight chain, or C 1 ~C 12 aliphatic branched chains, which may be substituted or unsubstituted and may or may not contain heteroatoms, or when Y is a bond, R A is a 5- or 6-membered (e.g., C 6 ~C 6 is not an alicyclic ring.

[0028] In some embodiments, R 1 , R 6 , R 11 , and R 12 each independently represents F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, tert-butyl, methoxy (e.g., ether), ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, acetyl (i.e., CH 3 C=O), propionyl, butyryl, acetamido (i.e., acetylamino), propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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. 11 and R 12 is hydrogen or absent.

[0029] In some embodiments, the TNIK kinase and / or MAP4K4 kinase can be a compound comprising the 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. [ka]

[0030] In some embodiments, R A is optionally substituted or unsubstituted C 3 Alicyclic rings, 4-12 membered (e.g., C 4 ~C 12 ) alicyclic heterocycle, aliphatic straight chain, or aliphatic branched chain, where C 3 The alicyclic ring, aliphatic straight chain, or aliphatic branched chain may or may not contain heteroatoms; 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 are each independently 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 are each independently 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; and n is 0, 1, or 2. In some embodiments, when the X group is an N in an aromatic ring, there is no R group attached to the X group.

[0031] The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the exemplary aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by 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 having the formula A: [ka] (In the formula, Ring 1 is an aromatic ring with or without heteroatoms; Ring 2 is an aromatic heterocycle; Ring 3 comprises at least one aromatic heterocycle and optionally at least one alicyclic ring fused to said 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; Each R 1 , R 6 , R 11 , and R 12 are independently chemical moieties; wherein the compound comprises at least one of the following conditions: If Y is a bond, R A is hydrogen, an aromatic ring, an alicyclic ring, an aliphatic straight chain, or an aliphatic branched chain, any of which may be substituted or unsubstituted, with or without heteroatoms, or combinations thereof; or When Y is a chemical moiety, R A is an aromatic ring, an alicyclic ring, an aliphatic straight chain, or an aliphatic branched chain, which may be substituted or unsubstituted, with or without heteroatoms, or combinations thereof; 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 is true: ring 1 is not a phenyl group; ring 2 is not a furanyl group; or ring 3 is not an imidazolyl group. 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 compound comprising a structure having any chirality at any chiral center. (Item 2) The compound is at least one of the following: Y 1 is an amide having a nitrogen attached to ring 1 and a carbon attached to ring 2; If Y is a bond, R A is C 3 an alicyclic ring, a 5-membered alicyclic heterocycle, a 6-membered alicyclic heterocycle, an aliphatic straight chain, or an aliphatic branched chain, any of which may be substituted or unsubstituted; When Y is a chemical moiety, R A is C 3 an alicyclic ring, a 5-membered alicyclic ring, a 5-membered heteroalicyclic ring, a 6-membered alicyclic ring, a 6-membered heteroalicyclic ring, an aliphatic straight chain, or an aliphatic branched chain, which may be substituted or unsubstituted and may or may not contain heteroatoms; Contains; or The compound is 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 is true: ring 1 is not a phenyl group; ring 2 is not a furanyl group; or ring 3 is not an imidazolyl group. The compound according to item 1, comprising: (Item 3) The compound is Ring 1 is a phenyl group, a pyridyl group, or a pyrimidinyl group; Ring 2 is a 5- or 6-membered aromatic heterocycle; Ring 3 comprises a 5-membered heteroaromatic ring or a 5-membered heteroaromatic ring fused to a 6-membered heteroaromatic ring, which is fused to a 5-membered alicyclic ring, where the bond to Y is through said 5-membered heteroaromatic 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; where Y is a bond, R A is not a five-membered alicyclic ring The compound according to item 1, comprising: (Item 4) Ring 1 is a phenyl group, a pyridyl group, or a pyrimidinyl group, and when Ring 1 is pyridyl or pyrimidinyl, the nitrogen is located at the para, meta, or ortho position within said 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 a pyridyl group, the nitrogen is located at the para-, meta-, or ortho-position within said ring; when Ring 4 is a pyrimidyl group, the nitrogen is located at the meta- or ortho-position within said ring; Y is a bond or C 1 ~C 6 Item 3. The compound according to item 1, which is aliphatic. (Item 5) Y is C 1 ~C 6 When R is an aliphatic linker, A is C 3 ~C 6 Alicyclic ring, C 5 ~C 6 Alicyclic heterocycles, aromatic rings, C 1 ~C 12 Aliphatic straight chain, or C 1 ~C 12 are aliphatic branched chains, which may be substituted or unsubstituted and may optionally contain or not contain heteroatoms; or If Y is a bond, R A is C 6 ~C 6 The compound according to item 1, which is not an alicyclic ring. (Item 6) Each R 1 , R 6 , R 11 , and R 12are 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, ethylacetate 2. The compound of claim 1 which is an amide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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. (Item 7) R 11 and R 12 is hydrogen or absent, and each R 1 or R 6are 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, ethylacetate 2. The compound of claim 1 which is an amide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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. (Item 8) Each R 1 are 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 combinations thereof. (Item 9) Each R 11 and R 12is hydrogen or absent, and each R 6 are 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, ethylacetate 2. The compound of claim 1 which is an amide, propionamide, butylamide, pentanamide, hexanamide, heptanamide, octanamide, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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. (Item 10) Y 1 is an amide, a hydrazide, a carbohydrazide, a hydroxy-substituted amide, an alkyl-substituted amide, a carboximidamide, or a sulfonimidamide. (Item 11) R Aare independently selected from hydrogen, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyridinyl, pyrimidinyl, bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.2octan-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, hydroxypropanyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, phenyl, or combinations thereof. (Item 12) Formula A1 or Formula A2 [ka] (In the formula, Ring D is a ring structure having one or more rings fused together; 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; 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 20are each independently a carbon atom or a heteroatom, 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; If 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; wherein when the X group is N in an aromatic ring, there is no R group attached to the X group; If the dashed line forms a double bond, X 12 is N), 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. (Item 13) Formula 4A or Formula 5A [ka] (In the formula, 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; X 1 , X 2 , X 3 , X 6 , X 7 , X 8 , X9 , X 10 , X 11 , X 12 , X 13 , X 14 , and X 20 are each independently a carbon atom or a heteroatom, with or without substituents; Y 1 is a linker; m is 1, 2, or 3; n is 0, 1, or 2; wherein when the X group is N in an aromatic ring, there is no R group attached to the X group; R 13 is hydrogen, aliphatic straight chain, aliphatic branched chain, [ka] any of which may be substituted or unsubstituted, and may optionally contain or not contain heteroatoms; Where: Y is a bond or a linker; Ring A is an aromatic ring, an alicyclic ring, or an alicyclic heterocyclic ring, or a combination thereof, optionally substituted or unsubstituted; Ring B is an aromatic ring, an alicyclic ring, or an alicyclic heterocyclic ring, or a combination thereof, optionally substituted or unsubstituted), 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. (Item 14) One of formulas 4B to 4E or one of formulas 5B to 5E [ka] [ka] 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. (Item 15) One of formulas 4F-4K or one of formulas 5F-5K [ka] [ka] [ka] (In the formula, X 4 is C, CH, CH 2 , C.R. 1 , C(R 1 ) 2 N, NH, NR 1 or NOH, optionally with or without substituents; X 5 is O, NH, NR 1 , NOR 1 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. (Item 16) Formula 5K1 or 5L1 [ka] 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. (Item 17) Each R 1 , R 2 , R 3 , R 4 , and R 5are 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 combinations thereof; Each R 6 , R 7 , R 8 , R 9 , or R 10 are 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, ethylacetamido, propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 combinations thereof; Each R 11 and R12 is hydrogen or does not exist Item 14. The compound according to item 13, comprising: (Item 18) 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; and X 14 are independently NH or O Item 14. The compound according to item 13, comprising: (Item 19) Y 1 14. The compound according to item 13, comprising an amide, a hydrazide, a carbohydrazide, a hydroxy-substituted amide, an alkyl-substituted amide, a carboximidamide, or a sulfonimidamide. (Item 20) R 13 is independently a bond or C coupled to at least one of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkoxy (optionally substituted or unsubstituted), or a combination thereof; 1 ~C 6 Item 14. The compound according to item 13, wherein the aryl group is alkyl. (Item 21) R 13is independently a bond or C 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[2.2.2octan-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, hydroxypropanyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, phenyl, or a combination thereof; 1 ~C 6 Item 14. The compound according to item 13, wherein the aryl group is alkyl. (Item 22) The compound is R 1 , R 2 , R 4 , and R 5 is hydrogen and 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; R 8 is a substituent; R 6 and R 9 has a substituent, and R 7 , R 8 , and R 10 is H; R 6 has a substituent, and R 7 , R 8 , R 9 , and R 10 is H; R8 has a substituent, and R 6 , R 7 , R 9 , and R 10 is H; or R 6 and R 8 has a substituent, and R 7 , R 9 , and R 10 is H Item 14. The compound according to item 13, comprising: (Item 23) n is 0, R 11 and R 12 The compound according to item 13, wherein (Item 24) The compound is one of the following: 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)picolinamide (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 The compound according to item 1, which is 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). (Item 25) The compound is one of the following: 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (compound A-1); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-2); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-(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'-biimidazole]-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)picolinamide (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-carboxamido)-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-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-60); rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-61); rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-62); or The compound according to item 1, which is 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). (Item 26) The compound is one of the following: 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-carboxamido)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-carboxamido)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-carboxamido)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-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 The compound according to item 1, which is 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide (compound B-79). (Item 27) The compound is one of the following: 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamido)-3-fluoropyridine 1-oxide (compound C-1); 3'-(tert-butyl)-N-(2-chloro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-2); 4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-methoxybenzoic acid (compound C-3); 3-(4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-fluorophenyl)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'-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); 4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-methoxypyridine 1-oxide (compound C-15); N-(2-fluoro-4-(2-hydroxyethyl)phenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-16); 3-chloro-4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamido)benzoic acid (compound C-17); 3-(4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-methoxyphenyl)propanoic acid (compound C-18); N-(2-fluoro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-19); N-(2-chloro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5'-(4-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-carboxamido)-3-methoxybenzoic acid (compound C-24); 3-(3-fluoro-4-(5'-(4-fluorophenyl)-3'-methyl-1H,3'H-[2,4'-biimidazole]-5-carboxamido)phenyl)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-carboxamido)-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'-biimidazole]-4-sulfonimidamide (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'-biimidazole]-4-carboxamide (compound C-58); or The compound according to item 1, which is 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N'-methylfuran-2-carbohydrazide (compound C-59). (Item 28) The compound is one of the following: 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide (Compound-1); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethoxyphenyl)furan-2-carboxamide (compound-2); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-difluorophenyl)furan-2-carboxamide (compound-3); 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (compound-4); 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide (Compound-5); 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (Compound-6); 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound-7); 5-(1-cyclohexyl-4-(p-tolyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide (Compound-8); N-(4-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-9); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-(trifluoromethyl)phenyl)furan-2-carboxamide (Compound-10); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide (Compound-11); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (Compound-12); N-(2-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-13); N-(2-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-14); N-(4-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-15); N-(4-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-16); N-(5-chloro-2-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-17); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethoxyphenyl)furan-2-carboxamide (Compound-18); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (Compound-19); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylphenyl)furan-2-carboxamide (Compound-20); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide (Compound-21); Ethyl 3-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate (Compound-22); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethylphenyl)furan-2-carboxamide (Compound-23); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound-24); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide (Compound-25); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluorophenyl)furan-2-carboxamide (Compound-26); Methyl 2-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate (Compound-27); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide (Compound-28); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide (Compound-29); N-(3-chloro-4-methylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-30); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,5-dimethylphenyl)furan-2-carboxamide (Compound-31); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide (Compound-32); Ethyl 4-(5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamido)benzoate (Compound-33); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-2-carboxamide (Compound-34); N-(3-acetylphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-35); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide (Compound-36); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethyl-6-methylphenyl)furan-2-carboxamide (Compound-37); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide (Compound-38); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide (Compound-39); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluoro-4-methylphenyl)furan-2-carboxamide (Compound-40); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (Compound-41); N-(4-chloro-2-fluorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-42); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-fluoro-2-methylphenyl)furan-2-carboxamide (Compound-43); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)furan-2-carboxamide (Compound-44); N-(3-chloro-4-methoxyphenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-45); N-(4-acetamidophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-46); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(p-tolyl)furan-2-carboxamide (Compound-47); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(m-tolyl)furan-2-carboxamide (Compound-48); N-(4-bromophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-49); 5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide (Compound-50); N-(4-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-51); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethoxyphenyl)furan-2-carboxamide (Compound-52); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-methoxyphenyl)furan-2-carboxamide (Compound-53); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-methoxyphenyl)furan-2-carboxamide (Compound-54); N-(2-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-55); N-(4-chlorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-56); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-difluorophenyl)furan-2-carboxamide (Compound-57); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,5-dimethoxyphenyl)furan-2-carboxamide (Compound-58); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,3-dimethylphenyl)furan-2-carboxamide (Compound-59); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,6-dimethylphenyl)furan-2-carboxamide (Compound-60); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-ethylphenyl)furan-2-carboxamide (Compound-61); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound-62); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-fluorophenyl)furan-2-carboxamide (Compound-63); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-ethoxyphenyl)furan-2-carboxamide (Compound-64); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(o-tolyl)furan-2-carboxamide (Compound-65); N-(3-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-66); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2,4-dimethylphenyl)furan-2-carboxamide (Compound-67); N-(2-chloro-4-methylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-68); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-dimethylphenyl)furan-2-carboxamide (Compound-69); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-mesitylfuran-2-carboxamide (Compound-70); N-(3-acetylphenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-71); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-(methylthio)phenyl)furan-2-carboxamide (Compound-72); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(4-isopropylphenyl)furan-2-carboxamide (Compound-73); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3-ethylphenyl)furan-2-carboxamide (Compound-74); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(3,4-difluorophenyl)furan-2-carboxamide (Compound-75); N-(4-chloro-2-fluorophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-76); 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxy-5-methylphenyl)furan-2-carboxamide (Compound-77); N-(4-acetamidophenyl)-5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound-78); or The compound according to item 1, which is 5-(1-cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-methoxyphenyl)furan-2-carboxamide (Compound-79). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] In the following detailed description, reference is made to the accompanying drawings, which form a part of this specification. In the drawings, similar symbols typically identify similar components unless the context dictates otherwise. The exemplary embodiments described in the detailed description, drawings, and claims are not intended to be limiting. Other embodiments may be utilized and other changes may be made without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein and illustrated by chemical structures, can be arranged, substituted, combined, separated, and designed into a wide variety of different configurations, all of which are expressly contemplated herein.

