Analogues for the Treatment of Disease

Abstract

Provided are TNIK and / or MAP4K4 kinase inhibitors for the treatment of disease. In one embodiment, disclosed herein are compounds of formula (A), (A * (IIA), (IIB), or (IIC). Further described herein are pharmaceutical compositions comprising these compounds and methods of using these compounds. In one aspect, disclosed herein is a method of treating a disease or condition by administering a kinase inhibitor described herein.

Description

[Technical field]

[0001] cross reference

[0001] This application claims the benefit of International Application No. PCT / CN2021 / 077706, filed February 24, 2021, and International Application No. PCT / CN2021 / 142622, filed December 29, 2021, each of which is hereby incorporated by reference in its entirety. [Background technology]

[0002]

[0002] A biologically active enzyme known as Traf2 and Nck interacting protein kinase, commonly known as TNIK in humans, is encoded by the TNIK gene. As a serine / threonine kinase, TNIK is involved in a variety of biological processes. There is a need for new drug candidates that can target TNIK. Summary of the Invention [Problem to be solved by the invention]

[0003]

[0003] TNIK is a serine / threonine kinase involved in various biological processes, including acting as an essential regulatory component of the Wnt signaling pathway. TNIK directly binds TCF4 and b-catenin and phosphorylates TCF4. Additionally, TNIK acts as an activator of Wnt target gene expression, modulates the actin cytoskeleton, and activates the c-Jun N-terminal kinase pathway, which is responsive to stress. It is also part of a signaling complex composed of NEDD4, RAP2A, and TNIK, which regulates neuronal dendritic outgrowth and arborization during development. More generally, TNIK plays a role in cytoskeletal reorganization and can regulate cell spreading. TNIK causes weak Smad1 T322 phosphorylation, which is involved in TGF-b1 signaling transduction.

[0004]

[0004] TNIK is thought to be a germinal center kinase (GCK) that can be characterized by an N-terminal kinase domain and a C-terminal GCK domain that serves a regulatory function.

[0005] TNIK 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]

[0006] Additionally, TNIK has been linked to cancer, including, for example, colorectal cancer, and therefore has been identified as an attractive candidate for drugs targeting certain cancers.

[0006]

[0007] Current data imply that TNIK is a potential target for the production of small molecule inhibitors to specifically block the Wnt pathway in disease states such as colorectal cancer or autosomal recessive forms of cognitive impairment.

[0007]

[0008] Moreover, it is known that TGF-β-activated EMT can be identified through the attenuation of Smad and non-Smad signaling pathways, including Wnt, FF-kB, FAK-Src-paxillin-associated focal adhesion and MAP kinase (ERK and JNK) signaling pathways. Therefore, therapeutic targets associated with EMT, such as TNIK, a target for inhibition, can be used for therapy to treat and / or prevent EMT-based disorders, such as cancer metastasis and fibrosis.

[0008]

[0009] Therefore, it would be advantageous to have a TNIK inhibitor capable of inhibiting the kinase activity of TNIK, as a member of the Ste20 family of MAP kinase kinase kinases (MAP4Ks).

[0009]

[0010] The present disclosure addresses the above needs and provides additional advantages as well. [Means for solving the problem]

[0010]

[0011] In some embodiments, the present disclosure provides a compound of formula (A):

[0011] [ka]

[0012] or a pharma- ceutically acceptable salt thereof, wherein: Z is an optionally substituted 3- to 12-membered heterocycle and an optionally substituted C-C 12 carbocyclic ring, where each of the substituents is selected from one or more -N(R 10 )2, halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C1-C 10 Alkyl, C 3~12 independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; Here, C1~C 10 Alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~10 Alkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; Here, C 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C1~10 Optionally substituted at each occurrence with one or more substituents independently selected from alkyl, where C 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2; R 10 is selected from optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; W is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl; Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0013] In some embodiments, the present disclosure provides a compound of formula (A*):

[0014] [ka]

[0015] providing a compound represented by: R 1 is selected from: -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~10 Alkyl), C2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally substituted 3- to 8-membered heterocycles; where the optional substituents on the 3- to 8-membered heterocycles are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2; W is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl; Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0016] In certain embodiments, the present disclosure provides a compound of formula (I):

[0017] [ka]

[0018] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is selected from: -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~10 Alkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally substituted 3- to 8-membered heterocycles; where the optional substituents on the 3- to 8-membered heterocycles are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3~10 carbocycle, where each of the optional substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~6 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; R 4 is selected from: hydrogen; Optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally replaced C 3~10 Carbocyclic ring, where C 3~10 Optional substituents on the carbocycle include one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; W is selected from optionally substituted 5- to 8-membered heteroaryl, where the substituents on the optionally substituted 5- to 8-membered heteroaryl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 and is independently selected at each occurrence from a carbocycle, and a 3- to 12-membered heterocycle.

[0019] In some embodiments, the present disclosure provides a compound represented by formula (A), * ) or a pharmaceutical composition comprising a compound or salt of formula (I) and a pharma- ceutically acceptable excipient. In some embodiments, the present disclosure provides a compound represented by formula (A), *The present invention provides a method for treating or preventing a disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound or salt of Formula (A), Formula (A*) or Formula (I) or a compound or salt of Formula (A), Formula (A*) or Formula (I) and a pharma- ceutical acceptable excipient. In some embodiments, the disease is cancer. In some cases, the cancer is selected from colorectal cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, chronic myeloid leukemia, cancer metastasis, fibrosis, and psychiatric disorders. In some cases, the pharmaceutical composition can be used as an inhibitor of tumor immunosuppression in combination with chemotherapy or immune checkpoint inhibitor therapy for cancer. In some cases, the pharmaceutical composition can be used to treat fibrotic diseases or conditions, including, but not limited to, chronic kidney fibrosis ("CKD"), liver cirrhosis, pulmonary fibrosis, interstitial renal fibrosis, myocardial infarction, skin fibrosis, systemic sclerosis ("SSc"), and graft versus host disease ("GVHD"). In some cases, the pharmaceutical composition can be used to treat kidney fibrosis.In some cases, the pharmaceutical composition can be used to treat skin fibrosis.In some cases, the pharmaceutical composition can be used to treat idiopathic pulmonary fibrosis (IPF).In some cases, the pharmaceutical composition can be used to treat diseases associated with TNIK kinase.

[0020] In some embodiments, the present disclosure provides a compound represented by formula (A), * ) or a compound or salt of formula (I) or formula (A), * The present invention provides a method for inhibiting TNIK kinase comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound or salt of formula (I) and a pharma- ceutically acceptable excipient.

[0021] In some embodiments, the present disclosure provides a compound represented by formula (A), * ) or a compound or salt of formula (I) or formula (A), *The present invention provides a method for inhibiting MAP4K4 kinase comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound or salt of formula (I) and a pharma- ceutically acceptable excipient.

[0022]

[0018] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, in which only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modification in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description should be regarded as illustrative in nature, and not restrictive.

[0023] Incorporation by Reference

[0019] All publications, patents, and patent applications described in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over any such conflicting matter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024]

[0020] While various embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used.

[0025] A.Definition

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0026]

[0022] "Alkyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from 1 to 15 carbon atoms (i.e., C1-C 15 Alkyl) refers to a straight or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (i.e., C1-C 13 In certain embodiments, the alkyl comprises 1 to 8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl comprises 1 to 5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl comprises 1 to 4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl comprises 1 to 3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl comprises 1 to 2 carbon atoms (i.e., C1-C2 alkyl). In other embodiments, the alkyl comprises 1 carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl comprises 5 to 15 carbon atoms (i.e., C5-C6 alkyl). 15In other embodiments, the alkyl comprises 5 to 8 carbon atoms (i.e., C5-C8 alkyl). In other embodiments, the alkyl comprises 2 to 5 carbon atoms (i.e., C2-C5 alkyl). In other embodiments, the alkyl comprises 3 to 5 carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Unless specifically stated otherwise in the specification, the alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0027]

[0023] "C x~y The term "alkyl," when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, "C 1~6 The term "alkyl" refers to alkyl groups which can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, including straight chain alkyl groups and branched chain alkyl groups.

[0028]

[0024] "Alkoxy" refers to a radical attached through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above. Unless otherwise specifically stated herein, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0029]

[0025] "Alkenyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from 2 to 12 carbon atoms (i.e., C2-C 12Alkenyl refers to a straight or branched hydrocarbon chain radical group. In certain embodiments, an alkenyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). An alkenyl is attached to the remainder of the molecule by a single bond, such as, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless specifically stated otherwise in the specification, an alkenyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0030] "Alkynyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from 2 to 12 carbon atoms (i.e., C2-C 12Alkynyl refers to a straight or branched hydrocarbon chain radical group. In certain embodiments, an alkynyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). An alkynyl is attached to the remainder of the molecule by a single bond, such as, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless specifically stated otherwise in the specification, an alkynyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0031]

[0027] "C x~y alkenyl" and "C x~y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively. x~y The term alkenylene- refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the alkenylene chain. For example, -C 2~6 Alkenylene- can be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any of which are optionally substituted. The alkenylene chain can have one double bond or more than one double bond in the alkenylene chain. -C x~yThe term alkynylene- refers to a substituted or unsubstituted alkynylene chain having x to y carbons in the alkenylene chain. For example, -C 2~6 Alkenylene- can be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any of which are optionally substituted. The alkynylene chain can have one triple bond or more than one triple bond in the alkynylene chain.

[0032]

[0028] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to the radical group, consists solely of carbon and hydrogen, contains no unsaturation, and preferably has 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, the alkylene contains 1 to 10 carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, the alkylene contains 1 to 8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene comprises 1 to 4 carbon atoms (i.e., a C1-C4 alkylene). In other embodiments, the alkylene comprises 1 to 3 carbon atoms (i.e., a C1-C3 alkylene). In other embodiments, the alkylene comprises 1 to 2 carbon atoms (i.e., a C1-C2 alkylene). In other embodiments, the alkylene comprises 1 carbon atom (i.e., a C1 alkylene). In other embodiments, the alkylene comprises 5 to 8 carbon atoms (i.e., a C5-C8 alkylene). In other embodiments, the alkylene comprises 2 to 5 carbon atoms (i.e., a C2-C5 alkylene). In other embodiments, the alkylene comprises 3 to 5 carbon atoms (i.e., a C3-C5 alkylene). -C x~yThe term alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbons in the alkylene chain. For example, -C 1~6 Alkylene- can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which are optionally substituted.

[0033]

[0029] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that links the rest of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has from 2 to 12 carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, an alkenylene contains from 2 to 10 carbon atoms (i.e., C2-C 10 alkenylene). In certain embodiments, the alkenylene comprises 2 to 8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, the alkenylene comprises 2 to 5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, the alkenylene comprises 2 to 4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, the alkenylene comprises 2 to 3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, the alkenylene comprises 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, the alkenylene comprises 5 to 8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, the alkenylene comprises 3 to 5 carbon atoms (i.e., C3-C5 alkenylene).

[0034]

[0030] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that links the rest of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon triple bond, and preferably has from 2 to 12 carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, the alkynylene contains from 2 to 10 carbon atoms (i.e., C2-C 10 alkynylene). In certain embodiments, the alkynylene comprises 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, the alkynylene comprises 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, the alkynylene comprises 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, the alkynylene comprises 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, the alkynylene comprises 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, the alkynylene comprises 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, the alkynylene comprises 3 to 5 carbon atoms (i.e., C3-C5 alkynylene).

[0035]

[0031] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms, where the ring system contains at least one aromatic ring. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon and 5 to 18 carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) pi-electron system according to the Huckel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.Unless otherwise specifically stated herein, aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0036]

[0032] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless specifically stated otherwise in the specification, heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0037] "Aralkyl" refers to a group of the formula -R c -aryl radical, where R c is an alkylene chain as defined above, for example, methylene, ethylene, etc.

[0038] "Aralkenyl" refers to a group of the formula -R d-aryl radical, where R d is an alkenylene chain as defined above. "Aralkynyl" refers to a group of the formula -R e -aryl radical, where R e is an alkynylene chain as defined above.

[0039] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring system in which each ring atom of the ring system is carbon. Carbocycles can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, where valences permit. Illustrative carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. In some embodiments, the carbocycle is aryl. In some embodiments, the carbocycle is cycloalkyl. In some embodiments, the carbocycle is cycloalkenyl. In some embodiments, the carbocycle contains a triple bond. Unless stated otherwise specifically in the specification, carbocycles may be optionally substituted.

[0040]

[0036] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical, consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having from 3 to 12 carbon atoms. In certain embodiments, cycloalkyls contain from 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain from 5 to 7 carbon atoms. A cycloalkyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless specifically stated otherwise herein, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0041]

[0037] "Heterocycloalkyl" refers to a cycloalkyl group, as defined above, in which one or more ring carbons are replaced with one or more heteroatoms, such as N, O, P, and S. Heterocycloalkyl may be optionally substituted.

[0042]

[0038] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having 3 to 12 carbon atoms and containing at least one double bond. In certain embodiments, a cycloalkenyl contains one double bond. In certain embodiments, a cycloalkenyl contains more than one double bond. In certain embodiments, a cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, a cycloalkenyl contains 5 to 7 carbon atoms. A cycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0043]

[0039] "Heterocycloalkenyl" refers to a cycloalkenyl group, as defined above, in which one or more ring carbons are replaced with one or more heteroatoms, such as N, O, P, and S. A heterocycloalkenyl may be optionally substituted.

[0044] "Cycloalkylalkyl" refers to a group of the formula -R c -cycloalkyl radical, where R c is an alkylene chain as described above. "Cycloalkylalkoxy" refers to a group of the formula -OR c -refers to a radical attached through the oxygen atom of a cycloalkyl, where R c is an alkylene chain as described above.

[0045] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0043] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, such as, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radical, each halogen may be independently selected, for example, 1-chloro, 2-fluoroethane.

[0046] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0047]

[0045] "Heterocycle" refers to a saturated, unsaturated or aromatic ring containing one or more heteroatoms. Illustrative heteroatoms include N, O, Si, P, B and S atoms. Heterocycles include, for example, 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated and aromatic rings. "Heterocyclene" refers to a divalent heterocycle that links the remainder of the molecule to a radical group. Unless specifically stated otherwise in this specification, the heterocycle is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heterocycle is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. In some embodiments, the heterocycle is heteroaryl. In some embodiments, the heterocycle is heterocycloalkyl. In some embodiments, the heterocycle is heterocycloalkenyl. In some embodiments, the heterocycle contains one or more triple bonds.

[0048] In some embodiments, the heterocycle contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycle contains one to three nitrogens. In some embodiments, the heterocycle contains one or two nitrogens. In some embodiments, the heterocycle contains one nitrogen. In some embodiments, the heterocycle contains one nitrogen and one oxygen. Unless specifically stated otherwise in the specification, the heterocycle radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spiro, or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocycle radical may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Representative heterocycles include the heteroaryl groups described below. Representative heterocycles include, but are not limited to, heteroaryl rings having 2 to 15 carbon atoms (C2-C4). 15 Heterocycloalkyl or C2-C 15 Heterocycloalkenyl, 2 to 10 carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocyclic radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperazinyl, and 4-piperazinyl. Examples of heterocyclic rings include donyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycle also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycle has 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycle, it is understood that the number of carbon atoms in the heterocycle is not the same as the total number of atoms (including heteroatoms) that make up the heterocycle (i.e., the skeletal atoms of the heterocycle). In some embodiments, the heterocycle is 3- to 8-membered. In some embodiments, the heterocycle is 3- to 7-membered. In some embodiments, the heterocycle is 3- to 6-membered. In some embodiments, the heterocycle is 4- to 6-membered.In some embodiments, the heterocycle is 5 to 6 membered.

[0049]

[0047] "Heteroaryl" or "aromatic heterocycle" refers to a radical derived from a heteroaromatic ring radical containing 1 to 13 carbon atoms, at least one heteroatom, each heteroatom being selected from N, O and S, and at least one aromatic ring. As used herein, a heteroaryl ring can be selected from monocyclic or bicyclic and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) pi-electron system according to the Huckel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl, where valence allows. Examples of heteroaryl include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzthiazole, and imidazopyridine. "X-membered heteroaryl" refers to the number of ring atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 ring atoms, such as triazole, oxazole, thiophene, etc. In some embodiments, the heteroaryl is a 5-membered to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, Examples of phenyl include isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated herein, a heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0050] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of a structure. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permissible valences of the atom and substituent being replaced, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0051] In some embodiments, the substituents can include any of the substituents described herein, such as halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazino (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b-OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which is alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a)2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2, where t is 1 or 2; a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, where each R a is, if valence permits, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b-N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2, where t is 1 or 2; and b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain; c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0052]

[0050] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharma-ceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0053]

[0052] The phrases "parenteral administration" and "administered parenterally", as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0054]

[0053] The phrase "pharmacologically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals and commensurate with a reasonable benefit / risk ratio without undue toxicity, irritation, allergic response, or other problem or complication.

[0055]

[0054] The phrase "pharmacologically acceptable excipient" or "pharmacologically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which serve as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and glycerin; and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0056]

[0055] In certain embodiments, the term "prevent" or "preventing" when referring to a disease or disorder can refer to a compound that, in a statistical sample, reduces the appearance of a disorder or condition in a treated sample relative to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of a disorder or condition relative to an untreated control sample.

[0057]

[0056] The terms "treat," "treating," or "treatment," as used herein, can include alleviating, relieving, or ameliorating disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying cause of the symptoms, inhibiting the disease or condition, e.g., arresting the onset of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating conditions caused by the disease or condition, or halting the symptoms of the disease or condition, either prophylactically and / or therapeutically.

[0058] B. Compounds of the Present Disclosure In certain embodiments, the present disclosure provides a compound of formula (A):

[0059] [ka]

[0060] or a pharma- ceutically acceptable salt thereof, wherein: Z is an optionally substituted 3- to 12-membered heterocycle and an optionally substituted C-C 12 carbocyclic ring, where each of the substituents is selected from one or more -N(R 10 )2, halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C1-C 10Alkyl, C 3~12 independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; Here, C1~C 10 Alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~10 Alkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; Here, C 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1~10 Optionally substituted at each occurrence with one or more substituents independently selected from alkyl, where C 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2; R 10 is selected from optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; W is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl; Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0061] In some embodiments, the compound of formula (A) is * ) In some embodiments, for the compound or salt of formula (A), Z is an optionally substituted 3- to 12-membered heterocycle and an optionally substituted C3-C 12 carbocycle, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 In some cases, for Z, the heterocycle includes at least one nitrogen atom. In some cases, Z is selected from optionally substituted phenyl and optionally substituted pyridine. In some cases, the optional substituents of the optionally substituted phenyl of Z are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 In some cases, the optional substituents of the optionally substituted phenyl of Z are selected from one or more substituents selected from halogen and C 1~10 In some cases, Z is selected from one or more substituents selected from alkyl. In some cases, the heterocycle is unsubstituted. In some cases, Z is selected from substituted phenyl and unsubstituted pyridine. In some cases, the heterocycle has one or two nitrogen atoms. In some cases, the heterocycle has only one nitrogen atom. In some cases, the heterocycle has only two nitrogen atoms. In some cases, the heterocycle is a 6-membered heterocycle. In some cases, Z is

[0062] [ka]

[0063] In some cases, the optional substituent of the optionally substituted phenyl of Z is halogen. In some cases, Z is selected from

[0064] [ka]

[0065] In some cases, Z is selected from the group consisting of phenyl, substituted phenyl, and halogen. In some embodiments, the present disclosure provides a compound of formula (A*):

[0066] [ka]

[0067] providing a compound represented by: R 1 is selected from: -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~10 Alkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally substituted 3- to 8-membered heterocycles; where the optional substituents on the 3- to 8-membered heterocycles are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2; W is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl; Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0068] In some embodiments, the compound of formula (A) or formula (A * ) is represented by formula (I): In some embodiments, the present disclosure provides a compound of formula (A*):

[0069] [ka]

[0070] providing a compound represented by: R 1 is selected from: -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6Alkyl-OC(O)(OC 1~10 Alkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally substituted 3- to 14-membered heterocycles; where the optional substituents on the 3- to 8-membered heterocycles are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Heteroalkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2; W is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl; Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, where each of the substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0071] In some embodiments, the present disclosure provides a compound of formula (A * ):

[0072] [ka]

[0073] providing a compound represented by: R 1 is selected from: -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl; optionally substituted C1-C6 alkyl; an optionally substituted 3- to 14-membered heterocycle or an optionally substituted 3- to 14-membered carbocycle; W is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles; Y is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles.

