Tnik inhibitors and uses thereof

Abstract

This invention provides TNIK and / or MAP4K4 kinase inhibitors for treating diseases. In one embodiment, kinase inhibitors having structures of formula (A), (A*), (I), (IIA), or (IIB) are disclosed herein. Pharmaceutical compositions comprising such compounds and methods of using such compounds are further described herein. In another embodiment, a method of treating a disease or condition by administering the kinase inhibitors described herein is disclosed.

Description

[Previous Technology]

[0001] The bioactive enzyme known as Traf2- and Nck-interacting protein kinase is commonly referred to as TNIK in humans and is encoded by the TNIK gene. TNIK participates in various biological processes as a serine / threonine kinase. Novel drug candidates that can target TNIK are needed. [Summary of the Invention]

[0002] TNIK is a serine / threonine kinase involved in various biological processes (including its role as a fundamental regulatory component in the Wnt signaling pathway). TNIK directly binds to TCF4 and β-catenin and phosphorylates TCF4. Additionally, TNIK acts as an activator of Wnt target gene expression and regulates the actin cytoskeleton and activates the c-Jun N-terminal kinase pathway, which is stress-responsive. It is also part of the signaling complex composed of NEDD4, RAP2A, and TNIK, regulating neuronal dendritic extension and arborization during development. More generally, TNIK plays a role in cytoskeleton rearrangement and regulates cell proliferation. TNIK also induces weak Smad1 T322 phosphorylation, participating in TGF-β1 signaling transduction.

[0003] It is believed that TNIK is a germinal center kinase (GCK) characterized by having an N-terminal kinase domain and a C-terminal GCK domain that play a regulatory role.

[0004] TNIK activation in Wnt communication plays an important role in carcinogenesis and embryonic development. Mutations in this gene are associated with autosomal recessive cognitive impairment.

[0005] In addition, TNIKs are associated with cancers (including, for example, colorectal cancer). Therefore, TNIKs have been identified as an attractive candidate for drugs targeting certain cancers.

[0006] Current data suggest that TNIK is a potential target for generating small molecule inhibitors to specifically block the Wnt pathway in disease states such as colorectal cancer or autosomal recessive cognitive impairment.

[0007] Furthermore, it is known that TGF-β-activated EMT can be identified through Smad and non-Smad signaling pathways, including Wnt, FF-kB, FAK-Src-pile protein-associated punctate adhesion, and MAP kinase (ERK and JNK) signaling pathway attenuation. Therefore, EMT-related therapeutic targets (such as TNIK as an inhibitory target) can be used for the treatment and / or prevention of EMT-based diseases (such as cancer metastasis and fibrosis).

[0008] Therefore, it would be advantageous for TNIK inhibitors that can inhibit the kinase activity of TNIK to be members of the Ste20 family of MAP kinase kinase kinase (MAP4K).

[0009] The present invention addresses the above-mentioned needs and also provides other advantages.

[0010] In some embodiments, the present invention provides a compound represented by formula (A): (A); or a pharmaceutically acceptable salt thereof, wherein: Z is selected from 3 to 12-membered heterocycles that are substituted as desired and C3-C12 carbon rings that are substituted as desired, wherein the substituents thereon are independently selected each time from one or more -N(R10)2, halogen, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-C10 alkyl, C3-12 carbon ring, 3 to 12-membered heterocycles; The C1-C10 alkyl group is substituted as required by one or more substituents selected independently each time from halogens, -OH, -CN, -NO2, -NH2, syloxy groups, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocyclic rings; The C3-12 carbon ring and the 3 to 12-membered heterocycle are each substituted as needed by one or more independent substituents selected from halogens, -OH, -CN, -NO2, -NH2, septyl groups, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12-membered heterocycles and C1-10 alkyl groups substituted as needed, wherein the substituents on the C1-10 alkyl group are each independently selected as one or more hydroxyl groups, halogens, septyl groups, -C1-10 haloalkyl groups, -NH2, -CN and -NO2; R10 is selected from C1-C6 alkyl groups that are substituted as desired, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocycles; The W group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as needed, wherein the substituents on each are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3- to 12-membered heterocycles, wherein the C3-12 carbon ring and the 3- to 12-membered heterocycles are each substituted as needed by one or more substituents that are independently selected from halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.The Y group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as desired, wherein the substituents on each are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon rings, and 3- to 12-membered heterocycles, wherein each of the C3-12 carbon rings and 3- to 12-membered heterocycles is substituted as desired by one or more substituents that are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.