[0033] In general, 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, thereby inhibiting the biological pathways related to TNIK activation.As a result, the molecules described herein can be used in therapeutic methods that can provide treatment to the subject administered the molecules described above by inhibiting TNIK.Therefore, each of the molecules described herein can be referred to as a TNIK kinase inhibitor, and some can be broad-spectrum inhibitors of multiple kinases, while others are specific inhibitors that inhibit certain kinases (such as TNIK kinase and / or MAP4K4 kinase).

[0034] method

[0035] Therefore, TNIK kinase inhibitor can be used to inhibit downstream biological pathways from TNIK inhibition.In some embodiments, TNIK inhibitor can inhibit fibrous collagen, thereby inhibiting the biological activity related to the regulation of extracellular matrix and the regulation of extracellular matrix remodeling.TNIK inhibitor can inhibit the regulation 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 aspects, inhibiting TNIK inhibits the Wnt pathway.

[0037] In some embodiments, inhibiting TNIK inhibits cytoskeletal rearrangement. 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 rearrangement).

[0038] In some embodiments, inhibiting 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 inhibit cancer cell migration to treat cancer. In some aspects, the cancer is colorectal cancer.

[0039] In some embodiments, inhibiting 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, inhibiting TNIK inhibits TGFβ signaling. The TGFβ signaling pathway is involved in various processes, and thus inhibiting 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 the 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 extracellular matrix or the excessive formation of extracellular matrix and problems associated therewith (e.g., fibrosis). In some aspects, inhibiting TGFβ signaling by inhibiting TNIK inhibits glycosaminoglycan formation. In some aspects, inhibiting TGFβ by inhibiting TNIK inhibits collagen formation. In some aspects, inhibiting TNIK inhibits fibrosis. In some aspects, the fibrosis inhibited is pulmonary fibrosis (e.g., idiopathic or radiation-induced), cystic fibrosis, liver fibrosis (e.g., cirrhosis), myocardial fibrosis (e.g., atrial fibrosis, endomyocardial fibrosis, old myocardial infarction), renal fibrosis, brain fibrosis (e.g., glial scar), arterial fibrosis, arthrofibrosis (e.g., knee, shoulder, other joints), intestinal fibrosis (e.g., Crohn's disease), Dupytren's contracture fibrosis ( For example, the fibrosis is selected from the group consisting of fibrosis of the hands, fingers), keloid fibrosis (e.g., skin), mediastinal fibrosis (e.g., soft tissue of the mediastinum), myelofibrosis (e.g., bone marrow), Peroni's fibrosis (e.g., penis), progressive massive fibrosis (e.g., lung, complications of coal workers' pneumoconiosis), retroperitoneal fibrosis (e.g., soft tissue of the retroperitoneal space), scleroderma, sclerosis, fibrosis (e.g., skin, lung), adhesive capsulitis fibrosis (e.g., shoulder), or a combination thereof.