[0074] In some embodiments, R is an optionally substituted 3- to 14-membered heterocycle. In certain embodiments, the present disclosure provides a compound of formula (I):

[0075] [ka]

[0076] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is selected from: -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~10 Alkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally substituted 3- to 8-membered heterocycles; where the optional substituents on the 3- to 8-membered heterocycles are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3~10 carbocycle, where each of the optional substituents is selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~6 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; R 4 is selected from: hydrogen; Optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; Optionally replaced C 3~10 Carbocyclic ring, where C 3~10 Optional substituents on the carbocycle include one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; W is selected from optionally substituted 5- to 8-membered heteroaryl, where the substituents on the optionally substituted 5- to 8-membered heteroaryl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 and is independently selected at each occurrence from a carbocycle, and a 3- to 12-membered heterocycle.

[0077] In certain embodiments, the present disclosure provides a compound of formula (I):

[0078] [ka]

[0079] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is selected from: -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl; substituted C1-C6 alkyl; and optionally substituted 3- to 14-membered heterocycles (such as 5- to 6-membered heterocycloalkyls); R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3~10 selected from carbocyclic rings; R 4 is selected from: hydrogen; optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; Optionally replaced C 3~10 a carbocycle or an optionally substituted 3- to 12-membered heterocycle; W is selected from optionally substituted 5- to 8-membered heteroaryl, such as 5- to 6-membered heteroaryl.

[0080] In some embodiments, R 4 is an optionally substituted C1-C6 alkyl. 4 is optionally replaced by C 3~10 It is a carbocyclic ring.

[0081] In some embodiments, the compound of formula (A), (A * ) or (I), R 1 When R is methylpiperazine and W is pyridine, 4 is not methyl. In some cases, R 1 but

[0082] [ka]

[0083] and W is pyridine, R 4 is not methyl. In some embodiments, the compound of formula (A), (A *For compounds or salts of formula (I), when W is furan, R 4 is not ethan-1-one. In some cases, W is furan and R 4 When is cyclopentyl or cyclohexyl, R 1 is not ethan-1-one. In some cases, W is furan and R 4 When is cyclopentyl or cyclohexyl, R 1 is not ethan-1-one. In some cases, R 1 teeth,

[0084] [ka]

[0085] isn't it. In some embodiments, the compound of formula (A), (A * For the compounds or salts of (I) or (I), W is selected from an optionally substituted 5- to 8-membered heterocycle. In some cases, the heterocycle of W is a 5- to 8-membered heteroaryl. In some cases, the heterocycle of W is an unsubstituted 5- to 8-membered heteroaryl. In some cases, the heterocycle of W is an unsubstituted 5-membered heteroaryl. In some cases, the heterocycle of W has at least 2 heteroatoms. In some cases, the heterocycle of W has at most 2 heteroatoms. In some cases, the heterocycle of W has only 2 heteroatoms. In some cases, the heterocycle of W is unsubstituted. In some cases, the heterocycle of W has 2 heteroatoms selected from nitrogen, sulfur and oxygen. In some cases, the heterocycle of W has at least 2 different heteroatoms. In some cases, the heterocycle of W has 2 nitrogen atoms. In some cases, the heterocycle of W has one nitrogen atom and one oxygen atom.

[0086] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB),1 is optionally substituted. In some embodiments, R 1 is optionally substituted with 1 to 4 substituents. 1 is optionally substituted with 1 to 3 substituents. 1 is optionally substituted with 1 to 2 substituents. In some embodiments, R 1 is optionally substituted with 1 substituent. 1 is optionally substituted with two substituents. 1 is optionally substituted with 3 substituents. 1 is monocyclic. In some embodiments, R 1 is bicyclic. In some embodiments, R 1 is a bridged ring. In some embodiments, R 1 is a fused ring. In some embodiments, R 1 is a spiro ring. In some embodiments, R 1 is an optionally substituted 3-12 membered ring. In some embodiments, R 1 is an optionally substituted 5-8 membered ring.

[0087] In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 1 is optionally substituted with oxide. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is selected from substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6Alkyl-OC(O)(OC 1~10 Alkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is selected from substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, =S, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~6 Alkyl), C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 In some embodiments, R is independently selected at each occurrence from a carbocycle, and a 3- to 12-membered heterocycle. 1 is an optionally substituted C1-C3 alkyl. 1 is oxo, halogen, -OC 1~10 Alkyl, -C 1~10 Optionally substituted with one or more substituents selected from haloalkyl, and -OH.

[0088] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is optionally substituted C1 to C 10 In some embodiments, the aryl group of formula (A), (A * ), (I), (IIA) or (IIB), 1 is an optionally substituted C1-C6 heteroalkyl, where the substituents on the C1-C6 heteroalkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, =S, -C 1~10 Haloalkyl, -C2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is an optionally substituted C1-C6 heteroalkyl, where the substituents on the C1-C6 heteroalkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, =S, -C 1~3 Haloalkyl, -C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 and independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle.

[0089] In some cases, when W is furan, R 1 is selected from substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~10 Alkyl), C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 and independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle.

[0090] In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 1 is -N(R 5 In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 1 is -N(R 5 )2, where R 5is selected from optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are selected from hydroxy.

[0091] In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 1 is selected from substituted C1-C6 alkyl and optionally substituted 3- to 8-membered heterocycle.

[0092] In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 1 is a substituted C1-C6 alkyl. * ), (I), (IIA) or (IIB), 1 is selected from substituted C1-C6 alkyl, where the substituents are hydroxy, oxo, and -OC 1~10 is selected from alkyl.

[0093] In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 1 is an optionally substituted 3- to 8-membered heterocycle. * ), (I), (IIA) or (IIB), 1 is selected from optionally substituted 5- to 6-membered heterocycles. 1 is monocyclic. In some embodiments, R 1 is bicyclic. In some embodiments, R 1 is a fused bicyclic group. In some embodiments, R 1 is a bridged bicyclic group. In some embodiments, R 1is an optionally substituted 5-membered heterocycle. In some embodiments, R 1 is an optionally substituted heteroaryl. In some embodiments, R 1 is an optionally substituted heterocycloalkyl. In some embodiments, R 1 contains 0-3 nitrogen and 0-1 oxygen atoms on the ring. 1 contains 1-2 nitrogen and 0-1 oxygen atoms on the ring. 1 contains 1 to 2 ring nitrogen atoms. In some embodiments, R 1 contains two ring nitrogen atoms. In some embodiments, R 1 contains one ring nitrogen atom.

[0094] In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 1 is an optionally substituted 6-membered heterocycle.

[0095] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is an optionally substituted piperazine. In some embodiments, R 1 is an optionally substituted piperazine, where the piperazine is attached to the remainder of the compound via the nitrogen (e.g., attached to the phenyl). In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is one or more C 1~6 In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 1is piperazine optionally substituted with one or more substituents selected from methyl, ethyl, and propyl. * ), (I), (IIA) or (IIB), 1 is piperazine optionally substituted with one or more methyl. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is one or more C 1~6 In some embodiments, the piperazine of formula (A), (A * ), (I), (IIA) or (IIB), 1 is piperazine optionally substituted with oxide.

[0096] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 Optional substituents on the optionally substituted piperazine are oxo, -S(O2)NH2, and optionally substituted C 1~10 alkyl, wherein C 1~10 The optional substituents on the alkyl are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, and -NH. * ), (I), (IIA) or (IIB), 1 The optional substituents on the optionally substituted piperazine are oxo, -S(O2)NH2, -S(O2)N(C 1~6 alkyl)2, -S(O2)NH(C 1~6 alkyl), and optionally substituted C 1~6 In some embodiments, the aryl group represented by formula (A), (A* ), (I), (IIA) or (IIB), 1 is optionally substituted with heteroalkyl. In some embodiments, R 1 is optionally substituted with one or more substituents selected from halogen, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, and C3-C6 cycloalkyl.

[0097] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is an optionally substituted 3- to 10-membered heterocycle. In some instances, R 1 is an optionally substituted 4- to 8-membered heterocycle. In some instances, R 1 is an optionally substituted 4-membered heterocycle. In some instances, R 1 is an optionally substituted 6-membered heterocycle. In some instances, R 1 When R is piperazine, the piperazine is substituted. 1 is not an unsubstituted piperazine. 1 is a substituted 3- to 10-membered heterocycle.

[0098] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1For the heterocycle, optional substituents are halogen, -OH, -CN, -NO2, -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, oxo, =S, -S(O2)NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, and optionally substituted C 1~10 and independently selected at each occurrence from one or more substituents selected from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 Haloalkyl, -NH2, -CN, -OC 1~10 and -NO2, independently at each occurrence.

[0099] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 The optional substituents are -NH, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl), oxo, and optionally substituted C 1~10 and independently selected at each occurrence from one or more substituents selected from alkyl, 1~10 Optional substituents on alkyl include one or more oxo and -OC 1~10 is independently selected at each occurrence from alkyl.

[0100] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 The optional substituents are -NH, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl), oxo, and optionally substituted C 1~10 and independently selected at each occurrence from one or more substituents selected from alkyl, 1~10 Optional substituents on alkyl include one or more oxo and -OC 1~10 is independently selected at each occurrence from alkyl.

[0101] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 For R, the heterocycle has at least one nitrogen atom, phosphorus atom, or oxygen atom. 1 For the heterocycle, R 1 For the heterocycle, R 1 For R, the heterocycle has at most two nitrogen atoms. 1 For R, the heterocycle has at most one nitrogen atom. 1 For the heterocycle, R 1 In some cases, the heterocycle is a spiro-heterocycle. 1 In some cases, R 1 In some cases, R 1 For Figure imgf000023_0001 the heterocycle is saturated.

[0102] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0103] [ka]

[0104] any of which is optionally substituted. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0105] [ka]

[0106] any of which is selected from -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, oxo, and optionally substituted C 1~10 Optionally substituted with one or more substituents selected from alkyl, 1~10 Optional substituents on alkyl include one or more oxo and -OC 1~10 In some embodiments, R 1 is -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, oxo, optionally substituted C 1~10 Heteroalkyl, and optionally substituted C 1~10 and optionally substituted with one or more substituents selected from alkyl.

[0107] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0108] [ka]

[0109] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0110] [ka]

[0111] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0112] [ka]

[0113] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0114] [ka]

[0115] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0116] [ka]

[0117] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is an optionally substituted 6- to 10-membered heterocycloalkyl. In some instances, R 1 The optional substituents of the optionally substituted 6- to 10-membered heterocycloalkyl on 1~6 In some cases, the 6- to 10-membered heterocycloalkyl is a spiroheterocycloalkyl.1 is selected from optionally substituted piperazine, optionally substituted diazabicyclo[3.2.1]octane, optionally substituted diazabicyclo[3.1.1]heptane, optionally substituted diazaspiro[3.5]nonane, and optionally substituted diazaspiro[3.3]heptane. In some cases, the optional substituents are 1~6 is selected from alkyl.

[0118] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 is optionally substituted. In some embodiments, R 3 is optionally substituted with 1 to 4 substituents. 3 is optionally substituted with 1 to 3 substituents. 3 is optionally substituted with 1 to 2 substituents. In some embodiments, R 3 is optionally substituted with 1 substituent. 3 is optionally substituted with two substituents. 3 is optionally substituted with three substituents.

[0119] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 is optionally replaced by C 3~6 In some embodiments, the aryl group represented by formula (A), (A * ), (I), (IIA) or (IIB), 3 is optionally replaced by C 3~6 cycloalkyl.

[0120] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 is optionally substituted phenyl. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 is phenyl optionally substituted with one or more halogens. * ), (I), (IIA) or (IIB), 3 is phenyl optionally substituted with 1 to 3 halogens. * ), (I), (IIA) or (IIB), 3 is phenyl optionally substituted with 1 to 2 halogens. * ), (I), (IIA) or (IIB), 3 is phenyl optionally substituted with one halogen.

[0121] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 The optional substituents on the phenyl are halogen and -C 1~10 In some embodiments, the compound of formula (A), (A * ), (I), (IIA) or (IIB), 3 The optional substituents on the phenyl are halogen and -C 1~3 haloalkyl.

[0122] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 are halogens, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~12 In some embodiments, R is substituted with one or more substituents selected from a carbocycle, and a 3- to 12-membered heterocycle. 4 are halogens, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1~6 Alkyl, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 In some embodiments, R is substituted with one or more substituents selected from a carbocycle, and a 3- to 12-membered heterocycle. 4 are halogens, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1~6 Alkyl, -C 1~6 Haloalkyl, and -OC 1~6 In some embodiments, R is substituted with one or more substituents selected from alkyl. 4 are halogens, -OH, -NO2, -NH2, oxo, -C 1~6 Haloalkyl, and -OC 1~6 In some embodiments, R is substituted with one or more substituents selected from alkyl. 4 is substituted with one or more halogens. In some embodiments, R 4 is substituted with one halogen. In some embodiments, R 4is substituted with two halogens. 4 is substituted with three halogens.

[0123] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 is hydrogen. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 is an optionally substituted C1-C6 alkyl and an optionally substituted C 3~6 In some embodiments, the aryl group represented by formula (A), (A * ), (I), (IIA) or (IIB), 4 is an optionally substituted cycloalkyl. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 is optionally substituted aryl.

[0124] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 The optional substituents of the C1-C6 alkyl are selected from halogen.

[0125] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 The optional substituents on the C3-C6 carbocyclic ring are selected from hydroxy.

[0126] In some embodiments, the formula (A), (A * For compounds or salts of formula (I), W is selected from 5- to 6-membered heteroaryl. In some embodiments, the formula (A), (A * For the compounds or salts of formula (I) or (I), the 5- to 6-membered heteroaryl of W is selected from imidazole, furan, thiophene, oxazole, isoxazole, thiazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0127] In some embodiments, the formula (A), (A * For the compounds or salts of formula (I), the 5- to 6-membered heteroaryl of W is selected from imidazole, furan, and pyridine.

[0128] In some embodiments, the formula (A), (A * For compounds or salts of formula (A), (A * ) or (I), W is pyridine.

[0129] In some embodiments, the formula (A), (A * For compounds or salts of formula (I), W is selected from optionally substituted 5- to 6-membered heteroaryl.

[0130] In some embodiments, the formula (A), (A * For the compounds or salts of formula (I), W is selected from pyridine, imidazole, thiazole, and furan. In some embodiments, the formula (A), (A * For the compounds or salts of formula (I), W is selected from pyridine and imidazole.

[0131] In some embodiments, the compound or salt of formula (I) has the formula (IIA):

[0132] [ka]

[0133] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound or salt of formula (I) has formula (IIB):

[0134] [ka]

[0135] or a pharma- ceutically acceptable salt thereof. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 is selected from optionally substituted C1-C6 alkyl and optionally substituted C6 carbocycle.

[0136] In some embodiments, the formula (A), (A * For a compound or salt of formula (A), (A * ), (I), (IIA) or (IIB), 3 is selected from C1-C6 alkyl, where the C6 carbocycle is selected from halogen and -C 1~10 and substituted with one or more substituents selected from haloalkyl.

[0137] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 teeth,

[0138] [ka]

[0139] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 is a C6 carbocycle substituted with one or more substituents selected from halogen.

[0140] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens.

[0141] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 teeth,

[0142] [ka]

[0143] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 3 teeth,

[0144] [ka]

[0145] It is. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 is optionally substituted with one or more substituents selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkyl optionally substituted with one or more substituents selected from hydroxy and amine;5~6 carbocycles.

[0146] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 is unsubstituted C1-C6 alkyl. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 is a substituted C1-C6 alkyl, where the C1-C6 alkyl is substituted with one or more halogens.

[0147] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 teeth,

[0148] [ka]

[0149] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 is selected from C1-C6 alkyl optionally substituted with one or more substituents selected from fluorine, and C6 cycloalkyl substituted with hydroxy.

[0150] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 teeth,

[0151] [ka]

[0152] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 teeth,

[0153] [ka]

[0154] In certain embodiments, R 4 teeth,

[0155] [ka]

[0156] It is. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 teeth,

[0157] [ka]

[0158] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 teeth,

[0159] [ka]

[0160] is selected from. In some cases, R 4 is unsubstituted C 1~10It is selected from alkyl, unsubstituted 3- to 6-membered heterocycle, and optionally substituted C3-C6 carbocycle.

[0161] In some embodiments, the formula (A), (A * For compounds or salts of (I), (IIA) or (IIB), each R 4 is C 1~10 Alkyl, C 3~12 and at each occurrence selected from a carbocycle, and a 3- to 12-membered heterocycle, 1~10 Alkyl, C 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1~10 Alkyl, -C 1~10 Haloalkyl, and -OC 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0162] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 is unsubstituted C 1~10 is selected from alkyl, unsubstituted 3- to 6-membered heterocycle, and optionally substituted C3-C6 carbocycle, where the optional substituents are one or more halogen -C 1~10 haloalkyl.

[0163] In some embodiments, the formula (A), (A * For compounds or salts of (I), (IIA) or (IIB), each R 4 is C 1~10 and at each occurrence selected from alkyl, unsubstituted 4-membered heterocycle, and optionally substituted C3-C5 carbocycle, where the optional substituents are one or more halogen -C 1~10 In some instances, R 4 is C 1~10In some cases, R 4 is selected from 4-membered heterocycles. 4 is a 4-membered heterocycle. In some cases, R 4 is a saturated four-membered heterocyclic ring.

[0164] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 4 teeth,

[0165] [ka]

[0166] In some cases, R 4 teeth,

[0167] [ka]

[0168] In some cases, R 4 teeth,

[0169] [ka]

[0170] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is selected from: -N(R 5 )2, where R 5 is selected from optionally substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1~10 Haloalkyl, -OC1~10 independently selected at each occurrence from alkyl, Substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -NH2, oxo, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, -OC 1~6 Alkyl-OC(O)(OC 1~10 alkyl) independently selected at each occurrence; Optionally substituted 6- to 8-membered heterocycles; where the optional substituents on the 6- to 8-membered heterocycles are one or more of oxo, -S(O2)NH2, -NH2, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, and optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 Independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2.