[0011] In some embodiments, the present invention provides a compound represented by formula (A*): (A*); R1 is selected from: -N(R5)2, wherein R5 is selected from hydrogen and C1-C6 alkyl groups that are substituted as desired, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbide ring, 3 to 12-membered heterocycles; The C1-C6 alkyl group is substituted as required, wherein the substituents on the C1-C6 alkyl group are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12 member heterocycles; The 3 to 8-membered heterocycles to be substituted as required; wherein the optional substituents on the 3 to 8-membered heterocycles are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12-membered heterocycles and C1-10 alkyl to be substituted as required, wherein the optional substituents on the C1-10 alkyl are independently selected each time from one or more hydroxyl groups, halogens, side oxygen, -C1-10 haloalkyl, -NH2, -CN and -NO2; The W group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as needed, wherein the substituents on each are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3- to 12-membered heterocycles, wherein the C3-12 carbon ring and the 3- to 12-membered heterocycles are each substituted as needed by one or more substituents that are independently selected from halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.The Y group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as desired, wherein the substituents on each are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon rings, and 3- to 12-membered heterocycles, wherein each of the C3-12 carbon rings and 3- to 12-membered heterocycles is substituted as desired by one or more substituents that are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.

[0012] In some embodiments, the present invention provides a compound represented by formula (I): (I); or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: -N(R5)2, wherein R5 is selected from hydrogen and, if necessary, substituted C1-C6 alkyl groups, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, syloxy group, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbide ring, 3 to 12-membered heterocycles; The substituted C1-C6 alkyl group, wherein the substituents on the C1-C6 alkyl group are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12 member heterocycles; The 3 to 8-membered heterocycles to be substituted as required; wherein the optional substituents on the 3 to 8-membered heterocycles are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12-membered heterocycles and C1-10 alkyl to be substituted as required, wherein the optional substituents on the C1-10 alkyl are independently selected each time from one or more hydroxyl groups, halogens, side oxygen, -C1-10 haloalkyl, -NH2, -CN and -NO2; R3 is selected from C1-C6 alkyl groups that are substituted as desired, 3- to 10-membered heterocycles that are substituted as desired, and C3-10 carbon rings that are substituted as desired, wherein the optional substituents thereon are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, C1-6 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon rings, and 3- to 12-membered heterocycles; R4 is selected from: hydrogen; The C1-C6 alkyl group may be substituted as required, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -O-C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocycles;The C3-10 carbon ring is substituted as desired, wherein the optional substituents on the C3-10 carbon ring are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocycles; and the W series is selected from 5 to 8-membered heteroaryl groups substituted as desired, wherein the substituents on the 5 to 8-membered heteroaryl groups substituted as desired are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocycles. ;

[0013] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound or salt of formula (A), formula (A*) or formula (I) and a pharmaceutically acceptable excipient.

[0014] In some embodiments, the present invention provides a method of treating or preventing a disease, comprising administering to a subject in need a compound or salt of formula (A), formula (A*), or formula (I), or a pharmaceutical composition comprising a compound or salt of formula (A), formula (A*), or formula (I), and a pharmaceutically 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 mental 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 renal fibrosis ("CKD"), cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, skin fibrosis, systemic sclerosis ("SSc"), and graft-versus-host disease ("GVHD"). In some cases, this pharmaceutical composition can be used to treat renal fibrosis. In some cases, this pharmaceutical composition can be used to treat skin fibrosis. In some cases, this pharmaceutical composition can be used to treat idiopathic pulmonary fibrosis (IPF). In some cases, this pharmaceutical composition can be used to treat diseases related to TNIK kinase.

[0015] In some embodiments, the present invention provides a method for inhibiting TNIK kinase, comprising administering to a subject in need a compound or salt of formula (A), formula (A*) or formula (I) or a pharmaceutical composition comprising a compound or salt of formula (A), formula (A*) or formula (I) and a pharmaceutically acceptable excipient.