[0042] In some embodiments, TNIK inhibitors 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 the inhibition of Smad signaling pathway.In some aspects, this can include the inhibition of non-Smad signaling pathway.In some aspects, this can include the inhibition of Wnt, NF-KB, FAC-Src-paxillin-associated focal adhesion, and MAP kinase (e.g., ERK and JNK) signaling pathway.

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

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

[0045] Similarly, inhibiting MAP4K4 kinase can inhibit its associated biological functions.

[0046] overview In some embodiments, the method of inhibiting a kinase (e.g., TNIK kinase and / or MAP4K4 kinase) comprises the step of inhibiting a kinase comprising a compound of formula A [ka] or a derivative, prodrug, salt, stereoisomer, tautomeric polymorph, or solvate thereof, or a structure with any chirality at any chiral center.

[0047] In some embodiments, ring 1 is an aromatic ring with or without heteroatoms; ring 2 is an aromatic heterocycle; ring 3 comprises at least one aromatic heterocycle and at least one alicyclic ring optionally fused to at least one aromatic heterocycle; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or a linker; and 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 any of which may or may not contain heteroatoms.

[0048] In some embodiments, ring 1 is a phenyl group, a pyridyl group, or a pyrimidinyl group; ring 2 is a 5- or 6-membered aromatic heterocycle; ring 3 comprises a 5-membered aromatic heterocycle or a 5-membered aromatic heterocycle fused with a 6-membered aromatic heterocycle, which is fused with a 5-membered alicyclic ring (wherein the bond to Y is through said 5-membered aromatic heterocycle); 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 heterocycle, an alicyclic ring, an alicyclic heterocycle, an aliphatic straight chain, or an aliphatic branched chain, which may be substituted or unsubstituted and may or may not contain heteroatoms.

[0049] In some embodiments, ring 1 is a phenyl group, a pyridyl group, or a pyrimidinyl group, and when ring 1 is pyridyl or pyrimidinyl, the 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, the nitrogen is located at the para-, meta-, or ortho-position within said ring; when ring 4 is a pyrimidyl group, the nitrogen is located at the meta- or ortho-position within said ring; Y is a bond or a 1- to 6-membered (e.g., C 1 ~C 6 ) is an aliphatic chain; Y 1 is an amide linker; R A is an aromatic ring, an aromatic heterocycle, a 1- to 6-membered ring (e.g., C 3 ~C 6) alicyclic rings, 5- to 6-membered alicyclic heterocycles; 1- to 12-membered (e.g., C 1 ~C 12 ) aliphatic straight chain, or 1-12 membered (e.g., C 1 ~C 12 ) aliphatic branched chains, which may be substituted or unsubstituted and may optionally contain or not contain heteroatoms.

[0050] In some embodiments, each R 1 , R 6 , R 11 , and R 12 are 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., CHC=O), propionyl, butyryl, acetamido (i.e., acetylamino), propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 absent.

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

[0052] In some embodiments, each R 1 , R 6 , R 11 , and R 12 are 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, ethylacetamido, propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 combinations thereof.

[0053] In some embodiments, R 11 and R 12 is hydrogen or absent, and each R 1 or R 6 are 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, ethylacetamido, propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 combinations thereof.

[0054] In some embodiments, each R 1are 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 combinations thereof.

[0055] In some embodiments, R 11 and R 12 is hydrogen or absent, and each R 6 are 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, ethylacetamido, propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 combinations thereof.

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

[0057] In some embodiments, R A are independently selected from hydrogen, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyridinyl, pyrimidinyl, bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.2octan-2yl, 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, hydroxypropanyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, phenyl, or combinations 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. [ka]

[0059] Here, 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 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 a substituent; 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 a substituent; Y is a bond or a linker; Y 1 is a linker; m is 1, 2, or 3; and n is 0, 1, or 2. In some embodiments, when the X group is an N in 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 does not exist. 11 and / or R 12 When present, may be present on any suitable ring atom. When n is 0, both the bond and R 11 and / or R 12 is not present. In some embodiments, R A The ring is connected to X via a covalent bond (i.e., Y) 1 It is directly connected to R A If is a ring, then R A can be any alicyclic or heteroalicyclic ring or combinations thereof.

[0060] In some embodiments, Y 1 teeth,

[0061] [ka] which may be [ka] or other linkers such as for Y, or X 4 and / or X 5 may 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 optionally be substituted with substituents such as R 1 ) with or without X 5 is O or N (e.g., NH, NR 1 , NOR 1 ) where R 1 is as defined herein, and examples include H, OH, methyl, ethyl, and trifluoromethyl. X 4 is C, NH, NOH, or NOR 1 It could be. X 5 is O or NR 1 , or NOR 1 It is.

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

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

[0064] In some embodiments, ring A is an alicyclic ring or an alicyclic heterocyclic ring, or a combination thereof, which may be substituted or unsubstituted with R groups. In some aspects, ring B may be exclusively an alicyclic heterocyclic ring. In some aspects, R 13 are independently a substituent (R 11 (e.g., the substituents described for X). 1 and / or X 2 is CH or N. X 3 is CH 2 , NH, O, or S. 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. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12are each independently hydrogen, halogen, hydroxyl, alkoxy, aliphatic straight chain, aliphatic branched chain, cycloaliphatic, substituted aliphatic, unsubstituted aliphatic, saturated aliphatic, unsaturated aliphatic, aromatic, polyaromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, aliphatic amine, carbonyl, carboxyl, amide, ester, amino acid, derivatives thereof, optionally substituted or unsubstituted, or combinations thereof.

[0065] In some embodiments, ring A is an alicyclic ring having 3-12 ring atoms, an alicyclic heterocyclic ring having 3-12 ring atoms, or a combination thereof, which can be substituted or unsubstituted; ring B is an alicyclic heterocyclic ring having 3-12 ring atoms, which can be substituted or unsubstituted; ring D is a polycyclic ring having at least one aromatic ring fused with a cycloaliphatic; and X is a cycloaliphatic ring. 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, 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 12each independently represents 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, cyano, R is an aryl group consisting of aryl, arylamino, arylsulfonyl, arylsulfanyl, arylsulfinyl, arylsulfon ... 13 is a 1- 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 3-6 ring atoms, an alicyclic heterocycle having 3-6 ring atoms, or a combination thereof, which can be substituted or unsubstituted; ring B is an alicyclic heterocycle having 3-6 ring atoms, which can be substituted or unsubstituted; ring D is cyclopentapyridine; and X is a cyclopentapyridine. 1 and X 2 is N;X 3 is O or NH; X 4 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 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 Alkarli, 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 Alkylcarbonate, C 6 ~C 20 Arylcarbonato, carboxy, carboxylato, carbamoyl, mono(C 1 ~C 24 Alkyl) substituted carbamoyl, di(C 1 ~C 24alkyl) 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 carbamides, di(C 1 ~C 24 alkyl) substituted carbamides, monosubstituted aryl carbamides, disubstituted aryl carbamides, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azido, 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 any one or more of the substituents selected from the group of arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, optionally with or without heteroatoms, optionally substituted or unsubstituted, derivatives thereof, and combinations thereof; R 13 is a 1- to 12-membered (e.g., C 1 ~C 12) aliphatic straight chain or 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, hexoxy, heptoxy, octoxy, acetyl (i.e., acetyl, CH 3 C=O), propionyl, butyryl, acetamido (i.e., acetylamino), propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 and other formulae 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 optionally be substituted with substituents such as R 1 ) with or without X 5 is O or N (e.g., NH, NR 1 , NOR 1 ) where R 1 is as defined herein, and examples include H, OH, methyl, ethyl, and trifluoromethyl. X 4 is C, NH, NOH, or NOR 1 It could be. X 5 is O or NR 1 , or NOR 1 It is.

[0070] In some embodiments, a kinase inhibitor (e.g., TNIK kinase and / or MAP4K4 kinase) can comprise a 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. [ka] [ka] [ka] [ka]

[0071] In some embodiments, ring A can be any ring structure with 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 with 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms. If it contains a heteroatom, the atom of ring A can be C, O, N, or S depending on the number of bonds, 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 of 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 or heteroalicyclic ring, or combinations thereof, which may be substituted or unsubstituted, which may include cyclopentyl or cyclohexyl, which may be substituted or unsubstituted.