[0171] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0172] [ka]

[0173] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0174] [ka]

[0175] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,:

[0176] [ka]

[0177] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is selected from: Substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, oxo, -C 1~10 Haloalkyl, and -OC 1~10 independently selected at each occurrence from alkyl; an optionally substituted 6- to 8-membered saturated heterocycle; where the optional substituents are one or more -S(O2)NH2 and optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 haloalkyl, and -NH2.

[0178] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0179] [ka]

[0180] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is selected from optionally substituted 6- to 8-membered saturated heterocycles; where the optional substituents are one or more -S(O2)NH2, and optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1~10 haloalkyl, and -NH2.

[0181] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0182] [ka]

[0183] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is selected from substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of halogen, -OH, oxo, -C 1~10 Haloalkyl, and -OC 1~10 is independently selected at each occurrence from alkyl.

[0184] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0185] [ka]

[0186] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is selected from: Substituted C1-C6 alkyl, where the substituents on the C1-C6 alkyl are one or more of -OH, oxo, and -OC 1~10 independently selected at each occurrence from alkyl; Optionally substituted 6- to 8-membered saturated heterocycles; wherein the optional substituents are one or more optionally substituted C 1~10 independently selected at each occurrence from alkyl, 1~10 Optional substituents on the alkyl include one or more hydroxy, oxo, -C 1~10 haloalkyl, and -NH2.

[0187] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,:

[0188] [ka]

[0189] is selected from. In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 is piperazine, where piperazine is an oxo, -S(O2)NH2, and C 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl, where C 1~10The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH. 1 is one or more C 1~3 Alkyl-substituted piperazine, wherein C 1~3 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH2.

[0190] In some embodiments, the formula (A), (A * ), (I), (IIA) or (IIB), 1 teeth,

[0191] [ka]

[0192] is selected from. In some embodiments, the formula (A), (A * For a compound or salt of formula (I), the compound is

[0193] [ka]

[0194] In some cases, the compound is

[0195] [ka]

[0196] isn't it. In some embodiments, the formula (A), (A * For a compound or salt of formula (I), R 1 is -N(R 5 )2, where R5 is selected from optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are hydroxy; Substituted C1-C6 alkyl, where the substituents are hydroxy, oxo, and -OC 1~10 alkyl; and Optionally substituted 5- to 6-membered heterocycles, where the optional substituents are oxo, -S(O2)NH2, and optionally substituted C 1~10 alkyl, wherein C 1~10 The optional substituents on alkyl are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, and -NH; is selected from R 3 is an optionally substituted phenyl, where R 3 The optional substituents on the phenyl are halogen and -C 1~10 haloalkyl; R 4 is an optionally substituted C1-C6 alkyl and an optionally substituted C 3~6 carbocyclic ring, where R 4 The optional substituents of the C1-C6 alkyl are selected from halogen, 4 the optional substituents on the C3-C6 carbocyclic ring are selected from hydroxy; W is selected from imidazole, furan, and pyridine.

[0197] In some embodiments, the formula (A), (A * For a compound or salt of formula (I), R 1 is -N(R 5 )2, where R 5 is selected from optionally substituted C1-C6 alkyl, where the optional substituents on the C1-C6 alkyl are hydroxy; Substituted C1-C6 alkyl, where the substituents are hydroxy, oxo, and -OC1~10 alkyl; and Optionally substituted 5- to 6-membered heterocycles, where the optional substituents are oxo, -S(O2)NH2, and optionally substituted C 1~10 alkyl, wherein C 1~10 The optional substituents on alkyl are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, and -NH; is selected from R 3 is an optionally substituted phenyl, where R 3 The optional substituents on the phenyl are halogen and -C 1~10 haloalkyl; R 4 is an optionally substituted C1-C6 alkyl and an optionally substituted C 3~6 carbocyclic ring, where R 4 The optional substituents of the C1-C6 alkyl are selected from halogen, 4 the optional substituents on the C3-C6 carbocyclic ring are selected from hydroxy; W is selected from imidazole.

[0198] In some embodiments, the formula (A), (A * For a compound or salt of (IIA), (IIB) or (I), R 1 teeth,

[0199] [ka]

[0200] Selected from; R 3 teeth,

[0201] [ka]

[0202] ;R4 teeth,

[0203] [ka]

[0204] is selected from.

[0153] Included in the present disclosure are salts of the compounds described herein, particularly pharma- ceutically acceptable salts. Compounds of the present invention that possess sufficiently acidic, sufficiently basic, or both functional groups can form salts by reacting with any of a number of inorganic bases, and inorganic and organic acids. Alternatively, compounds that are inherently charged, such as those with quaternary nitrogen, can form salts with suitable counterions, such as halides, e.g., bromide, chloride, or fluoride, especially bromide.

[0205]

[0154] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z, E and tautomeric forms as well.

[0206]

[0155] "Tautomer" refers to a molecule in which a proton shift from one atom of the molecule to another atom of the same molecule is possible. The compounds depicted herein exist as tautomers in certain embodiments. In situations in which tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of the tautomers depends on several factors, including the physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0207] [ka]

[0208]

[0156] The compounds disclosed herein may in some embodiments be used in different isotopically enriched forms, e.g. 2 H, 3 H, 11 C. 13 C and / or 14 The C content is enriched. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be produced by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thus increasing the duration of action of the drug.

[0209]

[0157] Unless otherwise specified, the compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this disclosure.

[0210] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I) or carbon-14 ( 14 It can be labeled with an isotope such as 1,2-dichloro-3,4-trimethylphenylacetate (C). 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F,17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 All isotopic substitutions at I are contemplated. All isotopic variations of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention. In some embodiments, where an isotopic variation is exemplified, the remaining atoms of the compound can optionally contain unnatural portions of atomic isotopes.

[0211] In certain embodiments, the compounds disclosed herein are 2 Replaced with H atom 1 Having some or all of the H atoms. Methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0212] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in: Dean, Dennis C.; editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0213]

[0161] Deuterated starting materials are readily available and can be subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0214] In some embodiments of the compounds disclosed herein, R 1 Group, R 3 Group, R 4 Group, R 5 group, W group, Z group, Y group and R 10 One or more of the groups contains deuterium at a percentage greater than the natural abundance of deuterium.

[0215] In some embodiments of the compounds disclosed herein, one or more hydrogens are selected from the group R 1 , R 3 , R 4 , R 5 , W, Z, Y, and R 10 is replaced with one or more deuterium atoms.

[0216] In some embodiments of the compounds disclosed herein, R 1 , R 3 , R 4 , R 5 , W, Z, Y and R 10 The abundance of deuterium in each of is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total number of hydrogen and deuterium.

[0217]

[0165] In some embodiments of the compounds disclosed herein, one or more hydrogens of ring W are replaced with one or more deuteriums.

[0166] The compounds of the present invention also include crystalline and amorphous forms of the compounds, pharma- ceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0218]

[0167] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. When the absolute stereochemistry is not specified, the compounds represented herein include all diastereomeric, enantiomeric, and epimeric forms, and the appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981, incorporated herein by reference for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0219] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. In addition, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0220] In certain embodiments, a compound or a salt of a compound may be a prodrug, for example, where a hydroxyl in a parent compound is shown as an ester or carbonate, or a carboxylic acid present in a parent compound is shown as an ester. The term "prodrug" is intended to encompass compounds that are converted to the pharmaceutical agents of the present disclosure under physiological conditions. One method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal, such as a specific target cell in the host animal. For example, esters or carbonates (e.g., esters of alcohols or carboxylic acids or esters of carbonates and phosphonic acids) are preferred prodrugs of the present disclosure.

[0221]

[0170] Prodrug forms of the compounds described herein, where the prodrug is metabolized in vivo to produce the compounds described herein, are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs for another derivative or active compound.

[0222]

[0171] Prodrugs are often useful because in some circumstances they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent is not. Prodrugs may help to enhance the cell permeability of the compound relative to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs can be designed as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues or to increase drug retention inside cells.

[0223]

[0172] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective aqueous solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; and Edward B. Roche, Bioreversible Carriers in See Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0224]

[0173] Synthetic chemical transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 2d., ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0225] C. Pharmaceutical Compositions

[0174] Provided herein, in certain embodiments, is a compound of formula (A), (A * and (IIA) or (IIB).

[0226]

[0175] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of pharmaceutical agents into medicament preparations for pharma- ceutical use. Appropriate formulations depend on the route of administration selected. Compendiums of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999).

[0227] The compositions and methods of the present disclosure can be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to an animal, such as a human, the composition or pharmaceutical agent is preferably administered as a pharmaceutical composition, for example, comprising a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art, and include, for example, aqueous solutions, such as water or physiological buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils, such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, such as injection or implantation, which avoid transport or diffusion through epithelial barriers, the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient can be selected, for example, to provide delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in dosage unit form, such as tablets, capsules, granules, lyophilisates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

[0228]

[0177] The pharmaceutical composition can be used as an inhibitor of tumor immunosuppression in combination with chemotherapy or immune checkpoint inhibitor treatment for cancer. In some cases, the pharmaceutical composition can be used to treat fibrotic diseases or conditions, including but not limited to chronic kidney fibrosis ("CKD"), liver cirrhosis, pulmonary fibrosis, interstitial renal fibrosis, myocardial infarction, skin fibrosis, systemic sclerosis ("SSc"), and graft versus host disease ("GVHD). In some cases, the pharmaceutical composition can be used to treat kidney fibrosis. In some cases, the pharmaceutical composition can be used to treat skin fibrosis. In some cases, the pharmaceutical composition can be used to treat idiopathic pulmonary fibrosis (IPF). In some cases, the pharmaceutical composition can be used to treat diseases associated with TNIK kinase.

[0229]

[0178] The pharma- ceutically acceptable excipient may contain a physiologically acceptable agent that acts, for example, to stabilize, increase the solubility, or increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose, or dextran, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharma- ceutical acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be, for example, a liposome or other polymer matrix into which the compound of the present invention may be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable and metabolizable carriers that are relatively simple to prepare and administer.

[0230]

[0179] The pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration, including, for example, orally, e.g., as a drench, tablet, capsule, including sprinkle capsule and gelatin capsule, in an aqueous or non-aqueous solution or suspension, bolus, powder, granule, paste for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, e.g., as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally, e.g., as a sterile solution or suspension; intranasally; intraperitoneally; subcutaneously; transdermally, e.g., as a patch applied to the skin; and topically, e.g., as a cream, ointment or spray applied to the skin or as eye drops. The compound can also be formulated for inhalation. In certain embodiments, the compound can be simply dissolved or suspended in sterile water.

[0231]

[0180] The pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or a therapeutically effective amount refers to the amount of one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series, that is effective to produce the desired therapeutic effect.

[0232]

[0181] Subjects can generally be monitored for therapeutic effectiveness using assays and methods appropriate for the condition being treated, which will be familiar to those of ordinary skill in the art and described herein. The pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, administered to a subject can be monitored by determining the level of the pharmaceutical agent or metabolite in a body fluid, e.g., blood, blood fractions, e.g., serum, and / or urine, and / or other biological samples or biological tissues from the subject. Any method practiced in the art and described herein for detecting pharmaceutical agents can be used to measure the level of the pharmaceutical agent or metabolite during the course of treatment.

[0233]

[0182] The dose of the pharmaceutical agent described herein for treating a disease or disorder may depend on the condition of the subject, i.e., the stage of the disease, the severity of the symptoms caused by the disease, the general health condition, as well as the age, sex and weight, and other factors that will be apparent to those skilled in the art of medicine. The pharmaceutical composition can be administered in a manner appropriate to the disease to be treated as determined by those skilled in the art of medicine. In addition to the factors described herein and above related to the use of the pharmaceutical agent for treating a disease or disorder, the appropriate duration and frequency of administration of the pharmaceutical agent can also be determined or adjusted by factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. The optimal dose of the drug can generally be determined using experimental models and / or clinical trials. The optimal dose may depend on the subject's body mass, weight or blood volume. The use of the minimum dose that is sufficient to provide effective treatment is usually preferred. The design and execution of preclinical and clinical studies for pharmaceutical agents, including those administered for the preventive benefits described herein, is well within the skill of those skilled in the art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than if either agent is administered alone as a single drug therapy. In certain particular embodiments, the two pharmaceutical agents in the combination may act synergistically or additively, and either agent may be used in a lower amount than if administered alone. The amount of pharmaceutical agent that can be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, for example, between about 0.1 and 1 mg / kg, between about 1 and 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of pharmaceutical agent that can be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimal dosage per day or course of treatment may differ for the disease or disorder to be treated and may also vary with the route of administration and therapeutic regimen.

[0234]

[0183] The pharmaceutical composition containing the pharmaceutical agent can be formulated in a manner suitable for the delivery method by using techniques routinely practiced in the art. The composition can be in the form of a solid, e.g., a tablet, a capsule, a semi-solid, e.g., a gel, a liquid, or a gas, e.g., an aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus injection.

[0235] Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)). Illustrative pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like can be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents can also be used. In general, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient(s). Alternatively, the compositions described herein can be formulated as a lyophilizate. The compositions described herein can be lyophilized or otherwise formulated as lyophilized products using one or more suitable excipient solutions to solubilize and / or dilute the pharmaceutical agent(s) of the composition upon administration.In other embodiments, the pharmaceutical agent can be encapsulated in liposomes using techniques known and practiced in the art.In certain particular embodiments, the pharmaceutical agent is not formulated in liposomes for application to stents used to treat highly, but not entirely, blocked arteries.The pharmaceutical composition can be formulated for any suitable mode of administration described herein and in the art.

[0236] For example, pharmaceutical compositions for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other methods may be in the form of a liquid. Liquid pharmaceutical compositions may, for example, contain one or more of the following: a sterile diluent, such as water, saline solution, preferably saline, Ringer's solution, isotonic sodium chloride, fixed oils that can act as a solvent or suspending medium, polyethylene glycol, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for adjusting tonicity, such as sodium chloride or dextrose. Parenteral compositions may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of saline is preferred, and injectable pharmaceutical compositions are preferably sterile. In another embodiment, for the treatment of ophthalmic conditions or diseases, the liquid pharmaceutical composition may be applied to the eye in the form of eye drops. The liquid pharmaceutical composition may be delivered orally.

[0237] For oral formulation, at least one of the pharmaceutical agents described herein can be used alone or in combination with suitable additives for preparing tablets, powders, granules or capsules, and, if desired, with diluents, buffers, wetting agents, preservatives, colorants and flavoring agents. The pharmaceutical agent can be formulated with a buffer to provide protection of the compound from the stomach environment and / or the low pH of an enteric coating. The pharmaceutical agent included in the pharmaceutical composition can be formulated for oral delivery, for example, with flavoring agents in liquid, solid or semi-solid formulations, and / or with an enteric coating.

[0238]

[0187] A pharmaceutical composition containing any one of the pharmaceutical agents described herein can be formulated for sustained or slow release, also referred to as sustained or controlled release. Such compositions are generally prepared using well-known scientific techniques and can be administered, for example, by oral, rectal, intradermal or subcutaneous implantation, or by implantation at a desired target site. A sustained release formulation can contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-controlling membrane. The excipients for use within such formulations are biocompatible and may be biodegradable; preferably, the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends on the site of implantation, the rate and expected duration of release, and the nature of the condition, disease, or disorder to be treated or prevented.

[0239] In certain embodiments, the pharmaceutical composition containing the pharmaceutical agent is formulated for transdermal, intradermal or topical administration. The composition can be administered as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste, using a syringe, bandage, transdermal patch, insert, or syringe-like applicator. It is preferably in the form of a controlled or sustained release formulation that is administered topically or injected directly into the skin adjacent to or in the area to be treated, for example, intradermally or subcutaneously. The active composition can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microbial organisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0240]

[0189] Pharmaceutical compositions containing pharmaceutical agents can be formulated as emulsions for topical application. Emulsions contain one liquid distributed in the body of a second liquid. Emulsions can be oil-in-water emulsions or water-in-oil emulsions. Either or both of the oil and aqueous phases can contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase can contain other oil-based pharma- ceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application can also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0241] Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickening agents, or colorants. Liquid sprays can be delivered, for example, from pressurized packs via specially shaped closures. Oil-in-water emulsions can also be used in compositions, patches, bandages, and articles. These systems are semisolid emulsion systems, micro-emulsion systems, or foam emulsion systems.

[0242] In some embodiments, the pharmaceutical agents described herein can be formulated in inhalants. Inhalation methods can deliver drug therapy directly to the airways. The pharmaceutical agents can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agents can be formulated with solvents, gases, nitrates, or any combination thereof. The compositions described herein are optionally formulated for delivery as liquid aerosols or inhalable dry powders. Liquid aerosol formulations are optionally primarily nebulized to particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tubules to the terminal bronchioles and ultimately to parenchymal tissues.

[0243]

[0192] The aerosolized formulations described herein are preferably selected and delivered using an aerosol-forming device, such as a jet vibrating porous plate or ultrasonic nebulizer, to allow the formation of aerosol particles having a mass median mean diameter between 1μ and 5μ. Furthermore, the formulations preferably have a balanced osmolality ionic strength and chloride concentration, and the smallest aerosolizable volume capable of delivering an effective dose of the pharmaceutical agent. Additionally, the aerosolized formulations preferably do not negatively impair the functionality of the airways and do not cause undesirable side effects.

[0244] Aerosolization devices suitable for administering the aerosol formulations described herein include jet vibrating porous plate, ultrasonic nebulizers and electric dry powder inhalers, which can nebulize the formulation into aerosol particle sizes primarily in the 1-5μ size range. In this application primarily means that at least 70% but preferably more than 90% of all generated aerosol particles are in the 1-5μ range. Jet nebulizers work by air pressure to break the solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum created by a rapidly vibrating porous plate to push solvent droplets through a porous plate. Ultrasonic nebulizers work by piezoelectric crystals that shear the liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb™ and AeroDose™ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0245] In some embodiments, the pharmaceutical agent(s) can be formulated with an oily base or ointment to form a semi-solid composition having a desired shape. In addition to the pharmaceutical agent, these semi-solid compositions can contain dissolved and / or suspended bactericides, preservatives and / or buffer systems. Petrolatum components that can be included can be any paraffin ranging in viscosity from mineral oils incorporating isobutylene, colloidal silica, or stearate salts to paraffin wax. Absorbent bases can be used with oily systems. Additives can include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and a wide variety of ionic and non-ionic surfactants, alone or in combination.

[0246]

[0195] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives such as polymeric structures, matrices, etc., available in the art. For example, the composition can be administered via the use of hot-melt extrusion articles, such as bioadhesive hot-melt extrusion films. The formulation can include a cross-linked polycarboxylic acid polymer formulation. The cross-linking agent can be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.

[0247] The insert, transdermal patch, bandage or article may contain a mixture or coating of polymers that provide release of the pharmaceutical agent at a constant rate over an extended period of time. In some embodiments, the article, transdermal patch or insert contains a water-soluble pore former such as polyethylene glycol (PEG) that can be mixed with a water-insoluble polymer to increase the durability of the insert and to extend the release of the active ingredient.

[0248]

[0197] Transdermal devices (inserts, patches, bandages) can also contain water-insoluble polymers. Rate-controlling polymers can be useful for administration to sites where pH changes can be used to effect release. These rate-controlling polymers can be applied using a continuous coating film during the process of spraying with the active compound and drying. In one embodiment, the coating formulation is used to coat pellets containing the active ingredient that are compressed to form a solid biodegradable insert.