[0016] In some embodiments, the present invention provides a method for inhibiting MAP4K4 kinase, comprising administering to a subject in need a compound or salt of formula (A), formula (A*) or formula (I) or a pharmaceutical composition comprising a compound or salt of formula (A), formula (A*) or formula (I) and a pharmaceutically acceptable excipient.

[0017] Further aspects and advantages of the present invention will become apparent to those skilled in the art from the following embodiments, wherein only illustrative embodiments of the invention are shown and described. It will be understood that the invention may have other and different embodiments, and certain details may be modified in various obvious ways without departing from the invention. Therefore, the drawings and description are essentially considered illustrative rather than restrictive.

Implementation Method

[0018] Cross-reference

[0019] This application claims the benefits 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 incorporated herein by reference in its entirety.

[0020] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is expressly and individually indicated to be incorporated herein by reference. In the event of any conflict between a publication, patent, or patent application incorporated herein by reference and any disclosure contained herein, this specification is intended to substitute for and / or give precedence to any such conflicting material.

[0021] Although various embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many changes, modifications, and substitutions can be made by those skilled in the art without departing from the invention. Various alternatives to the embodiments of the invention described herein should be understood. A. Definitions

[0022] 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 pertains. All patents and publications mentioned herein are incorporated herein by reference.

[0023] "alkyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, which is not unsaturated and preferably has one to fifteen carbon atoms (i.e., C1-C15 alkyl). In some embodiments, the alkyl group contains one to thirteen carbon atoms (i.e., C1-C13 alkyl). In some embodiments, the alkyl group contains one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl group contains one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl group contains one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl group contains one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl group contains one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, the alkyl group contains one carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl group contains five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, the alkyl group contains five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (i.e., C3-C5 alkyl). In some embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (secondary butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tertiary butyl), and 1-pentyl (n-pentyl). The alkyl group is bonded to the remainder of the molecule by a single bond. Unless otherwise expressly stated in this specification, the alkyl group may be substituted as needed (e.g., with a side-oxygen group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylic acid ester group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkyl group is substituted as needed with a side-oxygen group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group may be substituted with a halogen, -CN, -OH, or -OMe as desired. In some embodiments, the alkyl group may be substituted with a halogen as desired.

[0024] When the term "Cx-y" is used in conjunction with a chemical moiety (such as alkyl, alkenyl, or alkynyl), it is intended to include groups containing x to y carbon atoms in the chain. For example, the term "C1-6 alkyl" refers to an alkyl group that can be composed of 1, 2, 3, 4, 5, or 6 carbon atoms, including straight-chain alkyl and branched-chain alkyl.

[0025] "Alkoxy" refers to an -O-alkyl group bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above. Unless otherwise expressly stated in this specification, an alkoxy group may be substituted as needed (e.g., with a side oxygen group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylic acid ester group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkoxy group may be substituted as needed with a halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group may be substituted as needed with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group may be substituted as needed with a halogen.

[0026] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms (i.e., C2-C12 alkenyl). In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl group is attached to the remainder of the molecule by a single bond, for example, ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pent-1,4-dienyl, and the like. Unless otherwise expressly stated in this specification, the alkenyl group may be substituted as needed (e.g., with a side-oxygen group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylic acid ester group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkenyl group may be substituted as needed with a side-oxygen group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group may be substituted as needed with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group may be substituted as needed with a halogen.

[0027] "Alynyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms (i.e., C2-C12 alkynyl). In some embodiments, the alkynyl group comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, the alkynyl group comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, the alkynyl group comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl group is attached to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, and the like. Unless otherwise expressly stated in this specification, the alkynyl group may be substituted as needed (e.g., with a side-oxygen group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylic acid ester group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and the like. In some embodiments, the alkynyl group may be substituted with a side oxygen group, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2 as desired. In some embodiments, the alkynyl group may be substituted with a halogen, -CN, -OH, or -OMe as desired. In some embodiments, the alkynyl group may be substituted with a halogen as desired.