[0073] In some embodiments, the X ring atom can be carbon (C) or a heteroatom (such as O, N, or S), or other atom. As noted, when it is carbon, the X ring atom is R 11 and R 12 and the like, and the substituents can be present on any atom of each ring, such as on the X ring atom (if present, the X 1 , X 2 , X 3 , X 6 , X 10 , and X 11 As such, X 1 can be C (e.g., CH) or N with suitable hydrogen atoms. X 2 can be C (e.g., CH) or N with suitable hydrogen atoms. X 3 is C (e.g., CH 2 ) or NH, O or S. X 4 is C (e.g., CH2 ) or 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 optionally be substituted with substituents such as R 1 ) with or without X 5 is O or N (e.g., NH, NR 1 , NOR 1 ) where R 1 is as defined herein, and examples include H, OH, methyl, ethyl, and trifluoromethyl. X 4 is C, NH, NOH, or NOR 1 It could be. X 5 is O or NR 1 , or NOR 1 It is.

[0074] In some embodiments, Y 1 When Y is a chemical moiety that is more than just a bond, it can be a linker Y, where Y can be any linker (such as a chemical moiety or a bond). In some instances, Y is a bond, but in most cases it is a chemical moiety. When Y is a chain atom or more than one chain atom, it should have at least one R on the one or more chain atoms. 13 may be present, R 13 may be any R group as defined herein. The linker may be any of O, S, CH, with or without heteroatoms (such as those listed herein for the X ring atom). 2 , NH, or a hydrocarbon chain. 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, polyaromatic, substituted aromatic, heteroaromatic, amine, primary amine, secondary amine, tertiary amine, aliphatic amine, carbonyl, carboxyl, amide, ester, amino acid, derivatives thereof (substituted or unsubstituted), or combinations thereof. 1 ~C 24 Alkyl, C 2 ~C 24 Alkenyl, C 2 ~C 24 Alkynyl, C 6 ~C 20 Aryl, C 7 ~C 24 Alkarli, C 7 ~C 24 aralkyl, amino, mono- and di-(alkyl)-substituted amino, mono- and di-(aryl)-substituted amino, alkylamido, arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, optionally with or without heteroatoms, optionally substituted or unsubstituted, derivatives thereof, and combinations thereof. In some examples, Y is selected from the group consisting of at least one R 13 is a linker substituted with, which may be a substituent as 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 are 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 Alkarli, 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), 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 Alkylcarbonate (-O-(CO)-O-alkyl), C 6 ~C 20 Arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO - ), carbamoyl (-(CO)-NH 2 ), one (C 1 ~C 24 Alkyl) substituted carbamoyl (-(CO)-NH(C 1 ~C 24 Alkyl)), Bis(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 urea (-NH-(CO)-NH 2 ), a mono(C 1 ~C 24 alkyl)substituted urea (-NH-(CO)-NH(C 1 ~C 24 alkyl)), a di(C 1 ~C 24 alkyl)substituted urea (-NH-(CO)-N(C 1 ~C 24 alkyl) 2 ), a mono-substituted arylurea (-NH-(CO)-NH-aryl), a disubstituted arylurea (-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, where R is hydrogen, C 1 ~C 24 Alkyl, C 5 ~C 20 Aryl, C 6 ~C 24 Alkarli, C 6 ~C 24 aralkyl, etc.), alkylimino (-CR=N(alkyl) (where R=hydrogen, C 1 ~C 24 alkyl, aryl, alkaryl, aralkyl, etc.), arylimino (-CR=N(aryl) (where 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 ), phosphonate (-P(O)(O - ) 2 ), phosphinato (-P(O)(O-)), phospho (-PO 2 ), phosphino (-PH2 ) (optionally containing or not containing heteroatoms (e.g., N, O, S, or the like), where the heteroatoms may be replaced from carbon (e.g., heteroatoms replacing carbons in a chain or ring), attached to carbon (e.g., heteroatoms attached to a carbon chain or ring), optionally including straight chains, optionally including branched chains, optionally leading to a ring, and optionally substituted or unsubstituted), derivatives thereof, and combinations thereof.

[0076] In some embodiments, the method comprises the step of forming a compound of formula B or formula B1, wherein ring C is as defined herein (C 5 ~C 6 Compounds having a ring structure (eg, an alicyclic ring) are used. [ka]

[0077] In some embodiments, ring C is a C 5 ~C 6 It is an 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 are independently substituents; n is 0, 1, or 2. In some embodiments, ring C is a C 5 ~C 6 An alicyclic structure; each R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently 11 R 12is 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 with any chirality at any chiral center. [ka]

[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 The substituents are each independently selected from the group consisting of 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, acetamido (i.e., acetylamino), propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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, alkylsuflanyl (i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy, trifluoroalkyl, or acetamido (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 absent. This is applicable to all formulas listed 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 absent. This is applicable to all formulas listed herein.

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

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

[0085] In some embodiments, the compound comprises: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 9 is F or methoxy; and R 7 , R 8 , and R 10 is H. The remainder of the R groups can be hydrogen or absent. This is applicable to all formulas listed herein.

[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 groups can be hydrogen or absent. This is applicable to all formulas listed herein.

[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 groups can be hydrogen or absent. This is applicable to all formulas listed herein.

[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 groups can be hydrogen or absent. This is applicable to all formulas listed herein.

[0089] In some embodiments, the compound comprises: 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 groups can be hydrogen or absent. This is applicable to all formulas listed herein.

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

change

change

change

change

change

change

change

change

[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 patterns and substituents of the R groups shown in the structures of compounds 17-87 can be applied to any of the formulae provided herein.

[0093] In some embodiments, the compound is comprised in a pharmaceutical composition, said pharmaceutical composition comprising the compound; and a pharma- ceutically acceptable carrier comprising the compound.

[0094] Kinase inhibitors can be formulated for experimental or therapeutic use. Formulations are prepared by combining the purified kinase inhibitors of the present invention with pharma- ceutically acceptable vehicles (e.g., carriers, excipients) for storage and use (Remington, The Science and Practice of Pharmacy 20th Edition Mack Publishing, 2000). Suitable pharma-ceutically acceptable vehicles include non-toxic buffers (such as phosphate, citrate, and other organic acid buffers); salts (such as sodium chloride); antioxidants (including ascorbic acid and methionine); preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens (such as methylparaben or propylparaben); catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (e.g., less than about 10 amino acid residues); proteins, Examples of suitable surfactants include, but are not limited to, proteins (such as serum albumin, gelatin, or immunoglobulins); hydrophilic polymers (such as polyvinylpyrrolidone); amino acids (such as glycine, glutamine, asparagine, histidine, arginine, or lysine); carbohydrates (such as monosaccharides, disaccharides, glucose, mannose, or dextrins); 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)).

[0095] The pharmaceutical composition of the present invention can be administered by any method of local or systemic treatment.Administration can be by local administration (such as mucous membrane administration, including vaginal delivery and rectal delivery), such as transdermal patch, ointment, lotion, cream, gel, drops, suppository, spray, liquid, and powder); pulmonary administration (such as by inhalation or insufflation of powder or aerosol, including nebulizer, intratracheal, intranasal, epidermal, and transdermal); oral administration; or parenteral administration (including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion); intratumoral administration, or intracranial administration (for example, intrathecal or intraventricular).

[0096] Therapeutic preparations may be in unit dosage form. Such preparations 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 main active ingredient is mixed with a pharmaceutical carrier. Conventional ingredients for tableting include corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dibasic calcium phosphate, or gums, and other diluents (e.g., water) to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention or a non-toxic pharma-ceutically acceptable salt thereof. The solid preformulation composition is then subdivided into unit dosage forms of the above types. Tablets, pills, etc. of the novel composition can be coated or otherwise compounded to obtain a dosage form that provides the advantage of sustained action. For example, a tablet or pill can include an inner composition coated with an outer component. Moreover, the two components can be separated by an enteric layer which serves to resist disintegration and permit the inner component to pass intact through the stomach or be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0097] In some embodiments, pharmaceutical formulations may include the kinase inhibitors of the present invention complexed 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. Pat. Nos. 4,485,045 and 4,544,545). Liposomes with improved circulation time are disclosed in U.S. Pat. No. 5,013,556. Some liposomes can be produced by the reverse phase evaporation method using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0098] Kinase inhibitors can also be entrapped in microcapsules, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules are prepared, for example, by coacervation techniques or interfacial polymerization, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, respectively, 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 semipermeable matrices of solid hydrophobic polymers containing kinase inhibitors, where the matrices are in the form of shaped articles (for example, thin films or microcapsules).Examples of sustained release matrices include polyesters, hydrogels (such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactides (U.S. Pat. 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 lactic acid-glycolic acid copolymers and leuprolide acetate)), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0100] In some embodiments, the treatment involves the combined administration of the TNIK inhibitor of the present invention and a chemotherapeutic agent or a cocktail of multiple different chemotherapeutic agents. Combination therapy often uses drugs that act by different mechanisms of action. Combination therapy using drugs with different mechanisms of action often produces additive or synergistic effects. Combination therapy can reduce the dose of each drug compared to the dose used in monotherapy, thereby reducing toxic side effects. Combination therapy can reduce the likelihood of resistant cancer cells developing. In some embodiments, combination 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] Pharmaceutical compositions include, but are not limited to, lyophilized powders or aqueous or non-aqueous sterile injection solutions or suspensions, which may further include antioxidants, buffers, bacteriostats, and solutes that are substantially compatible with 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. Extemporaneous injection solutions or suspensions may be prepared from sterile powders, granules, tablets, or concentrated solutions or suspensions. Compositions may be supplied, for example, but not limited to, as lyophilized powders that are reconstituted with sterile water or saline prior to administration to a patient.