[0249]

[0198] Polymer formulations can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. As an example, sustained release gels and the compounds can be incorporated into polymeric matrices, such as hydrophobic polymer matrices. Examples of polymeric matrices include microparticles. The microparticles can be microspheres, and the core can be a different material than the polymer shell. Alternatively, the polymer can be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel, such as a hydrogel. The polymer can be in the form of a coating or part of a bandage, a stent, a catheter, a vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrix can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0250]

[0199] Kits are provided having one or more unit doses of the agents described herein, usually in oral or injectable doses. Such kits may include a container containing the unit dose, an information insert describing the use and associated benefits of the drug in treating a disease, and, optionally, an appliance or device for delivery of the composition.

[0251] D. Treatment Method The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of a disease or condition.In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administering to said subject a therapeutically effective amount of at least one compound described herein, or a pharma-ceutically acceptable salt, pharma-ceutically acceptable prodrug, or a pharma-ceutically acceptable solvate thereof, in a pharmaceutical composition.

[0252] The compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatment. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0253] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount will depend, as well, on the patient's health status, weight, and the like. When used in patients, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drug, and the judgment of the treating physician.

[0254]

[0203] In the event that the patient's condition does not improve, at the physician's discretion, administration of the compound can be administered chronically, i.e., for an extended period of time, including for the entire duration of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0255]

[0204] Once improvement of the patient's condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced as a function of symptoms to a level at which the improved disease, disorder, or condition is maintained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0256] The amount of a given agent corresponding to such amounts will vary depending on factors such as the particular compound, the disease or condition and its severity, the identity (e.g., body weight) of the subject or host requiring treatment, and the like, but can nevertheless be determined in an art-recognized manner according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses used for adult human treatment typically range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day. The desired dose can conveniently be presented in a single dose, or as divided doses administered simultaneously (or over a short period of time), or at appropriate intervals, e.g., as two, three, four or more subdoses per day. In some embodiments, the compounds and pharmaceutical compositions described herein are administered once per day. In some embodiments, the compounds and pharmaceutical compositions described herein are administered twice per day. In some embodiments, the compounds and pharmaceutical compositions described herein are administered three times a day. In some embodiments, the compounds and pharmaceutical compositions described herein are administered about once a week. In some embodiments, the compounds and pharmaceutical compositions described herein are administered twice a week. In some embodiments, the compounds and pharmaceutical compositions described herein are administered three to seven times a week. In some embodiments, the compounds and pharmaceutical compositions described herein are administered orally. In some embodiments, the compounds and pharmaceutical compositions described herein are administered intravenously. In some embodiments, the compounds and pharmaceutical compositions described herein are administered topically. For example, the compounds described herein can be administered topically at a dose of 0.001% to 10%.

[0257]

[0206] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers may be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, including but not limited to ampoules, or in multi-dose containers with added preservatives.

[0258]

[0207] The toxicity and therapeutic efficacy of such therapeutic regimens include, but are not limited to, LD 50 (a dose lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 The therapeutic index can be expressed as a ratio between ED and ED. Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds is preferably administered at a dose that is consistent with minimal toxicity and is within the range of ED. 50 The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.

[0259] In one aspect provided herein, the present invention provides an inhibitor of TNIK kinase. Thus, TNIK kinase inhibitors can be used to inhibit downstream biological pathways by inhibiting TNIK. In some aspects, TNIK inhibitors can inhibit fibrillar collagen, thereby inhibiting biological activities related to regulation of extracellular matrix, regulation of extracellular matrix remodeling. TNIK inhibitors can inhibit regulation of cell growth, differentiation, cell migration, proliferation and metabolism.

[0260]

[0209] In certain embodiments, inhibiting TNIK can inhibit certain TNIK-related biological pathways. In certain aspects, inhibiting TNIK inhibits the Wnt pathway.

[0261]

[0210] In certain embodiments, inhibition of TNIK inhibits cytoskeletal rearrangement. Inhibition of TNIK can inhibit c-Jun N-terminal kinase pathway. Inhibition of TNIK can inhibit phosphorylation of gelsolin. Inhibition of TNIK can inhibit regulation of the cytoskeleton, such as cytoskeletal rearrangement.

[0262] In certain embodiments, the inhibition of TNIK inhibits oncogenesis. In certain aspects, the administration of a TNIK inhibitor comprises a therapeutically effective amount of a compound sufficient to treat cancer by: inhibiting cancer cell growth; inhibiting cancer cell migration; inhibiting cancer cell proliferation; or inhibiting cancer cell migration.

[0263] In certain embodiments, the present invention provides a method of treating or preventing a disease, condition, or state in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of the embodiments of the present invention or a pharma- ceutically acceptable salt thereof. The disease, condition, or state may be selected from the group consisting of colorectal cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, chronic myelogenous leukemia, cancer metastasis, fibrosis, and psychiatric disorders. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is chronic myelogenous leukemia. In some embodiments, the cancer is cancer metastasis.

[0264] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is not a solid tumor.

[0214] In certain embodiments, inhibition of TNIK inhibits embryonic development. Thus, TNIK inhibitors can inhibit pregnancy progression and can be used to terminate pregnancy.

[0265] In some embodiments, inhibition of TNIK inhibits TGF beta signaling. The TGF beta signaling pathway is involved in a variety of processes, whereby inhibiting the TGF beta signaling pathway can inhibit these processes, some of which are described herein. This can include inhibiting embryonic development as described herein for inhibiting pregnancy progression. This can include inhibiting cell growth, cell differentiation, as well as inhibiting cancer, which can be used to inhibit pregnancy progression.

[0266] In certain embodiments, inhibiting TGF beta 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 embodiments, inhibiting TGF beta signaling by inhibiting TNIK inhibits glycosaminoglycan formation. In some embodiments, inhibiting TGF beta by inhibiting TNIK inhibits collagen formation. In some embodiments, inhibiting TNIK inhibits fibrosis. In some embodiments, the fibrosis inhibited is selected from pulmonary fibrosis (e.g., idiopathic or radiation-induced), cystic fibrosis, liver fibrosis (e.g., cirrhosis), myocardial fibrosis (e.g., atrial fibrosis, endomyocardial fibrosis, previous myocardial infarction), renal fibrosis, cerebral fibrosis (e.g., glial scar), arterial fibrosis, arthrofibrosis (e.g., knee, shoulder, other joints), intestinal fibrosis (e.g., Crohn's disease), Dupuytren's contracture fibrosis (e.g., hand, fingers), keloid fibrosis (e.g., skin), mediastinal fibrosis (e.g., soft tissue of the mediastinum), myelofibrosis (e.g., bone marrow), Peyronie's disease fibrosis (e.g., penis), progressive massive fibrosis (e.g., lung, complication of coal workers' pneumoconiosis), retroperitoneal fibrosis (e.g., soft tissue of the retroperitoneum), scleroderma fibrosis (e.g., skin, lung), adhesive capsulitis fibrosis (e.g., shoulder), or a combination thereof. In some embodiments, the fibrosis is dermal fibrosis.

[0267] In certain embodiments, TNIK inhibitors can be used to inhibit the epithelial to mesenchymal transition and / or development of fibrosis of cancer cells. In some embodiments, this can include inhibiting Smad signaling pathways. In some embodiments, this can include inhibiting non-Smad signaling pathways. In some embodiments, this can include inhibiting Wnt, NF-KB, FAC-Src-paxillin-associated focal adhesion, and MAP kinase (e.g., ERK and JNK) signaling pathways.

[0268] In certain embodiments, the present disclosure provides a method for treating or preventing a fibrotic disease or condition. In some embodiments, the fibrotic disease or condition is selected from pulmonary fibrosis, cystic fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, cerebral fibrosis, arterial fibrosis, arthrofibrosis, intestinal fibrosis, Dupuytren's contracture fibrosis, keloid fibrosis, mediastinal fibrosis, bone marrow fibrosis, Peyronie's disease fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma fibrosis, adhesive capsulitis fibrosis, or a combination thereof. In some embodiments, the fibrotic disease is selected from liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc), and graft versus host disease (GVHD). In some embodiments, the fibrotic disease is renal fibrosis.

[0269]

[0219] In certain embodiments, the present disclosure provides a method of treating kidney disease. In some embodiments, the kidney disease is chronic kidney fibrosis (CKD). In some embodiments, the kidney disease is kidney fibrosis.

[0270] In some embodiments, the fibrotic disease is liver cirrhosis. In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0271] In some embodiments, the fibrotic disease is renal fibrosis, wherein the disease is chronic or acute. In some embodiments, the renal fibrosis causes glomerulosclerosis or tubulointerstitial fibrosis. In some embodiments, the fibrotic disease is renal interstitial fibrosis. In some embodiments, the fibrotic disease is acute interstitial nephritis (AIN).

[0272] In some embodiments, the fibrotic disease is systemic sclerosis (SSc). In some embodiments, the fibrotic disease is graft versus host disease (GVHD). In some embodiments, the fibrotic disease is hypertrophic scarring (HTS).

[0273]

[0223] In some embodiments, provided herein are methods for suppressing fibrosis markers in a subject, such as alpha smooth muscle actin, or α-SMA, and collagen, by administering the compounds and pharmaceutical compositions disclosed herein.

[0274] In some embodiments, provided herein are methods of antagonizing fibroblast to myofibroblast transition (FMT) in primary human lung fibroblasts. In some embodiments, provided herein are methods of antagonizing epithelial to mesenchymal transition (EMT) in primary human epithelial cells.

[0275]

[0225] In some embodiments, provided herein are methods for reducing collagen and hydroxyproline in the skin by administering the compounds and pharmaceutical compositions of the present disclosure, for example, via oral or topical administration.

[0276]

[0226] In some embodiments, the compounds and pharmaceutical compositions described herein are administered with a second therapeutic agent. In some embodiments, the second therapeutic agent is pirfenidone. In some embodiments, the compounds and pharmaceutical compositions described herein are administered with a sub-therapeutic dose of pirfenidone.

[0277] The compounds and pharmaceutical compositions described herein can be administered to a subject for a period of about 1 day to about 30 years or more. In some embodiments, the compounds and pharmaceutical compositions described herein are administered to a subject for a period of more than 1 year. In some embodiments, the compounds and pharmaceutical compositions described herein are administered to a subject for a period of 3 months to 5 years. In some embodiments, the compounds and pharmaceutical compositions described herein are administered to a subject for a period of 1 month to 1 year or any number or range therebetween (e.g., 2-3 months, 1-6 months, 6-12 months, 1-3 months, etc.).

[0278] E. Further Embodiments

[0228] In one aspect, provided herein is a compound of formula (IIA):

[0279] [ka]

[0280] or a pharma- ceutically acceptable salt thereof, wherein: R 1 is piperazine, where piperazine is an oxo, -S(O2)NH2, and C 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl, where C 1~10 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; R 4 is unsubstituted C1-C6 alkyl.

[0281] In some embodiments, R 4 teeth,

[0282] [ka]

[0283] is selected from. In some embodiments, R 3 teeth,

[0284] [ka]

[0285] is selected from. In some embodiments, R 1 is one or more C 1~3 Alkyl-substituted piperazine, wherein C 1~3 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH2.

[0286] In some embodiments, R 1 teeth,

[0287] [ka]

[0288] is selected from.

[0233] In some embodiments, the compound is:

[0289] [ka]

[0290] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0291] [ka]

[0292] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0293] [ka]

[0294] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0295] [ka]

[0296] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0297] [ka]

[0298] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0299] [ka]

[0300] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0301] [ka]

[0302] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0303] [ka]

[0304] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0305] [ka]

[0306] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0307] [ka]

[0308] or a pharma- ceutically acceptable salt thereof.

[0243] In another aspect, provided herein is a method of treating a fibrotic disease or condition, comprising administering to a subject in need thereof a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0309] In some embodiments, the fibrotic disease or condition is idiopathic pulmonary fibrosis (IPF).

[0245] In some embodiments, the fibrotic disease or condition is dermal fibrosis.

[0310] In another aspect, provided herein is a compound according to (i) formula (IIA):

[0311] [ka]

[0312] or a pharma- ceutically acceptable salt thereof, R 1 is piperazine, where piperazine is an oxo, -S(O2)NH2, and C 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl, where C 1~10 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; R 4 is unsubstituted C1-C6 alkyl; and (ii) a pharma- ceutically acceptable excipient; A pharmaceutical composition comprising:

[0313] In some embodiments, R 1 teeth,

[0314] [ka]

[0315] Selected from; R 3 teeth,

[0316] [ka]

[0317] Selected from; R 4 teeth,

[0318] [ka]

[0319] is selected from.

[0248] In some embodiments, the compound represented by formula (IIA) is:

[0320] [ka]

[0321] or a pharma- ceutically acceptable salt thereof.

[0249] In some embodiments, the compound represented by formula (IIA) is

[0322] [ka]

[0323] or a pharma- ceutically acceptable salt thereof.

[0250] In some embodiments, the compound represented by formula (IIA) is

[0324] [ka]

[0325] or a pharma- ceutically acceptable salt thereof.

[0251] In some embodiments, the compound represented by formula (IIA) is

[0326] [ka]

[0327] or a pharma- ceutically acceptable salt thereof.

[0252] In some embodiments, the compound represented by formula (IIA) is

[0328] [ka]

[0329] or a pharma- ceutically acceptable salt thereof.

[0253] In some embodiments, the compound represented by formula (IIA) is

[0330] [ka]

[0331] or a pharma- ceutically acceptable salt thereof.

[0254] In some embodiments, the compound represented by formula (IIA) is

[0332] [ka]

[0333] or a pharma- ceutically acceptable salt thereof.

[0255] In some embodiments, the compound represented by formula (IIA) is

[0334] [ka]

[0335] or a pharma- ceutically acceptable salt thereof.

[0256] In some embodiments, the compound represented by formula (IIA) is

[0336] [ka]

[0337] or a pharma- ceutically acceptable salt thereof.

[0257] In some embodiments, the compound represented by formula (IIA) is

[0338] [ka]

[0339] or a pharma- ceutically acceptable salt thereof.

[0258] In one aspect, provided herein is a compound of formula (IIA):

[0340] [ka]

[0341] or a pharma- ceutically acceptable salt thereof, wherein: R 1is piperazine, where piperazine is an oxo and C 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl, where C 1~10 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; R 4 is a substituted C1-C6 alkyl, where the C1-C6 alkyl is substituted with one or more halogens.

[0342] In some embodiments, R 4 is substituted with 2 or 3 fluorines. In some embodiments, R 4 teeth,

[0343] [ka]

[0344] is selected from. In some embodiments, R 3 teeth,

[0345] [ka]

[0346] is selected from. In some embodiments, R 1 is one or more C 1~3 Alkyl-substituted piperazine, wherein C 1~3 The alkyl is optionally substituted with one or more halogens.

[0347] In some embodiments, R1 teeth,

[0348] [ka]

[0349] is selected from. In some embodiments, R 1 teeth,

[0350] [ka]

[0351] is selected from.

[0265] In some embodiments, the compound is:

[0352] [ka]

[0353] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0354] [ka]

[0355] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0356] [ka]

[0357] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0358] [ka]

[0359] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0360] [ka]

[0361] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0362] [ka]

[0363] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is

[0364] [ka]

[0365] or a pharma- ceutically acceptable salt thereof.

[0272] In another aspect, provided herein is a method of treating a fibrotic disease or condition, comprising administering to a subject in need thereof a compound provided herein, or a pharma- ceutically acceptable salt thereof.

[0366]

[0273] In some embodiments, the fibrotic disease or condition is renal fibrosis. In some embodiments, the fibrotic disease or condition is associated with TNIK kinase.

[0367] In another aspect, provided herein is a compound according to (i) formula (IIA):

[0368] [ka]

[0369] or a pharma- ceutically acceptable salt thereof, R 1 is piperazine, where piperazine is an oxo and C 1~10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl, where C 1~10 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; R 4 is a substituted C1-C6 alkyl, where C1-C6 alkyl is substituted with one or more halogens; and (ii) a pharma- ceutically acceptable excipient; A pharmaceutical composition comprising:

[0370] In some embodiments, R 1 is one or more C 1~3 Alkyl-substituted piperazine, wherein C 1~3 The alkyl is optionally substituted with one or more halogens.

[0371]

[0277] In some embodiments, R 1 teeth,

[0372] [ka]

[0373] Selected from; R 3 teeth,

[0374] [ka]

[0375] Selected from; R 4 teeth,

[0376] [ka]

[0377] is selected from.

[0278] In some embodiments, the compound represented by formula (IIA) is:

[0378] [ka]

[0379] or a pharma- ceutically acceptable salt thereof.

[0279] In some embodiments, the compound represented by formula (IIA) is

[0380] [ka]

[0381] or a pharma- ceutically acceptable salt thereof.

[0280] In some embodiments, the compound represented by formula (IIA) is

[0382] [ka]

[0383] or a pharma- ceutically acceptable salt thereof.

[0281] In some embodiments, the compound represented by formula (IIA) is

[0384] [ka]

[0385] or a pharma- ceutically acceptable salt thereof.

[0282] In some embodiments, the compound represented by formula (IIA) is

[0386] [ka]

[0387] or a pharma- ceutically acceptable salt thereof.

[0283] In some embodiments, the compound represented by formula (IIA) is

[0388] [ka]

[0389] or a pharma- ceutically acceptable salt thereof.

[0284] In some embodiments, the compound represented by formula (IIA) is

[0390] [ka]

[0391] or a pharma- ceutically acceptable salt thereof.

[0285] In some embodiments, the compound represented by formula (IIA) is

[0392] [ka]

[0393] or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0394]

[0286] The following examples are offered to illustrate, but not to limit, the claimed invention. The following examples further illustrate the present invention but, of course, should not be construed as in any way limiting its scope.

[0395]

[0287] The following synthesis schemes are provided for illustrative purposes, not for limitation. The following examples illustrate various methods of making the compounds described herein. It is understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to those skilled in the art. Moreover, it is understood that those skilled in the art can prepare in a similar manner to those described below by using appropriate starting materials and modifying the synthetic route as necessary. In general, starting materials and reagents can be obtained from commercial sources, or synthesized according to sources known to those skilled in the art, or prepared as described herein. Exemplary Synthesis Schemes

[0288] Formula (A), (A * The compounds and salts of (I), (IIA), or (IIB) can be synthesized according to one or more of the exemplary schemes herein and / or techniques known in the art. The materials used herein are either commercially available or prepared by synthetic methods generally known in the art. The schemes are not limited to the compounds listed in the Examples or by any particular substituents used for illustrative purposes. Although various steps are described and illustrated in the synthetic schemes below, the steps can, in some cases, be performed in a different order than shown below. The numbering or R groups in each scheme do not necessarily correspond to those in the claims or other schemes or tables herein.

[0396]

[0289] In some embodiments, the compounds in Table 1 can be prepared according to the following synthetic schemes. Example 1: Synthesis of Compound 102

[0397] [ka]

[0398] Example 2: General procedure for the preparation of 4-(4-fluorophenyl)-5-iodo-1-isopropyl-1H-imidazole (Compound B)

[0399] [ka]

[0400] To a solution of compound A (35 g, 171.36 mmol, 1 eq.) and NIS (115.66 g, 514.09 mmol, 3 eq.) in DCM (210 mL) was added TFA (5.86 g, 51.41 mmol, 3.81 mL, 0.3 eq.) at 20° C. The mixture was stirred at 20° C. for 16 h. TLC (PE:EA=1:1) showed that reactant 1 (Rf=0.4) was consumed and a new spot (Rf=0.6) was detected. The mixture was poured into aqueous NaNO2 (1000 mL). The mixture was extracted with EA (500 mL×3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=5:1 to 1:1) to give the desired compound. Compound B (14 g, 37.74 mmol, 22.02% yield, 89% purity) was obtained as a yellow solid, which was 1 Determined by HNMR and LCMS. LCMS: Retention time: 0.743 min, (M+H)=331.1. 1HNMR: (400 MHz, DMSO-d6), δ = 8.15 (s, 1H), 7.92 - 7.85 (m, 2H), 7.29 - 7.19 (m, 2H), 4.50 - 4.31 (m, 1H), 1.47 (d, J = 6.8 Hz, 6H).