[0028] The terms "Cx-y alkenyl" and "Cx-y ynyl" refer to substituted or unsubstituted unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyl groups described above, but each contains at least one double or triple bond. The term -Cx-y alkenyl- refers to a substituted or unsubstituted alkenyl chain having x to y carbons. For example, -C2-6 alkenyl- can be selected from alkenylene, alkenylpropenyl, alkenylbutenyl, alkenylpentenyl, and alkenylhexenyl, any of which may be substituted as required. The alkenyl chain may have one or more double bonds. The term -Cx-y ynyl- refers to a substituted or unsubstituted ynyl chain having x to y carbons. For example, -C2-6 enynyl- can be selected from enynylethynyl, enynylpropynyl, enynylbutynyl, enynylpentynyl, and enynylhexynyl, any of which may be substituted as required. The enynyl chain may have one or more triple bonds.

[0029] "alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain in which the remainder of a molecule is attached to a group, consisting only of carbon and hydrogen, without unsaturation, and preferably having one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the remainder of the molecule and to the group via single bonds. The alkylene chain may attach to the remainder of the molecule and to the group via any two carbons within the chain. In some embodiments, the alkylene chain comprises one to ten carbon atoms (i.e., C1-C8 alkylene). In some embodiments, the alkylene chain comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene chain comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene chain comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene chain comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkyl group comprises one or two carbon atoms (i.e., C1-C2 alkyl group). In other embodiments, the alkyl group comprises one carbon atom (i.e., C1 alkyl group). In other embodiments, the alkyl group comprises five to eight carbon atoms (i.e., C5-C8 alkyl group). In other embodiments, the alkyl group comprises two to five carbon atoms (i.e., C2-C5 alkyl group). In other embodiments, the alkyl group comprises three to five carbon atoms (i.e., C3-C5 alkyl group). The term -Cx-y alkyl group - refers to a substituted or unsubstituted alkyl group chain having x to y carbons in the alkyl group chain. For example, -C1-6 alkyl group - can be selected from methylene, ethyl, propyl, butyl, pentyl, and hexyl, any of which may be substituted as desired.

[0030] "Alkenyl" or "alkenyl chain" refers to a straight-chain or branched divalent hydrocarbon chain that connects the remaining portion of a molecule to a group, consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms. The alkenyl chain is bonded to the remaining portion of the molecule and to the group via single bonds. The bonding points of the alkenyl chain to the remaining portion of the molecule and to the group can be via any two carbons within the chain. In some embodiments, the alkenyl group comprises two to ten carbon atoms (i.e., C2-C10 alkenyl). In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In other embodiments, the alkenyl group comprises two to five carbon atoms (i.e., C2-C5 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C2-C4 alkenyl). In other embodiments, the alkenyl group comprises two to three carbon atoms (i.e., C2-C3 alkenyl). In other embodiments, the enylene group comprises two carbon atoms (i.e., C2 enylene). In other embodiments, the enylene group comprises five to eight carbon atoms (i.e., C5-C8 enylene). In other embodiments, the enylene group comprises three to five carbon atoms (i.e., C3-C5 enylene).

[0031] "Erythynyl" or "Erythynyl chain" refers to a straight-chain or branched divalent hydrocarbon chain that connects the remaining portion of a molecule to a group, consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms. The erythynyl chain is bonded to the remaining portion of the molecule and to the group via single bonds. The bonding sites of the erythynyl chain to the remaining portion of the molecule and to the group can be via any two carbons within the chain. In some embodiments, the erythynyl group comprises two to ten carbon atoms (i.e., C2-C10 erythynyl). In some embodiments, the erythynyl group comprises two to eight carbon atoms (i.e., C2-C8 erythynyl). In other embodiments, the erythynyl group comprises two to five carbon atoms (i.e., C2-C5 erythynyl). In other embodiments, the erythynyl group comprises two to four carbon atoms (i.e., C2-C4 erythynyl). In other embodiments, the erythynyl group comprises two to three carbon atoms (i.e., C2-C3 erythynyl). In other embodiments, the entynyl group comprises two carbon atoms (i.e., C2 entynyl). In other embodiments, the entynyl group comprises five to eight carbon atoms (i.e., C5-C8 entynyl). In other embodiments, the entynyl group comprises three to five carbon atoms (i.e., C3-C5 entynyl).