[0102] Suitable pharmaceutically acceptable carriers include essentially chemically inert and non-toxic compositions that do not interfere with the effectiveness of the biological activity of pharmaceutical compositions. 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 compound together with a suitable amount of carrier to provide a form for direct administration to patients.

[0103] The compositions described herein can be administered, for example, parenterally, intravenously, subcutaneously, intramuscularly, intracranially, intraorbitally, intraocularly, intraventricularly, intracapsularly, intraspinally, intracisternally, intraperitoneally, intranasally, by aerosol, or orally. Conventional carriers or excipients can be used to prepare pharmaceutical compositions designed for such routes of administration.

[0104] For the treatment of disease, the appropriate dosage of the kinase inhibitor of the present invention is at the discretion of the treating physician and depends on the type of disease to be treated, the severity and course of the disease, the responsiveness of the disease, whether the administration of the kinase inhibitor is for therapeutic or prophylactic purposes, previous treatments, and the clinical history of the patient. The kinase inhibitor can be administered once or over a series of treatments lasting from several days to several months, or until a cure or a reduction in the disease state is achieved (e.g., a reduction in tumor size). The optimal dosing regimen can be calculated from measurements of drug accumulation in the patient's body, which will vary depending on the relative potency of the individual kinase inhibitor. The administering physician can easily determine the optimal dosage, method of administration, and number of repetitions. In general, dosages are 0.01 μg to 100 mg / kg body weight and can be administered once or multiple times daily, weekly, monthly, or yearly. The treating physician can estimate the number of repetitions of administration based on measurements of the residence time and concentration of the drug in bodily fluids or tissues.

[0105] The present invention provides a kit comprising the 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 carry out a detection assay, including controls, instructions for carrying out the assay, and any software required for analyzing and displaying the results. Those skilled in the art will easily recognize that the disclosed kinase inhibitor 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 compounds may have inhibitory activity against wild-type or mutant (particularly clinically relevant mutant) kinases with an IC50 value of 1 μM or less (as determined using any scientifically accepted kinase inhibition assay), preferably an IC50 value 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.

[0107] In some embodiments, the compounds may have IC50 values ​​as measured in the TNIK enzyme assay provided in Table 1 below, and may be used to inhibit TNIK to provide the therapeutic benefits described herein, etc. [Table 1-1] [Table 1-2] [Table 1-3]

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

[0109] EXAMPLES

[0110] TNIK inhibition

[0111] Compounds were investigated for their function as TNIK inhibitors, generating the data in Table 1. Compounds were incubated in 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 250 μM TNIK control peptide, 10 mM magnesium acetate, and [γ- 33 P-APT] (specific activity and radioactivity concentration as required). The reaction is started by adding Mg / ATP mix. After 40 minutes of incubation at room temperature, the reaction is stopped by adding phosphoric acid to a concentration of 0.5%. 10 μl of the reaction is then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting. Further information can be found in the Eurofins Kinase Profiler™ Service Assay Protocol v85.2, specifically incorporated herein by reference in its entirety.

[0112] Fibrosis assay

[0113] cell culture

[0114] HDF / TERT166 working lot cells were thawed from liquid nitrogen and cultured under standard conditions (medium: antibiotic-free DMEM / Ham's F12 basal medium supplemented with 1x GlutaMax-I and 10% FBS; 37 °C, 5% CO 2 For treatment administration, cells can be plated at 7500 cells / cm in 12-well plates the day before the first treatment. 2Cells can be seeded at a cell density of 100 pg / mL TGF-β. Cells can be seeded in starvation medium (DMEM / Ham's F12 basal medium supplemented with 1x GlutaMax-I and 0.5% FBS and without antibiotics). Approximately 24 hours after seeding, substances can be dissolved in DMSO (stock: 10 mM) and diluted in starvation medium to a final concentration of 10 μM. Half of this working dilution can be supplemented with 100 pg / mL TGF-β. For each substance, two wells can be treated with the substance at a concentration of 10 μM and with the substance at a concentration of 10 μM supplemented with 100 pg / mL TGF-β. In parallel, cells can be treated only with 100 pg / mL TGF-β. Cells in starvation medium can serve as a control. For all cells, treatment can be performed by medium change. 24 hours after the first treatment (48 hours after seeding), the treatment can be repeated with 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 lysates can be collected in 1.5 mL tubes and stored at -80°C until RNA isolation.

[0115] qPCR analysis

[0116] RNA isolation

[0117] RNA can be extracted with 200 μL chloroform and phase separated by centrifugation at 12,000 g for 15 min at 4° C. 500 μL of the upper aqueous phase can be extracted and further precipitated and purified with a QIAcube liquid handling robot using the miRNeasy Mini Kit (Qiagen). To the 500 μL, 150 μL nuclease-free water and 7 μL glycogen can be added and precipitated with 750 μL 100% ethanol. The column can be washed with RWT and RPE buffers and the circular RNA can be eluted in one round with 30 μL nuclease-free water and stored at −80° C. RNA concentration can be determined by spectrophotometry using a Nanodrop instrument.

[0118] qPCR quantification of mRNA

[0119] From the isolated total RNA, cDNA can be synthesized using the GrandScript cDNA synthesis kit. Reverse transcription reactions can be performed with 200 ng of total RNA in a 20 μL reaction (10 μL RNA can be used for low concentration samples, if possible). For each sample, qPCR reactions can be performed in duplicate in 10 μL reactions with 2 μL of 1:2 diluted cDNA and 8 μL of qPCR Mix consisting of 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 in a Roche LightCycler 480II instrument. The following thermocycling conditions can be used: 95° C. for 30 s, 45 cycles of 95° C. for 5 s, 63° C. for 15 s, and 72° C. for 10 s, followed by analysis by melting curve. Cq values ​​can be calculated using the second derivative maximum method in the LC480 II software.

[0120] TNIK is associated with fibrosis and cancer metastasis

[0121] A collagen production assay was performed for a known TNIK inhibitor (5-(4-acetamidobenzamido)-2-(phenylamino)-1,3-thiazole-4-carboxamide). The data show that the TNIK inhibitor reduced the mRNA expression of collagen type 1 alpha 1 chain (COL1A1). The TNIK inhibitor also inhibited the effect of TGF-β treatment on COL1A1 mRNA expression. COL1A1 expression is involved in fibrosis, and upregulation of COL1A1 can increase fibrosis in a subject. Thus, reducing COL1A1 mRNA expression, especially in the early stages of overexpression, can treat or inhibit fibrosis in a subject. Elevated TGF-β expression and subsequent deregulation of TGF-β function in affected organs are known to correlate with the accumulation of abnormal connective tissue seen at the onset of fibrotic disease. Inhibiting the effect of TGF-β treatment on COL1A1 mRNA expression can treat and reduce fibrosis. Since it is known that TGF-β-activated EMT can be inhibited by attenuating Smad and non-Smad signaling pathways (including Wnt, NF-κB, FAK-Src-paxillin-associated focal adhesion, and MAP kinase (ERK and JNK) signaling pathways), there is evidence that TNIK inhibitors can be used to inhibit TGF-β-activated EMT.As such, TNIK is a therapeutic target for inhibition for treating and / or preventing EMT-induced disorders (such as cancer metastasis and fibrosis).As such, the above evidence indicates that the TNIK inhibitors described herein can be used in the treatment method for EMT-induced disorders (such as cancer metastasis and fibrosis).