[0401] Example 3: General procedure for the preparation of 4-(4-fluorophenyl)-1-isopropyl-5-(tributylstannyl)-1H-imidazole (Compound C)

[0402] [ka]

[0403] To a solution of compound B (2 g, 6.06 mmol, 1 equiv) in THF (20 mL) was slowly added n-BuLi (2.5 M, 3.15 mL, 1.3 equiv) and tributyl(chloro)stannane (2.96 g, 9.09 mmol, 2.44 mL, 1.5 equiv) at -70°C. The mixture was stirred at -70°C for 0.5 h. LCMS showed that reactant 1 was consumed and 74% of the desired mass was detected. The mixture was poured into aqueous NH4Cl (100 mL) and aqueous KF (100 mL). The mixture was diluted with EA (100 mL). * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=50:1-3:1) to give the desired compound. Compound C (2 g, 4.05 mmol, 66.93% yield) was obtained as a colorless oil, which was 1 Determined by HNMR. LCMS: Retention time: 0.982 min, (M+H)=492.9. 1H NMR: (400 MHz, DMSO-d6),δ= 8.05 (s, 1H), 7.46 - 7.31 (m, 2H), 7.27 - 7.07 (m, 2H), 4.18 (s, 1H), 1.48 (d, J = 6.8 Hz, 6H), 1.39 - 1.30 (m, 5H), 1.29 - 1.10 (m, 8H), 0.97 - 0.90 (m, 5H), 0.80 (t, J = 7.4 Hz, 9H).

[0404] Example 4: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound I)

[0405] [ka]

[0406] To a solution of NaH (8.56 g, 214.07 mmol, 60% purity, 1.5 equiv) in THF (200 mL) was added a mixture of compound H (20 g, 142.71 mmol, 1 equiv) in THF (100 mL) at 0° C. The mixture was stirred at 0° C. for 20 min, then at 20° C. for 30 min. SEM-Cl (35.69 g, 214.07 mmol, 37.89 mL, 1.5 equiv) was added to the mixture at 0° C. The mixture was stirred at 20° C. for 16 h. TLC (PE:EA=1:1) showed that reactant 1 (Rf=0.1) was consumed and a new spot (Rf=0.2) was observed. The mixture was poured into saturated NH4Cl (200 mL) and then extracted with EA (100 mL×2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA = 5:1 to 1:1). Compound I (15.9 g, 58.80 mmol, 41.20% yield) was obtained as a yellow oil, as determined by HNMR. 1H NMR: (400 MHz, chloroform-d),δ= 7.72 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 1.4 Hz, 1H), 5.30 (s, 2H), 4.37 (q, J = 7.2 Hz, 2H), 3.49 (dd, J = 7.8, 8.7 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H), 0.98 - 0.85 (m, 2H), 0.04 - -0.06 (m, 10H).

[0407] Example 5: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound J)

[0408] [ka]

[0409] To a solution of compound I (14.5 g, 53.62 mmol, 1 equiv.) in CHCl3 (150 mL) was added NBS (9.54 g, 53.62 mmol, 1 equiv.) and AIBN (880.56 mg, 5.36 mmol, 0.1 equiv.) at 20°C. The mixture was stirred at 60°C for 5 h. TLC (PE:EA=1:1) showed that reactant 1 (Rf=0.2) was consumed and a new spot (Rf=0.5) was observed. The mixture was concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (PE:EA=5:1 to 1:1). Compound J (11 g, 31.49 mmol, 58.73% yield) was obtained as a yellow solid, as determined by HNMR. 1 H NMR: (400 MHz, chloroform-d), δ = 7.76 (s, 1H), 5.31 (s, 2H), 4.38 (q, J = 7.2 Hz, 2H), 3.61 - 3.49 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.01 - 0.85 (m, 2H), 0.05 - -0.07 (m, 9H).

[0410] Example 6: General procedure for the preparation of ethyl 5'-(4-fluorophenyl)-3'-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (Compound D)

[0411] [ka]

[0412] To a solution of compound C (300 mg, 608.17 μmol, 1 equiv.) and compound J (318.64 mg, 912.25 μmol, 1.5 equiv.) in toluene (2 mL), [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(1-adamantyl)-butyl-phosphane (120.00 mg, 179.47 μmol, 2.95e-1 equiv.) was added under N2 at 20°C. The mixture was stirred at 110°C for 16 h. LCMS showed that reactant 1 was consumed and 58% of the desired mass was detected. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 * 40mm * The desired compound was obtained by purification using a 15 μm column (15 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 54%-64%, 14 min). Compound D (60 mg, 125.68 μmol, 20.67% yield, 99% purity) was obtained as a brown oil, which was 1 Determined by HNMR and LCMS. Compound D (100 mg, 84.63 μmol, 13.92% yield, 40% purity) was obtained as a brown oil, which was determined by LCMS. LCMS: Retention time: 0.920 min, (M+H)=473.1. LCMS: Retention time: 0.823 min, (M+H)=473.3. LCMS: Retention time: 0.842 min, (M+H)=473.3. 1H NMR: (400 MHz, DMSO-d6),δ= 8.41 (s, 1H), 8.24 (s, 1H), 7.42 - 7.34 (m, 2H), 7.27 - 7.19 (m, 2H), 5.17 - 4.92 (m, 2H), 4.51 - 4.34 (m, 2H), 4.24 - 4.07 (m, 1H), 3.37 - 3.30 (m, 2H), 1.54 - 1.41 (m, 9H), 0.67 (br d, J = 2.6 Hz, 2H), 0.02 - -0.02 (m, 9H).

[0413] Example 7: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylic acid (Compound E)

[0414] [ka]

[0415] To a solution of compound D (50.00 mg, 105.79 μmol, 1 equiv.) in THF (1 mL) and H2O (1 mL) was added LiOH.H2O (8.88 mg, 211.58 μmol, 2 equiv.) at 20° C. The mixture was stirred at 20° C. for 4 h. LCMS showed that reactant 1 was consumed and 93% of the desired mass was detected. To the mixture was added 1N HCl (10 mL). The mixture was diluted with EA (20 mL). * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Compound E (50 mg, crude) was obtained as a colorless oil. LCMS: Retention time: 0.778 min, (M+H)=445.3.

[0416] Example 8: General procedure for the preparation of methyl 3-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)propanoate (Compound F)

[0417] [ka]

[0418] To a solution of compound E (50 mg, 112.47 μmol, 1 equiv) and compound GG (30.23 mg, 168.70 μmol, 1.5 equiv) in DMF (2 mL) was added HATU (64.15 mg, 168.70 μmol, 1.5 equiv) and DIPEA (43.61 mg, 337.40 μmol, 58.77 μL, 3 equiv) at 20° C. The mixture was stirred at 20° C. for 2 h. LCMS showed that reactant 1 was consumed and 82% of the desired mass was detected. The mixture was poured into H2O (20 mL). The mixture was diluted with EA (20 mL). * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Compound F (65 mg, crude) was obtained as a colorless oil. LCMS: Retention time: 0.978 min, (M+H)=606.1.

[0419] Example 9: General procedure for the preparation of methyl 3-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)propanoate (Compound G)

[0420] [ka]

[0421] To a solution of compound F (60 mg, 99.05 μmol, 1 equiv) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 136.36 equiv) at 20° C. The mixture was stirred at 20° C. for 8 h. LCMS showed that reactant 1 was consumed and 80% of the desired mass was detected. The mixture was poured into aqueous NaHCO3 (20 mL). The mixture was diluted with EA (20 mL). * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Compound G (50 mg, crude) was obtained as a colorless oil. LCMS: Retention time: 0.748 min, (M+H)=476.3.

[0422] Example 10: General procedure for the preparation of 3-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)propanoic acid (compound 102)

[0423] [ka]

[0424] To a solution of compound G (40 mg, 84.12 μmol, 1 equiv) in THF (1 mL) and H2O (1 mL) was added LiOH.H2O (35.30 mg, 841.20 μmol, 10 equiv) at 20° C. The mixture was stirred at 20° C. for 2 h. LCMS showed that reactant 1 was consumed and 74% of the desired mass was detected. The mixture was poured into 1N HCl (100 mL). The mixture was diluted with EA (20 mL). * The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 * 50mm *The desired compound was obtained by purification using a 30 mL HPLC-MS column (3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 18%-38%, 10 min). Compound 102 (14.8 mg, 31.59 μmol, 37.55% yield, 98.5% purity) was obtained as a yellow solid, which was purified by HPLC-MS-MS / ... 1 Determined by HNMR, LCMS and HPLC and F NMR. LCMS: Retention time: 0.692 min, (M+H) = 462.3. LCMS: Retention time: 0.673 min, (M+H) = 462.3. HPLC: Retention time: 1.434 min. 1 HNMR: (400 MHz, DMSO-d6),δ= 13.30 - 12.87 (m, 1H), 9.86 (br s, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.72 (br d, J = 7.8 Hz, 2H), 7.43 - 7.35 (m, 2H), 7.25 - 7.07 (m, 5H), 4.30 - 4.18 (m, 1H), 2.79 (t, J = 7.6 Hz, 2H), 2.53 (br s, 2H), 1.40 (d, J = 6.8 Hz, 6H).

[0425] Example 11: Synthesis of Compound 112

[0426] [ka]

[0427] Example 12: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound K)

[0428] [ka]

[0429] To a mixture of compound E (6.5 g, 14.62 mmol, 1 eq.) and compound 3A (4.19 g, 21.93 mmol, 1.5 eq.) in DMF (50 mL) was added HATU (8.34 g, 21.93 mmol, 1.5 eq.) and DIEA (5.67 g, 43.86 mmol, 7.64 mL, 3 eq.). The mixture was stirred at 20° C. for 3 h. LCMS showed that compound E was consumed and the desired mass was detected. The residue was poured into water (500 mL) and extracted with ethyl acetate (150 mL×3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude compound was used in the next step without further purification. Compound K (9 g, crude) was obtained as a brown oil. LCMS: Retention time: 0.753 min, (M+H)=618.4.

[0430] Example 13: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 112)

[0431] [ka]

[0432] To a mixture of compound K (9 g, 14.57 mmol, 1 equiv.) in CH2Cl2 (2 mL) was added TFA (30.80 g, 270.12 mmol, 20.00 mL, 18.54 equiv.). The mixture was stirred at 20 °C for 5 h. LCMS showed that compound K was consumed and the desired mass was detected. The mixture was basified to pH = 8 with saturated NaHCO3 and extracted with ethyl acetate (200 mL x 4). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (0.1% NH3·H2O). Compound 112 (3.04 g, 6.20 mmol, 42.58% yield, 99.492% purity) was obtained as an off-white solid, which was checked by HNMR, LCMS, HPLC. LCMS: Retention time: 0.683 min, (M+H)=488.2. HPLC: Retention time: 1.157 minutes. HPLC: Retention time: 1.155 minutes. HNMR: (400 MHz, DMSO-d6) δ = 13.14 - 12.98 (m, 1H), 9.72 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.67 (d, J = 9.2 Hz, 2H), 7.44 - 7.34 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 4.30 - 4.18 (m, 1H), 3.13 - 3.04 (m, 4H), 2.47 - 2.42 (m, 4H), 2.22 (s, 3H), 1.40 (d, J = 6.4 Hz, 6H).

[0433] Example 14: Synthesis of Compound 113

[0301] Under the same synthetic route as for compound 112, 4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamido)benzoic acid (compound 113) was synthesized as a white solid, which was 1Determined by HNMR, F NMR, LCMS and HPLC. LCMS: Retention time: 0.750 min, (M+H) = 434.2. LCMS: Retention time: 0.760 min, (M+H) = 434.2. HPLC: Retention time: 1.384 min. 1 HNMR: (400 MHz, DMSO-d6),δ= 10.27 (s, 1H), 9.41 (s, 1H), 8.15 (s, 1H), 7.91 - 7.81 (m, 4H), 7.45 - 7.39 (m, 2H), 7.30 -7.21 (m, 2H), 4.46 (br d, J = 6.6 Hz, 1H), 1.40 (d, J = 6.8 Hz, 6H).

[0434] Example 15: Synthesis of Compound 111

[0302] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-N-(4-(2-hydroxyethyl)phenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 111) was synthesized as a white solid, which 1 Determined by HNMR, F NMR, LCMS and HPLC. LCMS: Retention time: 0.745 min, (M+H) = 434.3. LCMS: Retention time: 0.752 min, (M+H) = 434.2. HPLC: Retention time: 1.472 min. 1 HNMR: (400 MHz, DMSO-d6),δ= 13.08 (br s, 1H), 9.84 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.44 - 7.36 (m, 2H), 7.19 - 7.10 (m, 4H), 4.62 (t, J = 5.2 Hz, 1H), 4.29 - 4.18 (m, 1H), 3.64 - 3.53 (m, 2H), 2.73 - 2.67 (m, 2H), 1.40 (d, J = 6.8 Hz, 6H).

[0435] Example 16: Synthesis of Compound 116

[0303] Under the same synthetic route as for compound 112, N-(4-(bis(2-hydroxyethyl)amino)phenyl)-5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 116) was synthesized as a white solid, which 1 Determined by HNMR, F NMR, LCMS and HPLC. LCMS: Retention time: 0.837 min, (M+H) = 493.4. LCMS: Retention time: 0.790 min, (M+H) = 493.1. HPLC: Retention time: 0.993 min. 1 HNMR: (400 MHz, methanol-d4),δ= 9.53 (s, 1H), 8.19 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 9.0 Hz, 2H), 7.56 - 7.40 (m, 2H), 7.36 - 7.20 (m, 2H), 4.90 - 4.80 (m, 1H), 3.84 (br t, J = 5.2 Hz, 4H), 3.66 (br s, 4H), 1.62 (d, J = 6.8 Hz, 6H).

[0436] Example 17: Synthesis of Compound 117

[0304] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 117) was synthesized as a white solid, which 1 Determined by HNMR, F NMR, LCMS and HPLC. LCMS: Retention time: 0.839 min, (M+H) = 518.4. LCMS: Retention time: 0.670 min, (M+H) = 518.3. HPLC: Retention time: 1.484 min. 1HNMR: (400 MHz, methanol-d4),δ= 9.13 (s, 1H), 7.98 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.51 - 7.39 (m, 2H), 7. 21 (t, J = 8.8 Hz, 2H), 7.08 (d, J = 9.2 Hz, 2H), 4.82 - 4.74 (m, 1H), 3.96 (dd, J = 4.6, 5.9 Hz, 2H), 3.91 - 3.58 (m, 4H), 3.43 - 3.33 (m, 4H), 3.29 - 3.03 (m, 2H), 1.58 (d, J = 6.6 Hz, 6H).

[0437] Example 18: Synthesis of Compound 99

[0305] Under the same synthetic route as for compound 112, N-(4-(4-carbamoylpiperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 99) was synthesized as a white solid, which 1 Determined by HNMR, F NMR, LCMS and HPLC. LCMS: Retention time: 1.298 min, (M+H)=474.2. HPLC: Retention time: 0.732 min. 1 H NMR (400MHz, methanol-d4) δ = 8.06 (s, 1H), 7.89 (s, 1H), 7.60 (br d, J=8.6 Hz, 2H), 7.38 (dd, J=5.5, 9.0 Hz, 2H), 7.10 - 6.95 (m, 4H), 4.60 - 4.41 (m, 1H), 3.62 - 3.52 (m, 4H), 3.20 - 3.09 (m, 4H), 1.50 (d, J=6.7 Hz, 6H). 19 F NMR (376MHz, methanol-d4) δ = -116.70 (br s, 1F).

[0438] Example 19: Synthesis of Compound 97

[0306] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-sulfamoylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 97) was synthesized as a white solid, which 1 Determined by HNMR, F NMR, LCMS and HPLC. LCMS: Retention time: 0.956 min, (M+H)=553.3. HPLC: Retention time: 1.854 min. 1 H NMR (400MHz, DMSO-d6) δ = 9.90 - 9.65 (m, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.69 (br d, J=8.2 Hz, 2H), 7.38 (dd, J=5.5, 9.0 Hz, 2H), 7.13 (t, J=9.0 Hz, 2H), 6.94 (br d, J=9.0 Hz, 2H), 6.86 (br s, 2H), 4.30 - 4.16 (m, 1H), 3.19 (br d, J=4.7 Hz, 4H), 3.09 (br d, J=5.1 Hz, 4H), 1.39 (s, 3H), 1.38 (s, 3H). 19 F NMR (376MHz, DMSO-d6) δ = -115.64 (br s, 1F).

[0439] Example 20: Synthesis of Compound 181

[0307] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(piperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 181) was synthesized as a white solid, which 1 Determined by HNMR, F NMR, LCMS and HPLC. LCMS: Retention time: 0.825 min, (M+H)=474.2. HPLC: Retention time: 0.693 min. 1H NMR (400MHz, DMSO-d6) δ = 9.76 (br s, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.67 (br d, J=8.2 Hz, 2H), 7.44 - 7.31 (m, 2H), 7.13 (br t, J=9.0 Hz, 2H), 6.90 (br d, J=8.6 Hz, 2H), 4.30 - 4.14 (m, 1H), 3.09 (br s, 4H), 2.95 (br s, 4H), 1.39 (br d, J=6.7 Hz, 6H). 19 F NMR (376MHz, DMSO-d6) δ = -115.66 (br s, 1F).

[0440] Example 22: Synthesis of Compound 119

[0308] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-3'-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 119) was synthesized as a white solid, which 1 Determined by HNMR, F NMR, LCMS and HPLC. LCMS: Retention time: 0.851 min, (M+H)=460.4. HPLC: Retention time: 0.981 min. 1 H NMR (400MHz, DMSO-d6) δ = 12.97 (br s, 1H), 9.71 (s, 1H), 8.04 - 7.80 (m, 2H), 7.66 (br d, J=8.7 Hz, 2H), 7.55 - 7.30 (m, 2H), 7.14 (br t, J=8.9 Hz, 2H), 6.89 (br d, J=8.9 Hz, 2H), 3.59 (s, 3H), 3.13 - 2.99 (m, 4H), 2.48 - 2.40 (m, 4H), 2.21 (s, 3H). 19 F NMR (377MHz, DMSO-d6) δ= -115.52 (s, 1F).

[0441] Example 23: Synthesis of Compound 135

[0309] Under the same synthetic route as for compound 102, 5'-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3'-neopentyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 135) was synthesized as a white solid, which 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.640 min, (M+H) = 516.3. LCMS: Retention time: 0.715 min, (M+H) = 516.3. HPLC: Retention time: 1.789 min. 1 HNMR: (400 MHz, DMSO-d6),δ= 10.05 (br d, J = 2.2 Hz, 1H), 9.84 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.72 (d, J = 9.0 Hz, 2H), 7.44 (dd, J = 5.4, ​​8.8 Hz, 2H), 7.22 (t, J = 8.8 Hz, 2H), 7.00 (d, J = 9.2 Hz, 2H), 4.07 (s, 2H), 3.79 (br d, J = 12.2 Hz, 2H), 3.53 (br d, J = 11.0 Hz, 2H), 3.17 (br s, 2H), 3.00 - 2.82 (m, 5H), 0.72 (s, 9H).