[0032] "Aryl" refers to a group derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a self-ring carbon atom, wherein the ring system contains at least one aromatic ring. The aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon, and five to eighteen carbon atoms, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, non-localized (4n+2) π-electron system according to Hückel theory. The ring system from which the aryl group is derived includes (but is not limited to) groups such as benzene, fumonisin, indane, indene, tetrahydronaphthalene, and naphthalene. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl) group. Aryl groups include (but are not limited to) aryl groups derived from the following hydrocarbon ring systems: anthracene, anthracene, anthracene, anthracene, benzene, anthracene, fluoranthene, anthracene, asymmetric indole, symmetric indole, indane, naphthalene, phenanthrene, phenanthrene, heptane, pyrene, and terphenyl. Unless otherwise expressly stated in this specification, aryl groups may be substituted as needed (e.g., with halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid ester groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, the aryl group is substituted as needed with halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the aryl group is substituted as needed with halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the aryl group may be halogenated as required.

[0033] "Heteroalkyl" means an alkyl group in which one or more alkyl skeleton atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is bonded to the remainder of the molecule at the carbon atom of the heteroalkyl group. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group comprises 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is bonded to the remainder of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are (e.g.) -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise expressly stated in this specification, heteroalkyl groups may be substituted as needed (e.g., with oxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroalkyl group may be substituted as needed with oxy, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group may be substituted as needed with oxy, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group may be substituted with halogen.

[0034] "Aryl" refers to a group of the formula -Rc-aryl, wherein Rc is an alkyl chain as defined above, such as methylene, ethyl, and the like.

[0035] "Aryl" refers to a group of the formula -Rd-aryl, wherein Rd is an aryl chain as defined above. "Arylynyl" refers to a group of the formula -Re-aryl, wherein Re is an arylynyl chain as defined above.

[0036] "Carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring system in which each ring atom is carbon. A carbocyclic ring may include 3 to 10-membered monocyclic rings, 6 to 12-membered bicyclic rings, and 6 to 12-membered bridged rings. Each ring in a bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. Aromatic rings (e.g., phenyl) may be fused to saturated or unsaturated rings (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, where valence allows. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, dihydroindenyl, and naphthyl. In some embodiments, the carbocyclic ring is aryl. In some embodiments, the carbocyclic ring is cycloalkyl. In some embodiments, the carbocyclic ring is cycloalkenyl. In some embodiments, the carbocyclic ring contains a triple bond. Unless otherwise expressly stated in this specification, the carbocyclic ring may be substituted as needed.

[0037] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring or bridged ring systems, and preferably having three to twelve carbon atoms. In some embodiments, the cycloalkyl group contains three to ten carbon atoms. In other embodiments, the cycloalkyl group contains five to seven carbon atoms. The cycloalkyl group may be bonded to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. Unless otherwise expressly stated in this specification, cycloalkyl groups may be substituted as needed (e.g., with oxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the cycloalkyl group may be substituted as needed with oxy, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group may be substituted as needed with oxy, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group may be substituted with halogen.

[0038] "Heterocyclic alkyl" means a cycloalkyl group as defined above, wherein one or more cyclic carbons are replaced by one or more heteroatoms (such as N, O, P and S). Heterocyclic alkyl groups may be substituted as needed.

[0039] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring or bridged ring systems, preferably having three to twelve carbon atoms and containing at least one double bond. In some embodiments, the cycloalkenyl group contains one double bond. In some embodiments, the cycloalkenyl group contains more than one double bond. In some embodiments, the cycloalkenyl group contains three to ten carbon atoms. In other embodiments, the cycloalkenyl group contains five to seven carbon atoms. The cycloalkenyl group may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0040] "Heterocyclic alkenyl" refers to a cyclic alkenyl group as defined above, wherein one or more cyclic carbons are replaced by one or more heteroatoms (such as N, O, P and S). Heterocyclic alkenyl groups may be substituted as needed.

[0041] “Cycloalkylalkyl” refers to a group of the formula -Rc-cycloalkyl, wherein Rc is an alkyl chain as described above.

[0042] "Cycloalkylalkoxy" refers to a group of the formula -O-Rc-cycloalkyl bonded by oxygen atoms, wherein Rc is an alkyl chain as described above.

[0043] "Halogen" or "halogen" refers to halogen substituents such as bromine, chlorine, fluorine and iodine substituents.