[0122] TNIK is associated with lung cancer

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

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

[0125] Thus, the TNIK inhibitors described herein can be used in methods of inhibiting TNIK to inhibit TNIK activity or increased TNIK activity, or diseases or conditions associated with downstream upregulation or increased 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] overview In some embodiments, the kinase inhibitor compound (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) is represented by formula A [ka] 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.

[0129] In some embodiments, ring 1 is an aromatic ring with or without heteroatoms; ring 2 is an aromatic heterocycle; ring 3 comprises at least one aromatic heterocycle and at least one alicyclic ring optionally fused to at least one aromatic heterocycle; ring 4 is an aromatic ring with or without heteroatoms; Y is a bond or a linker; and 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 a chemical moiety (e.g., hydrogen or other substituent). In some embodiments, the compounds include at least one of the following proviso: if Y is a bond, then R A is aromatic C 3 or when Y is a chemical moiety, R A is C 3alicyclic 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 may be substituted or unsubstituted and may or may not contain heteroatoms; or the compound includes at least one of the following: if ring 1 is a phenyl group, then 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; if ring 2 is a furanyl group, then 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; if ring 3 is an imidazolyl group, then 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 if ring 4 is a phenyl group, then 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 heterocycle (e.g., when ring 1 or ring 4 is an aromatic heterocycle), o is only 0.

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

[0131] In some embodiments, the compound comprises at least one of the following: Y 1 includes 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 or when Y is a chemical moiety, R A is C 3alicyclic 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 may be substituted or unsubstituted and may or may not contain heteroatoms; or the compound includes at least one of the following: if ring 1 is a phenyl group, then 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; if ring 2 is a furanyl group, then 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; if ring 3 is an imidazolyl group, then 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 if ring 4 is a phenyl group, then 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 comprises: ring 1 is a phenyl group, a pyridyl group, or a pyrimidinyl group; ring 2 is a 5- or 6-membered aromatic heterocycle; ring 3 comprises a 5-membered aromatic heterocycle or a 5-membered aromatic heterocycle fused with a 6-membered aromatic heterocycle, which is fused with a 5-membered alicyclic ring (wherein the bond to Y is through said 5-membered aromatic heterocycle); 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 five-membered alicyclic ring.

[0133] In some embodiments, the compound comprises: ring 1 is a phenyl group, a pyridyl group, or a pyrimidinyl group, and when ring 1 is pyridyl or pyrimidinyl, the nitrogen is located at the para, meta, or ortho position in 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, the nitrogen is located at the para, meta, or ortho position in said ring; when ring 4 is a pyrimidyl group, the nitrogen is located at the meta or ortho position in said ring; Y is a bond or, for example, C 1 ~C 6 It is an aliphatic chain.

[0134] In some embodiments, Y is C 1 ~C 6 When R is an aliphatic linker, A is C 3 ~C 6 Alicyclic ring, C 5 ~C 6 Alicyclic heterocycles, aromatic rings, C 1 ~C 12 Linear alicyclic, or C 1 ~C 12 branched chain alicyclic, which may be substituted or unsubstituted and may or may not contain heteroatoms, or when Y is a bond, R A is C 6 ~C 6 It is not an alicyclic ring.

[0135] In some embodiments, each R 1 , R 6 , R 11 , and R 12are 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, ethylacetamido, propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 combinations thereof.

[0136] In some embodiments, R 11 and R 12 is hydrogen or absent, and each R 1 or R 6are 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, ethylacetamido, propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 combinations thereof.

[0137] In some embodiments, each R 1 are 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 combinations thereof.

[0138] In some embodiments, R 11and R 12 is hydrogen or absent, and each R 6 are 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, ethylacetamido, propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 combinations thereof.

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

[0140] In some embodiments, R Aare independently selected from hydrogen, cyclopentyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyridinyl, pyrimidinyl, bicycloheptanyl, bicyclooctanyl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.2octan-2yl, 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, hydroxypropanyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, phenyl, or combinations thereof.

[0141] In some embodiments, ring 1 is a phenyl group or a pyridyl group, and when ring 1 is pyridyl, the nitrogen is located at the para, meta, or ortho position in 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, the nitrogen is located at the para, meta, or ortho position in said ring; when ring 4 is a pyrimidyl group, the nitrogen is located at the meta or ortho position in said ring; Y is a bond or C 1 ~C 6 Aliphatic chain; Y 1 is an amide linker; Y is C 1 ~C 6 When R is an aliphatic linker, 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 12aliphatic branched chains, 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 It is not an alicyclic ring.

[0142] In some embodiments, each R 1 , R 6 are 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., CHC=O), propionyl, butyryl, acetamido (i.e., acetylamino), propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 absent.

[0143] In some embodiments, the kinase inhibitor (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) is a compound having the structure of Formula A1 or 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 one 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, 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; 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, 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; where if the X group is N in an aromatic ring, then there is no R group bonded to the X group; where the dashed line forms a double bond, then X 12 is N (e.g., a double bond to the oxygen for a ketone).

[0144] In some embodiments, R A is optionally substituted or unsubstituted C 3 An alicyclic ring, a C4 to C12 alicyclic heterocycle, an aliphatic straight chain, or an aliphatic branched chain, where C 3 The ring structure, aliphatic straight chain, or aliphatic branched chain may or may not contain heteroatoms; Ring D is a ring structure having one 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, 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. These variables can be as defined herein. In some embodiments, the substitution patterns of the R groups of some example compounds can be applied to these formulas. In some embodiments, the substitution patterns of the X groups of the example compounds 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. 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 are each independently a carbon atom or a heteroatom, with or without a substituent; Y 1 is a linker; m is 1, 2, or 3; n is 0, 1, or 2; where if the X group is an N in an aromatic ring, then there is no R group attached to the X group; R 13 is hydrogen, aliphatic straight chain, aliphatic branched chain, -Y-ring A; ring B; or -YR A and R is independently selected from any of the following: 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 optionally be substituted with substituents such as R 1 ) with or without X 5 is O or N (e.g., NH, NR 1 , NOR 1 ) where R 1 is as defined herein, and examples include H, OH, methyl, ethyl, and trifluoromethyl. X 4 is C, NH, NOH, or NOR 1 It could be. X 5 is O or NR 1 , or NOR 1 In some embodiments, X4 is C, CH, CH 2 , C.R. 1 , C(R 1 ) 2 or N, NH, NR 1 , NOH, which may or may not contain optional substituents.

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

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

[0149] In some embodiments, Y 1 teeth, [ka]

[0150] where X 4 , X 5 , and X 6 is a heteroatom. In some embodiments, X 4 is N and X 5 is O and R 1 is as defined herein. In some embodiments, X 4is N and X 5 is N and R 1 is as defined herein (e.g., hydrogen). In some embodiments, X 4 is N and X 5 is O and R 1 is hydrogen, methyl, hydroxyl, amine, with or without 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 optionally be substituted with substituents such as R 1 ) with or without X 5 is O or N (e.g., NH, NR 1 , NOR 1 ) where R 1 is as defined herein, and examples include H, OH, methyl, ethyl, and trifluoromethyl. X 4 is C, NH, NOH, or NOR 1 It could be. X 5 is O or NR 1 , or NOR 1 It is.

[0151] In some embodiments, Y 1 teeth,

[0152] [ka] It could be.

[0153] In some embodiments, the kinase inhibitor (e.g., a TNIK kinase inhibitor and / or a MAP4K4 kinase inhibitor) can comprise 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 for chemical moieties; X 4 is NH;X 5 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 optionally be substituted with substituents such as R 1 ) with or without X 5 is O or N (e.g., NH, NR 1 , NOR 1 ) where R 1 is as defined herein, and examples include H, OH, methyl, ethyl, and trifluoromethyl. X 4 is C, NH, NOH, or NOR 1 It could be. X 5 is O or NR 1 , or NOR 1 It is. [ka] [ka] where Y is a linker for chemical moieties; Y 1 is the chemical moiety; X 4 is NR 1 ;X 5 is O or N. In some embodiments, X 4 is C (e.g., CH, CH 2 ) or N (e.g., N, NH, NR 1 , NOR 1 ), which may optionally be substituted with substituents such as R1 ) with or without X 5 is O or N (e.g., NH, NR 1 , NOR 1 ) where R 1 is as defined herein, and examples include H, OH, methyl, ethyl, and trifluoromethyl. X 4 is C, NH, NOH, or NOR 1 It could be. X 5 is O or NR 1 , or NOR 1 It 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 with any chirality at any chiral center. [ka] [ka] [ka] Where X 4 is NR 1 ;X 5 is O or N. In some embodiments, X 4 is C (e.g., CH, CH 2 ) or N (e.g., N, NH, NR 1 , NOR 1 ), which may optionally be substituted with substituents such as R 1 ) with or without X 5 is O or N (e.g., NH, NR 1 , NOR 1 ) where R 1 is as defined herein, and examples include H, OH, methyl, ethyl, and trifluoromethyl. X 4 is C, NH, NOH, or NOR1 It could be. X 5 is O or NR 1 , or NOR 1 It is.