[0442] Example 24: Synthesis of Compound 130

[0443] [ka]

[0444] Example 25: General procedure for the preparation of ethyl 3'-(difluoromethyl)-5'-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (Compound BB)

[0445] [ka]

[0446] To a solution of compound AA (500 mg, 1.16 mmol, 1 equiv) in ACN (5 mL) was added NaH (46.45 mg, 1.16 mmol, 60% purity, 1 equiv) at 20° C. The mixture was stirred at 20° C. for 1 h. Dibromodifluoromethane (365.49 mg, 1.74 mmol, 161.01 μL, 1.5 equiv) and Zn (9.80 mg, 149.81 μmol, 1.29e-1 equiv) were added to the mixture at −15° C. The mixture was stirred at 20° C. for 16 h. LCMS showed that 42% of compound BB was left and 17% of the desired mass was detected. The mixture was poured into aqueous NH4Cl (10 mL). The mixture was extracted with EA (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=5:1 to 0:1) to give the desired compound, and 200 mg of reactant 1 was recovered. Compound BB (40 mg, 72.42 μmol, 6.24% yield, 87% purity) was obtained as a yellow oil, as determined by LCMS. Ethyl 5'-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (200 mg, 464.53 μmol, 40.00% yield) was recovered. LCMS: Retention time: 0.958 min, (M+H)=481.3. LCMS: Retention time: 0.968 min, (M+H)=481.3.

[0447]

[0311] 3'-(difluoromethyl)-5'-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 130) was synthesized as an oil from BB under the same synthetic route as for compound 112, 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.691 min, (M+H) = 496.3. LCMS: Retention time: 0.768 min, (M+H) = 496.2. HPLC: Retention time: 2.175 min. 1HNMR: (400 MHz, DMSO-d6),δ= 10.44 (br s, 1H), 9.83 (s, 1H), 8.51 (s, 1H), 8.14 - 7.78 (m, 2H), 7.71 (d, J = 9.2 Hz, 2H), 7.55 - 7.41 (m, 2H), 7.22 (t, J = 8.9 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 3.76 (br s, 2H), 3.48 (br s, 2H), 3.19 - 3.11 (m, 2H), 3.02 (br d, J = 11.8 Hz, 2H), 2.83 (d, J = 4.0 Hz, 3H).

[0448] Example 26: Synthesis of Compound 120

[0449] [ka]

[0450] Example 27: General procedure for the preparation of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound M)

[0451] [ka]

[0452] To a solution of compound J (28 g, 80.16 mmol, 1 equiv) in THF (300 mL) was added i-PrMgCl (2 M, 120.24 mL, 3 equiv) at -40 °C. The mixture was stirred at -40 °C for 10 min. To the mixture was added DMF (35.16 g, 480.97 mmol, 37.01 mL, 6 equiv) at -70 °C. The mixture was stirred at 20 °C for 1 h. LCMS showed that the desired mass was detected. The mixture was poured into 1N HCl (500 mL). The mixture was extracted with EA (300 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 3:1). Compound M (15 g, 50.27 mmol, 62.71% yield) was obtained as a yellow oil, which was checked by HNMR. LCMS: Retention time: 0.955 min, (M+H)=299.2. HPLC: Retention time: 2.170 min. 1 HNMR: (400 MHz, chloroform-d) δ = 8.03 - 7.95 (m, 1H), 5.80 (s, 2H), 4.47 - 4.41 (m, 2H), 3.63 - 3.57 (m, 2H), 1.46 - 1.40 (m, 3H), 0.99 - 0.93 (m, 2H), 0.00 (s, 8H).

[0453] Example 28: General procedure for the preparation of ethyl 5'-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (Compound N)

[0454] [ka]

[0455] To a solution of compound M (320 mg, 1.07 mmol, 1 equiv) in THF (12 mL) was added NH3·H2O (582.40 mg, 4.15 mmol, 640.00 μL, 25% purity, 3.87 equiv) at 20° C. The mixture was stirred at 20° C. for 3.5 h. To the mixture was added compound 1A (372.31 mg, 1.29 mmol, 1.2 equiv) and DIEA (415.78 mg, 3.22 mmol, 560.35 μL, 3 equiv) at 20° C. The mixture was stirred at 20° C. for 1.5 h. LCMS showed that compound M was consumed and 31% of the desired mass was detected. The mixture was poured into H2O (20 mL). The mixture was extracted with DCM (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=1:1 to 0:1) to give the desired compound. Compound N (330 mg, 490.54 μmol, 45.74% yield, 64% purity) was obtained as a yellow oil, as determined by LCMS. LCMS: Retention time: 0.803 min, (M+H)=431.3. LCMS: Retention time: 0.804 min, (M+H)=431.3.

[0456] Example 29: General procedure for the preparation of ethyl 5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (Compound O)

[0457] [ka]

[0458] To a solution of ethyl compound N (250 mg, 580.66 μmol, 1 equiv) in DMF (5 mL) was added K2CO3 (240.75 mg, 1.74 mmol, 3 equiv) and compound 2A (404.31 mg, 1.74 mmol, 3 equiv) at 20° C. The mixture was stirred at 20° C. for 16 h. LCMS showed that compound N was consumed and 86% of the desired mass was detected. The mixture was poured into H2O (20 mL). The mixture was extracted with DCM (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE:EA=1:1, product Rf=0.5) to give the desired compound. Compound O (80 mg, 156.08 μmol, 26.88% yield) was obtained as a colorless oil. LCMS: Retention time: 0.976 min, (M+H)=513.3.

[0459] Example 30: General procedure for the preparation of 5'-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 120)

[0460] [ka]

[0461]

[0315] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 120) was synthesized from compound O as a white solid, which was 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.680 min, (M+H) = 528.4. LCMS: Retention time: 0.747 min, (M+H) = 528.2. HPLC: Retention time: 1.849 min. 1HNMR: (400 MHz, DMSO-d6),δ= 9.83 (s, 2H), 8.09 (s, 1H), 7.95 (s, 1H), 7.71 (d, J = 9.0 Hz, 2H), 7.52 - 7.42 (m, 2H), 7.25 -7.14 (m, 2H), 7.00 (d, J = 9.2 Hz, 2H), 5.24 (br d, J = 9.2 Hz, 2H), 3.80 (br d, J = 12.7 Hz, 2H), 3.54 (br s, 2H), 3.20 - 3.11 (m, 2H), 2.93 (br t, J = 12.2 Hz, 2H), 2.87 (br s, 3H).

[0462] Example 31: Synthesis of Compound 167

[0463] [ka]

[0464] Example 32: General procedure for the preparation of 5'-(4-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 167) To a solution of 2-[5-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)imidazol-4-yl]-N-[4-(4-methylpiperazin-1-yl)phenyl]-1H-imidazole-4-carboxamide (50 mg, 77.94 μmol, 1 eq, TFA salt) in DCE (1 mL) was added 1-chloroethyl chloroformate (55.71 mg, 389.69 μmol, 5 eq) and TEA (31.55 mg, 311.75 μmol, 43.39 μL, 4 eq) and the mixture was stirred at 40° C. for 4 h. LCMS showed that reactant 1 was consumed and a main peak was detected, then MeOH (1.5 mL) was added to the reaction mixture and the mixture was stirred at 60° C. for 1 h. LCMS showed that 66% of the desired mass was detected. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 12%-42%, 8 min). Compound 167 (2.99 mg, 5.24 μmol, 6.72% yield, 90% purity) was obtained as an off-white solid. LCMS, HPLC, HNMR and FNMR confirmed the structure. LCMS: Retention time: 0.742 min, (M+H + )=310.5. LCMS: Retention time: 0.913 min, (M+H + )=514.4. LCMS: Retention time: 0.720 min, (M+H + )=514.1. HPLC: Retention time: 1.582 minutes. 1 H NMR: (400 MHz, methanol-d4) δ = 8.07 (s, 1H), 7.85 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.50 - 7.37 (m, 2H), 7.15 - 6.99 (m, 4H), 5.20 (q, J=8.8 Hz, 2H), 3.36 - 3.32 (m, 4H), 3.30 - 3.25 (m, 4H). 19 F NMR: (377 MHz, methanol-d4) δ = -73.58 (s, 1F).

[0465] Example 33: Synthesis of Compound 166

[0466] [ka]

[0467] Example 34: General procedure for the preparation of 4-(4-(5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)-1-methylpiperazine 1-oxide (compound 166) To a solution of 2-[5-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)imidazol-4-yl]-N-[4-(4-methylpiperazin-1-yl)phenyl]-1H-imidazole-4-carboxamide (45 mg, 70.14 μmol, 1 eq., TFA salt) in DCM (0.3 mL) was added m-CPBA (14.24 mg, 70.14 μmol, 85% purity, 1 eq.) and pyridine (16.65 mg, 210.43 μmol, 16.98 μL, 3 eq.) at 0° C. and the mixture was stirred at 25° C. for 0.5 h. LCMS showed that 23% of the desired mass was left and 35% of the desired mass was detected. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10%-40%, 8 min). Compound 166 (3.81 mg, 6.31 μmol, 8.99% yield, 89.98% purity) was obtained as a white solid. LCMS, HPLC, HNMR, and FNMR confirmed the structure. LCMS: Retention time: 0.632 min, (M+H + )=544.2. LCMS: Retention time: 0.777 min, (M+H + )=544.3. HPLC: Retention time: 1.447 minutes. 1HNMR: (400 MHz, methanol-d4) δ = 8.06 (s, 1H), 7.84 (s, 1H), 7.64 (d, J=9.0 Hz, 2H), 7.49 - 7.39 (m, 2H), 7.16 - 7.00 (m, 4H), 5.19 (q, J=8.8 Hz, 2H), 3.71 - 3.58 (m, 2H), 3.57 - 3.44 (m, 4H), 3.30 - 3.28 (m, 2H), 3.27 (s, 3H). 19 F NMR: (377 MHz, methanol-d4) δ = -73.57 (s, 1F).

[0468] Example 35: Synthesis of Compound 121

[0469] [ka]

[0470] Example 36: General procedure for the preparation of methyl 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxylate (Compound FF)

[0471] [ka]

[0472] To a solution of compound C (100 mg, 202.72 μmol, 1 equiv.) and compound EE (83.12 mg, 405.44 μmol, 2 equiv.) in toluene (2 mL) was added methylchloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (20 mg, 60.91 μmol, 0.3 equiv.) under N2 at 20° C. The mixture was stirred at 110° C. for 16 h. TLC showed that compound GG was consumed and a new spot was detected. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (PE:EA=1:1) to give the desired compound. Compound FF (65 mg, 181.54 μmol, 89.55% yield, 91.7% purity) was obtained as a colorless oil, as determined by LCMS. LCMS: Retention time: 0.715 min, (M+H)=329.2.

[0473] Example 37: General procedure for the preparation of 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)furan-2-carboxamide (121)

[0474] [ka]

[0475] Compound 125 was synthesized as an oil from compound FF under the same synthetic route as for compound 112, which was 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.653 min, (M+H) = 488.3. LCMS: Retention time: 0.718 min, (M+H) = 488.3. HPLC: Retention time: 1.784 min. 1H NMR: (400 MHz, DMSO-d6),δ= 10.14 (s, 1H), 9.98 - 9.63 (m, 1H), 8.37 (br s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.54 - 7.46 (m, 3H), 7.19 (t, J = 8.8 Hz, 2H), 7.04 - 6.97 (m, 3H), 4.27 (br d, J = 6.4 Hz, 1H), 3.79 (br s, 2H), 3.53 (br d, J = 11.4 Hz, 2H), 3.17 (br d, J = 8.2 Hz, 2H), 2.93 (br s, 2H), 2.87 (s, 3H), 1.45 (d, J = 6.8 Hz, 6H).

[0476] Example 38: Synthesis of Compound 102

[0477] [ka]

[0478] Example 39: Synthesis of Compound 132

[0320] Under the same synthetic route as for compound 102, 5-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)pentanoic acid (compound 132) was synthesized as a white solid, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.747 min, [M+H + ]=490.4. LCMS: Retention time: 0.801 min, [M+H + ]=490.4. HPLC: Retention time: 1.705 minutes. 1H NMR: (400 MHz, DMSO-d6), δ = 9.85 (br s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.43 - 7.34 (m, 2H),7.17 - 7.08 (m, 4H), 4.29 - 4.18 (m, 1H), 2.58 - 2.52 (m, 2H), 2.19 (t, J = 7.0 Hz, 2H), 1.61 - 1.46 (m, 4H), 1.39 (d, J = 6.7 Hz, 6H).

[0479] Example 40: Synthesis of Compound 126

[0321] Under the same synthetic route as for compound 121, 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(4-(2-hydroxyethyl)phenyl)furan-2-carboxamide (compound 126) was synthesized as a white solid, which was determined by HNMR, FNMR, LCMS and HPLC. LCMS: Retention time: 0.794 min, [M+H + ]=434. LCMS: Retention time: 0.805 min, [M+H + ]=434.1. HPLC: Retention time: 1.506 minutes. HPLC: Retention time: 1.494 minutes. 1 H NMR (400 MHz, DMSO-d6) δ = 10.19 (s, 1H), 8.66 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.56 - 7.47 (m, 3H), 7.28 - 7.14 (m, 4H), 7.01 (d, J = 3.6 Hz, 1H), 4.33 (td, J = 6.8, 13.2 Hz, 1H), 3.58 (s, 2H), 2.69 (t, J = 7.0 Hz, 2H), 1.46 (d, J = 6.8 Hz, 6H). 19 F NMR (400 MHz, DMSO-d6) δ = 74.404.

[0480] Example 41: Synthesis of Compound 162

[0322] Under the same synthetic route as for compound 121, 6-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)picolinamide (compound 162) was synthesized as a yellow solid, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.913 min, [M+H + ]=529.5. LCMS: Retention time: 0.923 min, [M+H + ]=529.5. HPLC: Retention time: 1.992 minutes. 1 H NMR: (400 MHz, DMSO-d6), δ = 10.23 (s, 1H), 8.18 - 8.03 (m, 3H), 7.69 (d, J = 9.0 Hz, 2H), 7.54 (dd, J = 1.0, 7.8 Hz, 1H),7.41 - 7.34 (m, 2H), 7.10 (t, J = 8.8 Hz, 2H), 6.94 (d, J = 9.2 Hz, 2H), 4.58 - 4.39 (m, 2H), 3.54 (q, J = 6.0 Hz, 2H), 3.10 (br d, J= 4.8 Hz, 4H), 2.57 (br s, 4H), 2.46 - 2.41 (m, 2H), 1.44 (d, J = 6.8 Hz, 6H).

[0481] Example 42: Synthesis of Compound 133 Under the same synthetic route as for compound 102, 3-(4-(3'-isopropyl-5'-(4-(trifluoromethyl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)propanoic acid (compound 133) was synthesized as a white solid, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.752 min, (M+H)=512.2. LCMS: Retention time: 0.834 min, (M+H)=512.2, 5-95AB_R_220&254.1cm HPLC: Retention time: 2.301 minutes. 1H NMR: (400 MHz, DMSO-d6),δ= 9.91 (s, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.79 - 7.66 (m, 4H), 7.56 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 4.38 (br d, J = 6.6 Hz, 1H), 2.79 (t, J = 7.6 Hz, 2H), 2.53 (br s, 2H), 1.43 (d, J = 6.8 Hz, 6H).

[0482] Example 43: Synthesis of Compound 137 Under the same synthetic route as for compound 102, 3-(4-(5'-(4-chlorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)propanoic acid (compound 137) was synthesized as a white solid, which was determined by HNMR, LCMS and HPLC. LCMS: retention time: 0.790 min, (M+H)=478.3. LCMS: retention time: 0.788 min, (M+H)=478.3. HPLC: retention time: 1.644 min. 1 H NMR: (400 MHz, DMSO-d6) δ = 9.89 (s, 1H), 8.52 (br s, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.45 - 7.40 (m, 2H), 7.39 - 7.34 (m, 2H), 7.17 (d, J = 8.4 Hz, 2H), 4.42 - 4.31 (m, 1H), 2.78 (t, J = 7.6 Hz, 2H), 2.54 - 2.52 (m, 2H), 1.42 (d, J = 6.8 Hz, 6H).

[0483] Example 44: Synthesis of Compound 134 Under the same synthetic route as for compound 102, 3-(4-(5'-(4-chlorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)propanoic acid (compound 134) was synthesized as a yellow oil, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.671 min, (M+H)=568.3, 5-95AB_R_220&254.1cm. LCMS: Retention time: 0.755 min, (M+H)=568.2. HPLC: Retention time: 1.869 min. 1 H NMR: (400 MHz, DMSO-d6),δ= 9.86 (s, 1H), 9.71 (br s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.71 (t, J = 8.2 Hz, 4H), 7.56 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 4.38 - 4.31 (m, 1H), 3.83 - 3.71 (m, 4H), 3.60 (br d, J = 11.2 Hz, 2H), 3.30 - 3.14 (m, 4H), 3.10 - 2.94 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H).

[0484] Example 45: Synthesis of Compound 139

[0326] Under the same synthetic route as for compound 137, 5'-(4-chlorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 139) was synthesized as a brown solid, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.850 min, (M+H) = 534.4. LCMS: Retention time: 0.713 min, (M+H) = 534.4. HPLC: Retention time: 1.265 min. 1H NMR: (400 MHz, DMSO-d6) δ = 9.84 (s, 1H), 9.67 (br d, J = 3.6 Hz, 1H), 8.43 (s, 1H), 8.03 (s, 1H), 7.70 (d, J = 9.2 Hz, 2H), 7.48 - 7.29 (m, 4H), 6.98 (d, J = 9.2 Hz, 2H), 4.37 - 4.27 (m, 1H), 3.80 - 3.75 (m, 4H), 3.32 - 3.14 (m, 6H), 3.07 - 2.97 (m, 2H), 1.41 (d, J = 6.8Hz, 6H).

[0485] Example 46: Synthesis of Compound 146

[0327] Under the same synthetic route as for compound 102, 5'-(3,4-difluorophenyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 146) was synthesized as a yellow solid, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.717 min, [M+H + ]=536.2. LCMS: Retention time: 0.627 min, [M+H + ]=536.3. HPLC: Retention time: 1.252 minutes. 1 H NMR: (400 MHz, DMSO-d6), δ = 9.85 (s, 1H), 9.65 (br s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.71 (d, J = 9.2 Hz, 2H), 7.45 - 7.32(m, 2H), 7.10 (ddd, J = 1.8, 4.2, 8.4 Hz, 1H), 6.98 (d, J = 9.2 Hz, 2H), 4.32 - 4.21 (m, 1H), 3.77 (br d, J = 5.0 Hz, 4H), 3.57 (brs, 2H), 3.29 - 3.16 (m, 4H), 3.07 - 2.96 (m, 2H), 1.40 (d, J = 6.8 Hz, 6H).