[0044] As used herein, the terms "haloalkyl" or "haloalkyl" refer to an alkyl group as defined above, substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl group may be further substituted as required. Examples of halogen-substituted alkanes (“haloalkanes”) include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di and trihalomethanes (e.g., chloroform, 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 alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen group, each halogen can be chosen independently, for example, 1-chloro-2-fluoroethane.

[0045] "Fluoroalkyl" means an alkyl group as defined above that has been substituted with one or more fluorine groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0046] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary 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. The rings in a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. "Extended heterocyclic group" refers to a divalent heterocycle to which the remaining portion of the molecule is attached. Unless otherwise expressly stated in this specification, the heterocycle is substituted as needed, for example, with oxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxyl ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, and the like. In some embodiments, the heterocycle is substituted as needed with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is substituted as needed with halogen. In some embodiments, the heterocyclic group is a heteroaryl group. In some embodiments, the heterocyclic group is a heterocyclic alkyl group. In some embodiments, the heterocyclic group is a heterocyclic alkenyl group. In some embodiments, the heterocycle contains one or more triple bonds.

[0047] In some embodiments, the heterocycle comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycle comprises one to three nitrogen atoms. In some embodiments, the heterocycle comprises one or two nitrogen atoms. In some embodiments, the heterocycle comprises one nitrogen atom. In some embodiments, the heterocycle comprises one nitrogen atom and one oxygen atom. Unless otherwise expressly stated in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring, spirocyclic, or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic group may be oxidized as needed; the nitrogen atom may be quaternized as needed. Representative heterocycles include heteroaryl groups described below. Representative heterocycles also include (but are not limited to) heterocycles having two to fifteen carbon atoms (C2-C15 heterocyclic alkyl or C2-C15 heterocyclic alkenyl), two to ten carbon atoms (C2-C10 heterocyclic alkyl or C2-C10 heterocyclic alkenyl), two to eight carbon atoms (C2-C8 heterocyclic alkyl or C2-C8 heterocyclic alkenyl), two to seven carbon atoms (C2-C7 heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to six carbon atoms (C2-C6 heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to five carbon atoms (C2-C5 heterocyclic alkyl or C2-C5 heterocyclic alkenyl), or two to four carbon atoms (C2-C4 heterocyclic alkyl or C2-C4 heterocyclic alkenyl). Examples of such heterocyclic groups include (but are not limited to) azahexylpropenyl, azahexylbutyl, oxacyclobutyl, dioxacyclopentyl, thienyl[1,3]dithiayl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-sideoxypiperazinyl, 2-sideoxypiperidinyl, 2-sideoxypyrrolidinyl, oxazolinyl, piperidinyl, piperazinyl, 4-piperidinoneyl Pyrrolidyl, pyrazolidyl, quininyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiomorpholinyl, thiomorpholinyl, 1-sideoxythiomorpholinyl, 1,1-sideoxythiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-sideoxy-1,3-dihydroisobenzofuran-1-yl, methyl-2-sideoxy-1,3-dioxacyclopenten-4-yl, and 2-sideoxy-1,3-dioxacyclopenten-4-yl. The term heterocycle also includes all cyclic forms of sugars, including (but not limited to) monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the ring of a heterocycle has 2 to 10 carbon atoms. It should be understood that when referring to the number of carbon atoms in a heterocycle, the number of carbon atoms in that heterocycle is different from the total number of atoms (including heteroatoms) constituting the heterocycle (i.e., the skeletal atoms of the heterocycle). In some embodiments, the heterocycle is 3 to 8 members. In some embodiments, the heterocycle is 3 to 7 members. In some embodiments, the heterocycle is 3 to 6 members. In some embodiments, the heterocycle is 4 to 6 members. In some embodiments, the heterocycle is 5 to 6 members.