[0155] In some embodiments, the kinase inhibitor can include 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 with any chirality at any chiral center. [ka]

[0156] In the formulas provided herein, the compounds include 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. The other R groups can be hydrogen or absent. In some embodiments, the compound includes 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 embodiments, the compound comprises: R 3 is F or methyl; and R 1 , R 2 , R 4 , and R 5 is H. In some embodiments, the compound comprises at least one of the following: R 6 and R 9 has a substituent, R 7 , R 8 , and R 10 is H;R 6 has a substituent, R7 , R 8 , R 9 , and R 10 is H;R 8 has a substituent, R 6 , R 7 , R 9 , and R 10 is H; or R 6 and R 8 has a substituent, R 7 , 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 9 is F or methoxy; and R 7 , R 8 , 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; and R 7 , R 8 , 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 8 is F methoxy, or methyl; and R 6 , R 7 , 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 is each independently halogen, alkyl, branched alkyl, alkoxy, alkyl ester, alkylsulfanyl (i.e., thioalkyl), acetyl, alkyl ester, (trifluoroalkyl)oxy, trifluoroalkyl, or acetamido (i.e., acetylamino). 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, acetamido (i.e., acetylamino), and the remainder of the R groups are hydrogen or absent. In some embodiments, n is 0 and R 11 and R 12 does not exist.

[0158] In some embodiments, each R 1 , R 2 , R 3 , R 4 , and R 5are 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 combinations thereof;

[0159] In some embodiments, each R 6 , R 7 , R 8 , R 9 , or R 10 are 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, ethylacetamido, propionamido, butylamido, pentanamido, hexanamido, heptanamido, octanamido, fluoromethyl, bifluoromethyl, trifluoromethyl, fluoromethoxy, bifluoromethoxy, 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 combinations 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 are 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 combinations thereof or C 1 ~C 6 alkyl.

[0163] In some embodiments, R 13is independently a bond or C 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[2.2.2octan-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, hydroxypropanyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, phenyl, or a combination thereof; 1 ~C 6 It is an alkyl.

[0164] In some embodiments, the compound is one of the following compounds 80-106: [ka] [ka] [ka] [ka] [ka] [ka]

[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 can be indicative of the corresponding compounds 80-106. In some aspects, the substitution patterns of the following compounds and their substituents 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 compounds A-1 through A-63 below: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0167] In some embodiments, the compound has one of the following structures of compounds B-1 through B-79: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0168] In some embodiments, the compound has one of the structures of compounds C-1 through C-59 below: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[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 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-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound 82); )-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-((tetrahydrofuran-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide 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 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)picolinamide (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 (Compounds A-1 to A-63): 5-(1-(cyclopentylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl)-N-(2-fluorophenyl)furan-2-carboxamide (Compound A-1); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-2); N-(2-fluorophenyl)-5-(4-(4-fluorophenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxamide (Compound A-3); )-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-5-carboxamide 2-(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'-biimidazole]-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) 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); 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-fluoro rac-5-(4-(4-fluorophenyl)-1-((4R)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)-N-(pyrimidin-4-yl)furan-2-carboxamide (compound A-55); N-(3-fluoro-5-hydroxypyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-56); rac-5-(4-(4-fluorophenyl)-1-((4R)-4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5 -yl)-N-(2-oxo-1,2-dihydropyridin-4-yl)furan-2-carboxamide (compound A-57); N-(5-fluoro-2-methylpyridin-4-yl)-5-(4-(4-fluorophenyl)-1-(4-fluorotetrahydrofuran-3-yl)-1H-imidazol-5-yl)furan-2-carboxamide (compound A-58); rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridine- 4-yl)furan-2-carboxamide (compound A-60); rac-5-(4-(4-fluorophenyl)-1-((1R,2R)-2-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-61); rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-62);or rac-5-(4-(4-fluorophenyl)-1-((1R,3S)-3-hydroxycyclopentyl)-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)furan-2-carboxamide (compound A-63);

[0172] In some embodiments, the compound is one of the following (Compounds 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-chlorophenyl)-5-(1-cyclopentyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)furan-2-carboxamide N-(5-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-1 8); 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 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) 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-methylphenyl)furan-2-carboxamide (compound B-45); N-(4-acetamidophenyl)-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-a cetylphenyl)-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 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-fluorophenyl)-1H-imidazol-5-yl)-N-(2-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 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-cyclo Hexyl-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-carboxamido)-3-methoxybenzoic acid (compound C-3); 3-(4-(3'-(tert-butyl)-5'-(4-fluorophenyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamido)-3-fluorophenyl)propanoic acid (compound C-4); 3'-(tert-butyl)-N-(2-chloro-4-(piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)propanoic acid (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'-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'-(trifluoro Methyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-12); N-(2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-carboxamide (compound C-13); N-(4-(bis(2-hydroxyethyl)amino)-2-chlorophenyl)-5'-(4-fluorophenyl)-3'-(trifluoromethyl)-1H,3'H-[2 ,4'-biimidazole]-5-carboxamide (compound C-14); 4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-5-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'-biimidazole]-5-carboxamide (compound C-16); 3-chloro-4-(5'-(4-fluorophenyl)- 3'-Methoxy-1H,3'H-[2,4'-biimidazole]-5-carboxamide)benzoic acid (compound C-17); 3-(4-(5'-(4-fluorophenyl)-3'-methoxy-1H,3'H-[2,4'-biimidazole]-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'-biimidazole]-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) N-(2-chloro-4-(2-hydroxyethyl)phenyl)-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-methyl 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) N-(4-(bis(2-hydroxyethyl)amino)-2-fluorophenyl)-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'-biimidazole]-4-sulfonimidamide (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)furan-2-carboximidamide; 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(3-fluoropyridin-4-yl)-N'-methylfuran-2-carbohydrazide (compound C-59).

[0174] In some embodiments, the compound is comprised in a pharmaceutical composition, said pharmaceutical composition comprising a TNIK kinase inhibitor compound; and a pharma- ceutically acceptable carrier having said compound.

[0175] In some embodiments, the core structures of TNIK kinase inhibitors compounds 80-106 (e.g., the claimed compounds) may lack the substitution patterns and substituents of compounds 1-79 not specifically recited in this paragraph.

[0176] In some embodiments, the compound recited in the claims is not one of Compounds 1-79. However, these Compounds 1-79 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, wherein 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, wherein Ring A is as defined herein; however, these compounds can be used in the methods described herein.

[0182] Protocol for in vitro assay

[0183] MAP4K4(h) is incubated with 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 250 uM, 10 mM Mg acetate, and [gamma-33P-ATP] (specific activity and radioactivity concentration as required). The reaction is started by adding the Mg / ATP mix. After 40 minutes of incubation at room temperature, the reaction is stopped by adding phosphoric acid to a concentration of 0.5%. 10 μl of the reaction is then spotted onto a P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting.

[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 growing cells in 12-well plates for 24 hours, the cell culture medium was replaced with the same medium as above except that 0.4% fetal bovine serum was used. After growing in serum-reduced medium for 20 hours, cells were treated with the indicated doses of compounds for 30 minutes. Cells were then stimulated with 4 ng / mL TGF-b (R&D Systems, 240-B-002) for 48 hours. Cells were rinsed twice with DPBS and then harvested at 4°C with 100 μL RIPA buffer (Sigma, R0278) supplemented with protease inhibitor cocktail (Roche, 04693132001). Total protein in each sample was quantified using a BCA protein assay kit (Pierce™, 23227), and equal amounts of total protein from each sample were subjected to Western blot analysis. 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] The term "alkyl" or "aliphatic" as used herein refers to a branched or unbranched saturated hydrocarbon group typically, but not necessarily, containing from 1 to about 24 carbon atoms, including 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, but also not necessarily, alkyl groups herein contain from 1 to about 18 carbon atoms, or from 1 to about 12 carbon atoms. The term "lower alkyl" contemplates an alkyl group of 1 to 6 carbon atoms. "C 1 ~C 6 Substituents designated as "alkyl" or "lower alkyl" contain 1-3 carbon atoms, such substituents containing 1 or 2 carbon atoms (i.e., methyl and ethyl). "Substituted alkyl" refers to an alkyl substituted with one or more substituents, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to an alkyl in which at least one carbon atom is replaced with a heteroatom, as further detailed below. Unless otherwise indicated, the terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl or lower alkyl, respectively. 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, and the like. Alkyl may be 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, and the like.