[0486] Example 47: Synthesis of Compound 158

[0328] Under the same synthetic route as for compound 120, 5'-(4-fluorophenyl)-3'-((1r,4r)-4-hydroxycyclohexyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 158) was synthesized as a white solid, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.683 min, (M+H)=574.3. HPLC: Retention time: 1.600 min. 1 H NMR: (400 MHz, DMSO-d6),δ= 9.85 (s, 2H), 8.76 (s, 1H), 8.06 (s, 1H), 7.71 (d, J = 9.0 Hz, 2H), 7.49 - 7.36 (m, 2H), 7.24 (t, J = 8.9 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 4.03 - 3.95 (m, 1H), 3.82 - 3.72 (m, 4H), 3.60 (br d, J = 9.9 Hz, 2H), 3.49 - 3.44 (m, 1H), 3.31 - 3.17 (m, 4H), 3.05 (br d, J = 11.0 Hz, 2H), 2.04 - 1.78 (m, 6H), 1.30 - 1.13 (m, 2H).

[0487] Example 48: Synthesis of Compound 156

[0329] Under the same synthetic route as for compound 102, 5'-(3,4-difluorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 156) was synthesized as a white solid, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.886 min, (M+H) = 506.4. LCMS: Retention time: 0.890 min, (M+H) = 506.4. LCMS: Retention time: 0.713 min, (M+H) = 506.2. HPLC: Retention time: 1.254 min. 1H NMR: (400 MHz, DMSO- d6) δ= 9.73 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.66 (br d, J = 8.8 Hz, 2H), 7.42 - 7.31 (m, 2H),7.08 (br d, J = 1.6 Hz, 1H), 6.90 (br d, J = 8.8 Hz, 2H), 4.30 - 4.16 (m, 1H), 3.09 (br d, J = 4.4 Hz, 4H), 2.52 (br s, 2H), 2.24 (s,3H), 2.07 (s, 2H), 1.39 (d, J = 6.8 Hz, 6H).

[0488] Example 49: Synthesis of Compound 159

[0330] Under the same synthetic route as for 158, 5'-(4-fluorophenyl)-3'-((1r,4r)-4-hydroxycyclohexyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 159) was synthesized as a yellow solid, which was determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.613 min, (M+H) = 544.2. LCMS: Retention time: 0.690 min, (M+H) = 544.3. HPLC: Retention time: 1.614 min. 1H NMR: (400 MHz, DMSO-d6) δ = 9.81 (br s, 2H), 8.48 - 8.20 (m, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.72 (br d, J = 8.8 Hz, 2H), 7.44 - 7.35 (m, 2H), 7.20 - 7.10 (m, 2H), 6.99 (br d, J = 9.2 Hz, 2H), 3.79 (br d, J = 13.2 Hz, 6H), 3.19 - 3.13 (m, 2H), 2.97 - 2.84 (m, 6H), 1.99 - 1.82 (m, 6H), 1.17 (br d, J = 12.4 Hz, 2H). HNMR: (400 MHz, DMSO-d6+D2O) δ = 8.75 - 8.49 (m, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.67 (br d, J = 7.2 Hz, 2H), 7.47 - 7.32 (m, 2H), 7.28 - 7.09 (m, 2H), 6.99 (d, J = 9.2 Hz, 2H), 3.99 - 3.91 (m, 1H), 3.77 (br d, J = 12.4 Hz, 2H), 3.55 - 3.44 (m, 3H), 3.16 (br t, J = 10.8 Hz, 2H), 3.00 - 2.84 (m, 5H), 2.06 - 1.77 (m, 6H), 1.27 - 1.13 (m, 2H).

[0489] Example 50: Synthesis of Compound 142

[0331] Under the same synthetic route as for compound 102, 3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-5'-(4-(trifluoromethyl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 142) was synthesized as a white solid, which was determined by HNMR, LCMS and HPLC. LCMS: retention time: 0.678 min, (M+H) = 538.3. LCMS: retention time: 0.663 min, (M+H) = 538.3. HPLC: retention time: 1.889 min. 1H NMR: (400 MHz, DMSO-d6),δ= 9.85 (s, 2H), 8.27 (s, 1H), 8.04 (s, 1H), 7.71 (dd, J = 8.8, 12.9 Hz, 4H), 7.56 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.30 (br s, 1H), 3.79 (br d, J = 13.2 Hz, 2H), 3.53 (br d, J = 12.2 Hz, 2H), 3.17 (br d, J = 10.4 Hz, 2H), 3.09 - 2.78 (m, 5H), 1.42 (d, J = 6.8 Hz, 6H) Example 51: Synthesis of Compound 150

[0332] Under the same synthetic route as for compound 120, 5'-(4-chlorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[4,4'-biimidazole]-2-carboxamide (compound 150) was synthesized as a white solid, which 1 Determined by H NMR, LCMS and HPLC. LCMS: Retention time: 0.714 min, [M+H + ]=504.3. HPLC: Retention time: 1.992 minutes. 1 H NMR: (400 MHz, DMSO-d6), δ = 9.67 (br s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.64 (br d, J = 8.8 Hz, 2H), 7.44 - 7.30 (m, 4H), 6.89 (d, J = 9.1 Hz, 2H), 4.31 - 4.21 (m, 1H), 3.11 - 3.04 (m, 4H), 2.46 - 2.42 (m, 4H), 2.21 (s, 3H), 1.38 (d, J = 6.8 Hz, 6H).

[0490] Example 52: Synthesis of Compound 153

[0333] Under the same synthetic route as for compound 166, 4-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamido)phenyl)-1-methylpiperazine 1-oxide (compound 153) was synthesized as a white solid, which was 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.782 min, (M+H) = 504.5. LCMS: Retention time: 0.615 min, (M+H) = 504.2. HPLC: Retention time: 1.225 min. 1 H NMR: 1H NMR (400 MHz, DMSO-d6) δ = 9.85 - 9.61 (m, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.69 (br d, J = 7.6 Hz, 2H), 7.41 (dd, J = 6.0, 8.4 Hz, 2H), 7.18 - 7.08 (m, 2H), 6.95 (d, J = 9.2 Hz, 2H), 4.24 (td, J = 6.8, 13.2 Hz, 1H), 3.56 - 3.39 (m, 6H), 3.10 (s, 3H), 2.98 (br d, J = 10.4 Hz, 2H), 1.40 (d, J = 6.8 Hz, 6H).

[0491] Example 53: Synthesis of Compound 205

[0334] Under the same synthetic route as for compound 120, 3',5'-diisopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 205) was synthesized as a white solid, which 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.853 min, [M+H + ]=436.5. LCMS: Retention time: 0.850 min, [M+H + ]=436.5. LCMS: Retention time: 0.863 min, [M+H + ]=436.4. HPLC: Retention time: 1.605 minutes. 1H NMR: (400 MHz, DMSO-d6), δ = 13.02 - 12.24 (m, 1H), 9.59 (br s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.63 (br d, J = 8.7 Hz, 2H), 6.89 (br d, J = 9.0 Hz, 2H), 4.48 - 4.37 (m, 1H), 3.13 - 3.05 (m, 4H), 2.92 - 2.83 (m, 1H), 2.47 - 2.41 (m, 4H), 2.21 (s, 3H), 1.33 (d, J = 6.7 Hz, 6H), 1.11 (d, J = 6.8 Hz, 6H).

[0492] Example 54: Synthesis of Compound 196

[0335] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(3,4,5-trimethylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 196) was synthesized as a white solid, which 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.965 min, [M+H + ]=516.4. LCMS: Retention time: 0.711 min, [M+H + ]=516.4. HPLC: Retention time: 1.075 min, 10~80AB_4 min.lcm, EW25973-78-P1A6. 1H NMR: (400 MHz, DMSO-d6) δ = 13.28 - 12.82 (m, 1H), 9.69 (br s, 1H), 8.05 (s, 1H), 7.97 (s, 1H), 7.66 (br d, J = 8.0 Hz, 2H), 7.39 (dd, J = 5.6, 8.7 Hz, 2H), 7.13 (t, J = 8.9 Hz, 2H), 6.89 (br d, J = 8.9 Hz, 2H), 4.38 - 4.17 (m, 1H), 3.50 (br d, J = 10.9 Hz, 2H), 2.39 - 2.31 (m, 2H), 2.29 - 2.14 (m, 5H), 1.39 (d, J = 6.7 Hz, 6H), 1.07 (d, J = 5.9 Hz, 6H).

[0493] Example 55: Synthesis of Compound 185

[0336] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methyl-3-oxopiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 185) was synthesized as a white solid, which was determined by 1H NMR, LCMS and HPLC. LCMS: Retention time: 0.846 min, (M+H) = 502.5. LCMS: Retention time: 0.763 min, (M+H) = 502.2. HPLC: Retention time: 1.499 min. 1 H NMR: (400 MHz, DMSO-d6) δ = 13.18 - 12.93 (m, 1H), 9.76 (s, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.71 (d, J = 9.2 Hz, 2H), 7.44 - 7.33 (m, 2H), 7.20 - 7.07 (m, 2H), 7.00 - 6.85 (m, 2H), 4.29 - 4.18 (m, 1H), 3.71 (s, 2H), 3.46 - 3.40 (m, 4H), 2.90 (s, 3H), 1.40 (d, J = 6.8Hz, 6H).

[0494] Example 56: Synthesis of Compound 188

[0337] Under the same synthetic route as for compound 112, N-(4-(4-acetylpiperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 188) was synthesized as a white solid, which 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.851 min, [M+H + ]=516.5. LCMS: Retention time: 0.756 min, [M+H + ]=516.1. HPLC: Retention time: 1.475 minutes. 1 H NMR: (400 MHz, DMSO-d6), δ = 13.03 (br s, 1H), 9.74 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.69 (br d, J = 8.8 Hz, 2H), 7.42 -7.33 (m, 2H), 7.13 (t, J = 8.9 Hz, 2H), 6.93 (br d, J = 8.8 Hz, 2H), 4.29 - 4.17 (m, 1H), 3.57 (br d, J = 3.7 Hz, 4H), 3.14 - 3.08(m, 2H), 3.06 - 3.00 (m, 2H), 2.04 (s, 3H), 1.39 (d, J = 6.7 Hz, 6H).

[0495] Example 57: Synthesis of Compound 189

[0338] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 189) was synthesized as a white solid, which was determined by 1H NMR, LCMS and HPLC. LCMS: Retention time: 0.726 min, (M+H) = 556.3. LCMS: Retention time: 0.805 min, (M+H) = 556.3. HPLC: Retention time: 1.635 min. HNMR: (400 MHz, DMSO-d6),δ= 9.84 (s, 1H), 8.88 (br s, 1H), 8.07 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.51 - 7.38 (m, 2H), 7.32 - 7.21 (m, 2H), 6.99 (br d, J = 8.8 Hz, 2H), 4.45 (s, 1H), 3.30 (d, J = 10.2 Hz, 2H), 3.22 - 3.12 (m, 4H), 2.89 - 2.76 (m, 4H), 1.45 (d, J = 6.8 Hz, 6H).

[0496] Example 58: Synthesis of Compound 186

[0339] Under the same synthetic route as for compound 112, 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 186) was synthesized as a white solid, which 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.635 min, (M+H) = 514.3. LCMS: Retention time: 0.712 min, (M+H) = 514.3. HPLC: Retention time: 1.285 min. 1HNMR: (400 MHz, DMSO-d6),δ= 8.77 (s, 1H), 8.03 (s, 1H), 7.65 (br d, J = 9.0 Hz, 2H), 7.48 - 7.35 (m, 2H), 7.23 (t, J = 8.8 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 4.40 (s, 1H), 4.04 (br s, 2H), 3.78 - 3.70 (m, 2H), 3.06 (br d, J = 12.0 Hz, 2H), 2.77 (s, 3H), 2.26 - 2.15 (m, 2H), 2.00 (br d, J = 8.2 Hz, 2H), 1.43 (d, J = 6.8 Hz, 6H).

[0497] Example 59: Synthesis of Compound 190

[0340] Under the same synthetic route as for compound 120, 5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-N-(4-(3,4,5-trimethylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 190) was synthesized as a white solid, which 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.937 min, (M+H)=556.5. HPLC: Retention time: 1.519 min. 1 H NMR: (400 MHz, chloroform-d) δ = 8.75 (s, 1H), 7.74 (br d, J = 14.3 Hz, 2H), 7.60 (br d, J = 8.4 Hz, 2H), 7.52 - 7.47 (m, 2H), 7.12 (br t, J = 7.5 Hz, 2H), 6.96 (br d, J = 8.7 Hz, 2H), 5.14 - 5.07 (m, 2H), 3.47 (br d, J = 11.2 Hz, 2H), 2.61 (br t, J = 11.0 Hz, 2H), 2.44 (br s, 2H), 2.36 (s, 3H), 1.21 (d, J = 6.1Hz, 6H).

[0498] Example 60: Synthesis of Compound 194

[0341] Under the same synthetic route as for compound 120, 5'-(4-fluorophenyl)-N-(4-(4-methyl-3-oxopiperazin-1-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 194) was synthesized as a white solid, which 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 0.832 min, (M+H)=542.4. HPLC: Retention time: 1.704 min. 1 H NMR: (400 MHz, chloroform-d) δ = 8.78 (s, 1H), 7.76 (d, J = 12.5 Hz, 2H), 7.65 (d, J = 9.0 Hz, 2H), 7.53 - 7.49 (m, 2H), 7.13 (t, J = 8.7 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 5.12 (q, J = 8.4 Hz, 2H), 3.87 (s, 2H), 3.50 (s, 4H), 3.06 (s, 3H).

[0499] Example 61: Synthesis of Compound 191

[0342] Under the same synthetic route as for compound 120, N-(4-(4-acetylpiperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 191) was synthesized as a white solid, which was determined by 1H NMR, LCMS and HPLC. LCMS: Retention time: 0.847 min, (M+H)=556.5. HPLC: Retention time: 1.706 min. 1H NMR: (400 MHz, chloroform-d) δ = 9.67 (br s, 1H), 8.79 (s, 1H), 7.77 - 7.71 (m, 2H), 7.63 (d, J = 8.9 Hz, 2H), 7.52 - 7.47 (m, 2H), 7.12 (t, J = 8.6 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 5.10 (q, J = 8.5 Hz, 2H), 3.81 - 3.76 (m, 2H), 3.67 - 3.63 (m, 2H), 3.21 - 3.17 (m, 2H), 3.17 - 3.13 (m, 2H), 2.15 (s, 3H).

[0500] Example 62: Synthesis of Compound 192

[0343] Under the same synthetic route as for compound 120, 5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-N-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 192) was synthesized as a white solid, which was determined by 1H NMR, LCMS and HPLC. LCMS: Retention time: 0.943 min, (M+H)=596.5. HPLC: Retention time: 1.965 min. 1 H NMR: (400 MHz, chloroform-d) δ = 9.78 (br d, J = 0.7 Hz, 1H), 8.76 (s, 1H), 7.70 (d, J = 14.1 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.47 (dd, J = 5.6, 8.2 Hz, 2H), 7.10 (t, J = 8.6 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 5.08 (q, J = 8.4 Hz, 2H), 3.24 - 3.20 (m, 4H), 3.07 (q, J = 9.6 Hz, 2H), 2.89 - 2.86 (m, 4H).

[0501] Example 63: Synthesis of Compound 193

[0344] Under the same synthetic route as for compound 120, 5'-(4-fluorophenyl)-N-(4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 193) was synthesized as a white solid, which 1 Determined by HNMR, LCMS and HPLC. LCMS: Retention time: 1.036 min, (M+H)=554.5. HPLC: Retention time: 1.544 min, 10-80AB_4 min.lcm. 1 H NMR: (400 MHz, chloroform-d) δ = 8.73 (br s, 1H), 7.71 (br d, J = 14.4 Hz, 2H), 7.55 (br d, J = 8.6 Hz, 2H), 7.48 (br dd, J = 5.9, 7.4 Hz, 2H), 7.09 (br t, J = 8.3 Hz, 2H), 6.81 (br d, J = 8.8 Hz, 2H), 5.05 (br d, J = 7.7 Hz, 2H), 4.76 (s, 1H), 3.35 (br d, J = 9.7 Hz, 2H), 3.26 (br s, 2H), 3.00 (br d, J = 10.5 Hz, 2H), 2.34 (s, 3H), 2.07 - 2.02 (m, 2H), 1.81 (br d, J = 7.6 Hz, 2H).

[0502] Certain compounds in Table 1 can be prepared using the alternative reagents in the above examples. Illustrative compounds include, but are not limited to, compounds selected from Table 1, or salts thereof, that can be prepared using the above examples and accompanying procedures described herein.

[0503] [Table 1-1]

[0504] [Table 1-2]

[0505] [Table 1-3]

[0506] [Table 1-4]

[0507] [Table 1-5]

[0508] [Table 1-6]

[0509] [Table 1-7]

[0510] [Table 1-8]

[0511] Example 64: Metabolic stability in human and mouse liver microsomes

[0512] [Table 2]

[0513] 2.1. Test Compound and Control Working Solution Preparation: Working solutions: 5 μL of compound and control stock solutions (10 mM in dimethylsulfoxide (DMSO)) were diluted with 495 μL of acetonitrile (ACN) (intermediate solution concentration: 100 μM, 99% ACN).

[0514] 2.2.NADPH cofactor preparation

[0348] 2.2.1. Materials: NADPH Powder: β-Nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt; NADPH·4Na (Supplier: Chem-Impex International, Cat No. 00616).

[0515] 2.2.2. Preparation procedure: An appropriate amount of NADPH powder was weighed and diluted in 10 mM MgCl2 solution (working solution concentration: 10 units / mL; final concentration in reaction: 1 unit / mL).

[0516] 2.3. Liver Microsome Preparation:

[0351] 2.3.1.Materials:

[0517] [Table 3]

[0518] 2.3.2. Preparation Procedure: Microsome working solutions of appropriate concentrations were prepared in 100 mM potassium phosphate buffer.

[0353] 2.4. Stop solution preparation: Cold (4°C) acetonitrile (ACN) containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS) was used as the stop solution.

[0519] 2.5. Assay Procedure:

[0355] 2.5.1. Pre-warm empty "incubation" plates T60 and NCF60 for 10 minutes.

[0520]

[0356] 2.5.2. Dilute liver microsomes to 0.56 mg / mL in 100 mM phosphate buffer. 2.5.3. 445 μL of microsome working solution (0.56 mg / mL) is transferred into pre-warmed "incubation" plates T60 and NCF60, and "incubation" plates T60 and NCF60 are then pre-incubated for 10 minutes at 37° C. with constant shaking. 54 μL of liver microsomes are transferred to the blank plate, then 6 μL of NAPDH cofactor is added to the blank plate, and then 180 μL of quench solution is added to the blank plate.

[0521] 2.5.4.5 μL of compound working solution (100 μM) is added into the "incubation" plates (T60 and NCF60) containing microsomes and mixed thoroughly three times.

[0522] For NCF60 plates, add 50 μL of buffer and mix thoroughly 3 times. Start timing: Plates are incubated at 37° C. for 60 minutes with shaking.

[0523] In the "Quench" plate TO, add 180 μL of Quench Solution and 6 μL of NAPDH cofactor. Ensure plate is chilled to prevent evaporation.

[0524] 2.5.7. For the T60 plate, mix thoroughly 3 times and immediately remove 54 μL of the mixture to the "quench" plate at 0 minutes. Then add 44 μL of NAPDH cofactor to the incubation plate (T60). Start timing; plates are incubated at 37° C. for 60 minutes with shaking.

[0525] [Table 4]

[0526]

[0362] 2.5.8. At 5, 10, 20, 30, and 60 minutes, add 180 μL of Quench Solution to the "Quench" plate, mix once, and serially transfer 60 μL samples from the T60 plate per time point to the "Quench" plate.

[0527] [Table 5]

[0528]

[0363] 2.5.9. For NCF60: Mix once and transfer 60 μL sample from the NCF60 incubation to the "Quench" plate containing Quench Solution at 60 minutes.

[0529] [Table 6]

[0530]

[0364] 2.5.10. All sampling plates are shaken for 10 minutes and then centrifuged at 4000 rpm for 20 minutes at 4°C.

[0365] 2.5.11. Transfer 80 μL of the supernatant into 240 μL of HPLC water and mix on a plate shaker for 10 minutes.

[0531]

[0366] 2.5.12. Each bioanalytical plate was sealed and shaken for 10 minutes prior to LC-MS / MS analysis.

[0367] 3.1. T1 / 2 and intrinsic clearance (CLint mic) were calculated in (μL / min / mg) using a first order kinetic equation.

[0532]

[0368] Equation of first order rate law.

[0533]

number

[0534]

[0369] Table 1 contains μM / min / mg values ​​for selected compounds; compounds have an LM Clint of μM / min / mg between 1-10 μM / min / mg for +++, between 10-100 μM / min / mg for ++, and >100 μM / min / mg for +.

[0535] Example 65: TNIK Human STE Kinase Enzymatic Radiometric Assay

[0370] Assay Information

[0371] Assay type: Biochemistry

[0372] Assay SUB type: Enzyme

[0373] Function mode: antagonist

[0374] Detection method: Radiometric Measured response: Scintillation Procedure Summary: TNIK(h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM RLGRDKYKTLRQIRQ, 10 mM magnesium acetate and [gamma-33P-ATP] (specific activity and concentration as required). The reaction is initiated by the addition of Mg / ATP mix. After incubation at room temperature for 40 minutes, the reaction is stopped by the addition of phosphoric acid to a concentration of 0.5%. 10 ul of the reaction is then spotted onto a P30 filtermat and washed 4 times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting.

[0536]

[0377] Substrate: 250 μM RLGRDKYKTLRQI

[0378] Tracer: 33P

[0379] ATP concentration: 70μM Incubation: 40 minutes at room temperature Control inhibitor: 1-NM-PP1

[0382] Compound concentration: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM Compound dilution scheme: All compounds supplied were prepared to working stocks of 50x final assay concentration in 100% DMSO. Where appropriate, more concentrated stocks were manually diluted to 50x using 100% DMSO. Compounds supplied as powders were further diluted to 50x after reconstitution to a 10 mM stock in 100% DMSO. Assay procedure: The required volume of a 50x stock of test compound was added to the assay followed by the reaction mix containing enzyme and substrate. The reaction was initiated by the addition of ATP at the selected concentration. There was no pre-incubation of compounds with the enzyme / substrate mix prior to ATP addition. Please refer to the website or attached protocol documents for further details of each individual assay. Data Analysis: Data are handled using custom in-house analytical software. Results are expressed as kinase activity remaining as a percentage of DMSO control. This is calculated using the following formula: Sample count average - Blank count average Mean control counts For IC50 determinations, data are analyzed using XLFit version 5.3 (ID Business Solutions). Sigmoidal dose-response (variable slope) curves are fitted based on the average results for each test concentration using nonlinear regression analysis. If the upper and / or lower ends of the curve are >10% at 100 and 0, respectively, one or both of these limits can be constrained to 100 and 0, provided that the QC criteria for R2 are met.

[0537] Table 1 shows the IC for TNIK of selected compounds. 50 compounds have IC50 values ​​between 1 and 12 nM for +++, between 12 and 120 nM for ++, and >120 nM for +. 50 The values ​​can be found in Table 1.

[0538] Example 66: MAP4K4 Human STE Kinase Enzymatic Radiometric Assay

[0384] Assay type: Biochemistry

[0385] Assay SUB type: Enzyme

[0386] Function mode: antagonist

[0387] Detection method: Radiometric Measured response: Scintillation

[0389] Procedure summary: MAP4K4(h) is incubated in 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM RLGRDKYKTLRQIRQ, 10 mM magnesium acetate and [gamma-33P-ATP] (specific activity and concentration as required). The reaction is initiated by the addition of Mg / ATP mix. After incubation at room temperature for 40 minutes, the reaction is stopped by the addition of phosphoric acid to a concentration of 0.5%. 10 ul of the reaction is then spotted onto a P30 filtermat and washed 4 times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting.

[0539]

[0390] Substrate: 250μM RLGRDKYKTLRQI

[0391] Tracer: 33P

[0392] ATP concentration: 200μM Incubation: 40 minutes at room temperature

[0394] Reference inhibitor: Staurosporine

[0395] Compound concentration: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM.

[0540] Compound dilution scheme: All compounds supplied were prepared to working stocks of 50x the final assay concentration in 100% DMSO. Where appropriate, more concentrated stocks were manually diluted to 50x using 100% DMSO. Compounds supplied as powders were reconstituted to 10 mM stocks in 100% DMSO before being further diluted to 50x.

[0541] Assay procedure: The required volume of a 50x stock of test compound was added to the assay followed by the reaction mix containing enzyme and substrate. The reaction was initiated by the addition of ATP at the selected concentration. There was no pre-incubation of compounds with the enzyme / substrate mix prior to ATP addition. Please refer to the website or attached protocol documents for further details of each individual assay.

[0542] Data Analysis: Data is handled using custom in-house analysis software. Results are expressed as kinase activity remaining as a percentage of DMSO control. This is calculated using the following formula: Sample count average - Blank count average Mean control counts

[0399] IC 50 For determination, data are analyzed using XLFit version 5.3 (ID Business Solutions). Sigmoidal dose-response (variable slope) curves are fitted based on the average results for each test concentration using nonlinear regression analysis. If the upper and / or lower ends of the curve are >10% at 100 and 0, respectively, one or both of these limits can be constrained to 100 and 0, provided that the QC criteria for R2 are met.

[0543] Table 1 shows the IC of selected compounds for MAP4K4. 50 values; compounds have IC50 values ​​between 1 and 12 nM for +++, between 12 and 120 nM for ++, and >120 nM for +.

[0544] Example 67: Masson's Trichrome (M&T) Staining and Ashcroft Scoring Masson's Trichrome (M&T) Staining Protocol: Lung sections were cut at 4 μm thickness, dried in an oven for 1 hour, and stained with M&T by standard staining protocol. Sections were briefly stained with Weigert's iron hematoxylin working solution for 10 minutes. This was followed by staining in Biebrich scarlet acid fuchsin solution for 10 minutes and differentiation in phosphomolybdenum-phosphotungstic acid solution for 5 minutes or until collagen was no longer red. Samples were then transferred to aniline blue solution and stained for 1 minute, followed by dedifferentiation in 1% acetic acid solution. This was followed by dehydration and mounting of coverslips for subsequent image analysis.

[0545] For image analysis of collagen deposition, Masson's trichrome stained slides were scanned at 200X magnification using an Aperio Scan Scope Model:CS2 (Leica). The area of ​​fibrosis stained with Masson's trichrome stain was quantified with the HALO® image analysis platform from Indica Labs. The entire left lung section was selected as the annotation layer.

[0546]

[0403] Fiber modifications were determined morphologically and graded semiquantitatively according to a scale of 0 to 8 defined by Ashcroft et al. and modified by Hubner et al., as described below in Table 3. The final score was expressed as the average of the individual scores observed across all microscopic fields.

[0547] [Table 7]

[0548] Example 68: Alpha-SMA IHC Assay Protocol: For immunohistochemical staining, 4 μm thick sections were placed on slides and dried overnight, after which the paraffin was removed with xylene. Sections were placed in a graded ethanol series and immersed in distilled water. After unmasking of heat-induced Citrate antigen (pH=6.0), sections were immersed in 3% hydrogen peroxide solution for 5 min. To avoid non-specific staining, sections were then incubated in blocking serum for 15 min at room temperature, followed by the addition of primary rabbit polyclonal anti-α-SMA antibody at a dilution of 1:400 for 1 h. This was followed by the addition of secondary goat polyclonal antibody conjugated to HRP.

[0549] For image analysis of fibrosis, α-SMA stained sections were scanned via Aperio CS2 Scan machine. The area of ​​fibrosis was quantified with HALO® image analysis platform from Indica Labs. The entire left lung section was selected as annotation layer. Bronchi were excluded in the annotation layer. The area occupied by collagen fibers was measured using the "Area Quantification v2.1.3" module. The percentage of positive area in the selected annotation was then calculated by the program. Fibrosis was expressed as percentage per lung section.

[0550] Example 69: Bleomycin-induced pulmonary fibrosis mouse model Protocol: Eight-week-old C57BL / 6 male mice were anesthetized with pentobarbital (60 mg / kg body weight, ip) and received bleomycin by intratracheal administration at a dose of 0.66 mg / kg (equivalent to 1 U / kg) on ​​day 1. Compound treatment was initiated on day 7 after induction of pulmonary fibrosis, when the initial lung injury and inflammation had already subsided.

[0551] Example 70: Bleomycin-induced rat model for skin fibrosis Protocol: Five- to six-week-old male Sprague Dawley rats are transiently anesthetized using isoflurane and their dorsal areas are shaved using a Wahl pet groomer. Bleomycin (BLM) is diluted to 1 mg / ml in sterile phosphate buffered saline (PBS). Using a 1 ml syringe containing a 27 gauge needle, 100 μl of BLM solution is injected subcutaneously into two sites on the shaved area once daily for four weeks. Untreated controls are injected daily with an equivalent volume of sterile PBS.

[0552] Example 71: Unilateral ureteral obstruction renal fibrosis model Protocol: On day 0, UUO surgery was performed on 7-week-old female C57BL / 6 mice under a triple-type mixed anesthetic (medetomidine, midazolam, butorphanol). After shaving, the abdomen was incised and the left ureter was exposed. The ureter was ligated with 4-0 silk suture at two points. The peritoneum and skin were closed with sutures and the mice were transferred to clean cages to keep until recovery from anesthesia. The mice were divided into two slots based on their weight before the day of surgery. Compounds were administered orally from day 0 to day 13. On day 14, the weights of the ligated left and right kidneys were measured at the time of sacrifice.

[0553] Example 72: Collagen and alpha-SMA in LX-2 Methods: Culture medium was prepared with DMEM supplemented with 2% FBS and 1% P / S. Medium was removed from culture flasks containing a confluent layer of LX-2 cells. 3 ml of 0.25% trypsin-EDTA solution was then added and cells were incubated for 5 min at 37°C for each T150-flask. Trypsinization was stopped by adding 7 ml of culture medium. Cells were centrifuged at 300×g for 5 min. Supernatant medium was discarded and cells were resuspended in fresh culture medium. Cells were counted in a cell viability analyzer. 5.0E+05 cells / well were seeded in a 6-well plate containing 2.0 mL of culture medium. Cells were cultured overnight at 37°C. The next day, complete medium was replaced with medium with 0.4% FBS for starvation. After 24 hours of incubation in medium with reduced serum, LX-2 cells were treated with compounds (8 concentrations, 3-fold dilutions) in duplicate for 30 minutes and then stimulated with 4ng / ml TGF-β for another 48 hours. In parallel, medium containing DMSO and TGF-β only was used as blank and positive controls, respectively. TGF-β induction was used as a maximum induction positive control. Culture medium was discarded at the end of induction. Cells were washed once using ice-cold DPBS. Cells were lysed for 20 minutes by adding RIPA buffer. Cells were then scraped off the culture plate, collected in tubes and centrifuged. Supernatants were stored at -80°C. Total amount of protein in the lysates was determined using a BCA protein assay kit. Fibrosis assay cell treatments were performed for each compound in three independent experiments.

[0554] All lysate samples were adjusted to the same protein concentration after BCA assay with RIPA buffer. Samples with the same protein amount were mixed with 4x LDS sample buffer and boiled at 95°C for 5 min. Denatured samples were used for electrophoresis. Western blot was performed according to standard protocols. Equal volumes of protein were loaded onto 4-12% Bis-Tris gels. Duplicate lysates of samples were loaded onto two gels. Gels were run at 80V for 0.5 h and 120V for another 1 h. When electrophoresis was completed, gels containing the target protein collagen I (COL1A1) were transferred onto NC membranes using a Trans-Blot Electrophoretic Transfer Cell at 100V for 90 min. α-SMA and GAPDH were transferred at 20V for 7 min using an iBlot™2 Gel Transfer Device. All membranes were blocked in TBST buffer with 5% nonfat dry milk for 1 hour at room temperature, then incubated with primary antibodies anti-COL1A1 and anti-α-SMA in TBST buffer containing 5% BSA overnight at 4°C. For GAPDH detection, the membranes with α-SMA immunoblots were stripped with Restore™ Western Blot Stripping Buffer after detection. The membranes were then reblocked and reprobed with primary antibody anti-GAPDH antibody for 2 hours at room temperature (RT). After incubation with the primary antibody, the membranes were washed with TBST and then incubated with secondary antibody for 1 hour at room temperature. The blots were visualized using the instrument Image Quant LAS-4000. The chemiluminescence signal derived from ECL Western blotting reagent was captured. The band integrated intensity from the 16-bit blot images was used for quantification with the software (1D component of ImageQuant TL). Quantification raw data of two duplicate gels was obtained from ImageQuant TL. Collagen I and α-SMA protein expression levels were normalized to GAPDH for each gel. The average normalized data from two duplicate gels was calculated and IC was calculated using the equation for a sigmoidal dose response (variable slope) in GraphPad™ Prism software. 50was applied to calculate the equation: Y=Bottom+(Top-Bottom) / (1+10^(LogIC50-X) * Note: X is the logarithm of compound concentration and Y is the mean normalized data.

[0555] Table 4 shows the IC values ​​of selected compounds for collagen. 50 values; compounds were graded with an IC of <0.1 nM as +++, 0.1-1.0 nM as ++, and >1.0 nM as +. 50 It has a value.

[0556] [Table 8-1]

[0557] [Table 8-2]

[0558]

[0412] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, R １ is selected from the following: -N(R ５ ) ２ , where each R ５ is hydrogen and optionally substituted C １ ~C ６ alkyl, wherein C １ ~C ６ Alkyl is a halogen, -OH, -CN, -NO ２ , -NH ２ , oxo, =S, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; Substitution C １ ~C ６ Alkyl, where C １ ~C ６ Alkyl is a halogen, -OH, -CN, -NO ２ , -NH ２ , oxo, =S, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, —O—C １～６ Alkyl-O-C(O)(O-C １～１０ Alkyl), C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１２ is optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted 3- to 8-membered heterocycles; wherein the 3- to 8-membered heterocycles are selected from the group consisting of halogen, -OH, -CN, -NO ２ , -NH ２ , oxo, =S, -S(O ２ ) N.H. ２ , -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１２ Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C １～１０ Optionally substituted with one or more substituents independently selected at each occurrence from alkyl, where C １～１０ Alkyl is hydroxy, halogen, oxo, -C １～１０ Haloalkyl, -NH ２ , -CN, and -NO ２ optionally substituted with one or more substituents independently selected at each occurrence from R ３ is an optionally substituted C １ ~C ６ Alkyl, optionally substituted 3- to 10-membered heterocycle and optionally substituted C ３～１０ carbocycle, wherein each of alkyl, heterocycle and carbocycle is selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １～６ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R ４ is selected from the following: hydrogen; Optionally substituted C １ ~C ６ Alkyl, where C １ ~C ６ Alkyl is a halogen, -OH, -CN, -NO ２ , -NH ２ , oxo, =S, -O-C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１２ is optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C ３～１０ Carbocyclic ring, where C ３～１０ Carbocycles include halogens, -OH, -CN, -NO ２ , -NH ２ , oxo, = S, C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; W is selected from optionally substituted 5- to 8-membered heteroaryl, where the 5- to 8-membered heteroaryl is selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -S(O ２ ) N.H. ２ , -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ Alkynyl, C ３～１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; Here, R １ When R is methylpiperazine and W is pyridine, ４ is not methyl; W is furan and R ４ When R is cyclopentyl or cyclohexyl, １ is not ethan-1-one).

2. R ３ is optionally substituted C ３～６ 2. The compound or salt of claim 1, wherein the ring is selected from carbocycles.

3. R ３ 3. The compound or salt of claim 1 or 2, wherein is optionally substituted phenyl, the optional substituents on phenyl being selected from halogen and -C 1-10 haloalkyl.

4. 4. The compound or salt of claim 1, wherein W is selected from 5- to 6-membered heteroaryl.

5. 5. The compound or salt of claim 1, wherein the 5-8 membered heteroaryl of W is selected from imidazole, furan, and pyridine.

6. Formula (IIA): 【Chemistry 2】 The compound or salt according to any one of claims 1 to 5, which is represented by:

7. Formula (IIB): 【Chemistry 3】 The compound or salt according to any one of claims 1 to 5, which is represented by:

8. R ４ is optionally substituted with one or more substituents selected from hydrogen, halogen １ ~C ６ C optionally substituted with one or more substituents selected from alkyl, hydroxy and amine ５～６ 8. A compound or salt according to claims 1 to 7, selected from carbocycles.

9. R ４ is optionally substituted with one or more substituents selected from fluorine １ ~C ６ C substituted with alkyl and hydroxy ６ 9. The compound or salt of claim 8, wherein said alkyl is selected from cycloalkyl.

10. R １ is selected from: -N(R ５ ) ２ , where R ５ is an optionally substituted C １ ~C ６ alkyl, wherein C １ ~C ６ The substituents on the alkyl are one or more of halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, -C １～１０ Haloalkyl, —O—C １～１０ independently selected at each occurrence from alkyl, Substituted C １ ~C ６ Alkyl, where C １ ~C ６ The substituents on the alkyl are one or more of halogen, -OH, -NH ２ , oxo, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, —O—C １～６ Alkyl-O-C(O)(O-C １～１０ alkyl); an optionally substituted 6- to 8-membered heterocycle; wherein the optional substituents on the 6- to 8-membered heterocycle are one or more of oxo, -S(O ２ ) N.H. ２ , -NH ２ , -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, and optionally substituted C １～１０ independently selected at each occurrence from alkyl, １～１０ Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C １～１０ Haloalkyl, -NH ２ , -CN, and -NO ２ 10. The compound or salt of any one of claims 1 to 9, independently selected at each occurrence from:

11. R １ is selected from optionally substituted 6- to 8-membered saturated heterocycles; where the optional substituents are one or more -S(O ２ ) N.H. ２ and optionally substituted C １～１０ independently selected at each occurrence from alkyl, １～１０ Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C １～１０ Haloalkyl, and -NH ２ 10. The compound or salt of any one of claims 1 to 9, independently selected at each occurrence from:

12. The compound is 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 or a pharma- ceutically acceptable salt thereof.

2. The compound or salt of claim 1,

13. The following formula: 【Chemistry 5】 2. The compound according to claim 1, wherein the compound is represented by the formula: or a pharma- ceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 13 and a pharma- ceutically acceptable excipient.

15. For use in a method for treating or preventing a disease comprising administering to a subject in need thereof a compound or salt according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14. A compound or salt according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14.

16. The compound or pharmaceutical composition of claim 15, wherein the disease is a fibrotic disease or condition, and the disease may be a fibrotic disease or condition selected from cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc), and graft-versus-host disease (GVHD).

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