[0188] The term "alkenyl" as used herein refers to straight, branched, or cyclic hydrocarbon groups 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, but not necessarily, alkenyl groups herein contain 2 to about 18 carbon atoms, or 2 to 12 carbon atoms. The term "lower alkenyl" contemplates alkenyl groups of 2 to 6 carbon atoms, and the specific term "cycloalkenyl" contemplates cyclic alkenyl groups or those having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to alkenyl substituted with one or more substituents, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl having at least one carbon atom substituted with a heteroatom. Unless otherwise indicated, the terms "alkenyl" and "lower alkenyl" include straight-chain, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyl and lower alkenyl, respectively.

[0189] The term "alkynyl" as used herein refers to straight or branched chain hydrocarbon groups of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl and n-propynyl. Generally, but not necessarily, alkynyl groups herein contain from 2 to about 18 carbon atoms, or from 2 to 12 carbon atoms. The term "lower alkynyl" contemplates 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 "heteroatom-containing alkynyl" and "heteroalkynyl" refer to an alkynyl having at least one carbon atom substituted with a heteroatom. Unless otherwise indicated, the terms "alkynyl" and "lower alkynyl" include straight, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl, respectively.

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

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

[0192] The term "aryloxy" as used herein refers to an aryl group bonded through a single terminal ether bond, where "aryl" is as defined above. An "aryloxy" group may be represented as -O-aryl, where aryl is as defined above. Exemplary aryloxy groups contain 5-20 carbon atoms, and aryloxy groups contain 5-14 carbon atoms. Exemplary 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, and the like.

[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 defined above. Exemplary aralkyl groups contain 6 to 24 carbon atoms, and aralkyl groups contain 6 to 16 carbon atoms. Exemplary 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. Exemplary 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 the conventional sense to refer to chloro, bromo, and fluoro or iodo substituents.

[0196] The term "heteroatom-containing," as in "heteroatom-containing alkyl group" (also referred to as "heteroalkyl" group) or "heteroatom-containing aryl group" (also referred to as "heteroaryl" group) or other uses of "hetero," refers to a molecule, bond, or substituent in which one or more carbon atoms are replaced with an atom 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 that contains a heteroatom, the term "heterocyclic" refers to a cyclic substituent that contains a heteroatom, the terms "heteroaryl" and "aromatic heterocycle" refer to "aryl" and "aromatic" substituents, respectively, that contain a heteroatom, and the like. 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, and the like; examples of alicyclic groups containing heteroatoms are pyrrolidino, morpholino, piperazino, piperidino, and the like.

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

[0198] "Substituted," as 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, as implied by some of the above definitions, is replaced with one or more non-hydrogen substituents.

[0199] Additionally, the aforementioned functional groups may be further substituted, where a particular group permits, with one or more additional functional groups or one or more hydrocarbyl moieties (such as those specifically enumerated).Similarly, the aforementioned 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 or refers to a list of possible substituents, it is intended that the term apply to every member of said group. For example, the phrase "substituted alkyl, alkenyl, and aryl" should be interpreted as "substituted alkyl, substituted alkenyl, and substituted aryl." Similarly, when the term "heteroatom-containing" precedes a list of possible heteroatom-containing groups, it is intended that the term apply to every member of said group. For example, the phrase "heteroatom-containing alkyl, alkenyl, and aryl" should be interpreted as "heteroatom-containing alkyl, heteroatom-containing alkenyl, and heteroatom-containing aryl."

[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., mammalian animal) that is to be the recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein when referring to a human subject.

[0203] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or state government for use in animals, including humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia.

[0204] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharma-ceutically acceptable and that possesses 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 together with at least one TNIK inhibitor of the present disclosure, does not destroy its pharmacological activity, and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the TNIK inhibitor.

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

[0207] The term "effective amount", "therapeutically effective amount" or "therapeutic effect" refers to the amount of TNIK inhibitor, polypeptide, polynucleotide, organic small 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, it can reduce the number of cancer cells; can reduce tumorigenicity, tumor formation frequency, or tumor formation ability; can reduce the number or frequency of cancer stem cells; can reduce tumor size; can inhibit and stop the invasion of cancer cells into peripheral organs (including, for example, cancer metastasis to soft tissue and bone); can inhibit and stop tumor metastasis; can inhibit and stop tumor growth; can somewhat alleviate one or more symptoms associated with cancer; can reduce morbidity and mortality; can improve quality of life; and combinations of such effects are possible.

[0208] Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to both 1) therapeutic measures that cure, slow, alleviate symptoms, and / or halt progression of a diagnosed pathological condition or disorder, and 2) prophylactic or preventative measures that prevent and / or delay the onset of the targeted pathological condition or disorder. Thus, those in need of treatment include those already suffering from the disorder; those prone to suffering from the disorder, and those in whom the disorder is to be prevented.

[0209] Those skilled in the art will recognize that for this and other processes and methods disclosed herein, the operations performed in the processes and methods may be performed in a different order. Moreover, the outlined steps and operations are provided for illustrative purposes only, and some of the steps and operations may be combined into fewer steps and operations or expanded into additional steps and operations, as appropriate, without departing from the essence of the disclosed embodiments.

[0210] The present disclosure is not intended to be limited to the specific embodiments described in this application, which are intended to be illustrative of various aspects. As will be apparent to those skilled in the art, many modifications and variations are possible without departing from the spirit and scope of the present invention. In addition to the methods and devices recited herein, functionally equivalent methods and devices within the scope of the present disclosure will be apparent to those skilled 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, along with the full scope of equivalents to which such claims are entitled. It is to be understood that the present disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the present invention.

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

[0212] In general, those skilled in the art will understand that the terms used herein, and particularly in the appended claims (e.g., the body of the appended claims), are generally interpreted as "open" terms (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," and the term "includes" should be interpreted as "including, but not limited to"). It will be further understood by those skilled in the art that where a specific number is intended in a claim recitation, such intention will be clearly stated in the claim, and in the absence of such recitation, no such intention exists. For example, to aid in understanding, the following appended claims may introduce the introductory phrases "at least one" and "one or more" into the claim recitation. However, even if such a phrase is used, the introduction of the indefinite article "a" or "an" at a statement in a claim should not be interpreted as meaning that any particular claim including such a statement in a claim is limited to an embodiment including only one of such statements, even if the same claim includes the introductory phrase "one or more" or "at least one" and the indefinite article "a" or "an" (e.g., "a" and / or "an" should be interpreted as meaning "at least one" or "one or more"); the same applies when introducing a definite article at a statement in a claim. Moreover, even if a particular number is expressly recited in a statement in a claim, a person skilled in the art will recognize that such statement should be interpreted as meaning at least the recited number (e.g., the mere recitation of "two statements" without other qualifiers means at least two statements, or two or more statements).Furthermore, in instances where conventional language similar to "at least one of A, B, and C, etc." is used, such construction generally intends the meaning of the conventional language as understood by one of ordinary skill in the art (e.g., "a system having at least one of A, B, and C" would include, but is not limited to, systems 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, etc.). In instances where conventional language similar to "at least one of A, B, or C, etc." is used, such construction generally intends the meaning of the conventional language as understood by one of ordinary skill in the art (e.g., "a system having at least one of A, B, or C" would include, but is not limited to, systems 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, etc.). It will be further understood by those skilled in the art that virtually any disjunctive word and / or disjunctive phrase expressing two or more alternative terms, whether in the description, claims, or drawings, should be understood to sanction the possibility of including one of those terms, either of those terms, or both of those terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B," or "A and B."

[0213] Moreover, when features or aspects of the disclosure are described in Markush format, those of skill in the art will recognize that the disclosure also describes any individual members or subgroups of members of the Markush group.

[0214] As will be understood by those of skill in the art, for any and all purposes, including in light of the specification provided, all ranges disclosed herein include any and all possible subranges and combinations thereof. Any recited range can be readily recognized as being fully described and divisible at least equally into half, one-third, one-quarter, one-fifth, one-tenth, etc., of said range. As a non-limiting example, each range discussed herein can be readily divided into a lower third, a middle third, an upper third, etc. Also, as will be understood by those of skill in the art, all expressions such as "up to" and "at least" refer to ranges that are inclusive of the recited numbers and can then be divided into the subranges discussed above. Finally, as will be understood by those of skill in the art, ranges include individual members. Thus, for example, a group having 1-3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to a group having 1, 2, 3, 4, or 5, etc., cells.

[0215] From the foregoing, it will be appreciated that various embodiments of the present disclosure have been 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 be limiting of the present invention, the true scope and spirit of which is indicated by the following claims.

[0216] All references cited herein are specifically incorporated by reference in their entirety for all that they teach.

Claims

[Claim 1] The invention described in the present specification.

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