[0048] “Heteroaryl” or “aromatic heterocycle” refers to a group derived from a heteroaromatic ring group comprising one to thirteen carbon atoms, at least one heteroatom, wherein each heteroatom may be selected from N, O, and S, and at least one aromatic ring. As used herein, the heteroaryl ring may be selected from monocyclic, bicyclic, fused-ring, or bridged-ring systems, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, nonlocal (4n+2) π-electron system according to the Huckell theory. The heteroatom in the heteroaryl group may be oxidized as needed. One or more nitrogen atoms, if present, may be quaternized as needed. Where valence permits, the heteroaryl group may be bonded to the remainder of the molecule via any atom of the heteroaryl group (such as the carbon or nitrogen atom of the heteroaryl group). Examples of heteroaryl groups include (but are not limited to) pyridine, pyrimidine, oxazole, furan, thiophene, benzothiazole, and imidazopyridine. "X-membered heteroaryl" refers to the number of inner ring atoms in the ring (i.e., X). For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 inner ring atoms, such as triazole, oxazole, thiophene, etc. In some embodiments, the heteroaryl group is 5 to 10-membered heteroaryl. In some embodiments, the heteroaryl group is 5 to 6-membered heteroaryl. In some embodiments, the heteroaryl group is 6-membered heteroaryl. In some embodiments, the heteroaryl group is 5-membered heteroaryl. Examples include (but are not limited to) aziridine, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxane, benzonaphthuryl, benzoxazolyl, benzodioxacyclopentenyl, benzodioxinyl, benzopiperanyl, benzopiperanone, benzofuranyl, benzofuranone, benzothiophene (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, zozolyl, zolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanone, isothiazolyl, imidinyl Azolyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indolazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-side oxy-nitropyridyl, oxazolyl, ethylene oxide, 1-oxopyridyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyrazinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyrazinyl, quinazolinyl, quinoxolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).Unless otherwise expressly stated in this specification, heteroaryl groups may be substituted as needed (e.g., with halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid ester groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and the like. In some embodiments, the heteroaryl group is substituted as needed with halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heteroaryl group is substituted as needed with halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the heteroaryl group is substituted as needed with halogens.

[0049] The term "substituted" refers to a portion of a substituent replacing one or more carbon atoms or substituted heteroatoms (e.g., NH) on a structure. It will be understood that "substitution" or "substituted via" includes the following implicit conditions: the substitution conforms to the permissible valence of the substituted atom and the substituent, and the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations (such as by rearrangement, cyclization, elimination, etc.). In some embodiments, substituted means a portion of a substituent replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon atom with a side-oxygen group, an imine group, or a thio group. As used herein, the term "substituted" includes, upon careful consideration, all permissible substituents of an organic compound. In a broad sense, such permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For a suitable organic compound, such permissible substituents may be one or more and may be the same or different. For the purposes of this invention, such heteroatoms (such as nitrogen) may have hydrogen substituents of the organic compounds described herein and / or any permissible substituents that satisfy the valence of such heteroatoms.

[0050] In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, syloxy (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)Ra. ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, Aryl, arylynyl, cycloalkyl, cycloalkylalkyl and heterocyclic, any of which may, as needed, be derived from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, seroyl group (=O), thioyl group (=S), cyano (-CN), nitro (-NO2), imino group (=NH), oxime group (=N-OH), hydrazine group (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb -C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2) are substituted;Each Ra group is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocyclic compounds. Where the valence allows, each Ra group may be derived from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, seroyl group (=O), thioyl group (=S), cyanoyl group (-CN), nitroyl group (-NO2), imino group (=NH), oxime group (=N-OH), hydrazine group (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)O The substitutions are Ra, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Rb series is independently selected from direct-chain or straight-chain or branched alkyl, alkenyl, or alkyne chains, and each Rc series is a straight-chain or branched alkyl, alkenyl, or alkyne chain.

[0051] As used in this specification and the accompanying claims, unless otherwise expressly stated in the text, the singular forms “a,” “an,” and “the” include a plurality of indicators.

[0052] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic relative ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from both inorganic and organic acids. Inorganic acids that can be derived from salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids that can be derived from salts can 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 from both inorganic and organic bases. Inorganic bases that can be derived from salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases that can be derived into salts include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0053] As used herein, the phrase “parenteral administration and administered parenterally” means administration methods other than enteral and local administration, usually by injection, including (but not limited to) intravenous, intramuscular, intra-arterial, intrasheath, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal, and intrasternal injections and infusions.

[0054] The phrase “medically acceptable” is used herein to mean, to the extent of reasonable medical judgment, compounds, materials, compositions and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and whose benefits / risks are commensurate with a reasonable risk-benefit ratio.

[0055] As used herein, the phrases “medically acceptable excipients” or “medically acceptable carriers” mean pharmaceutically acceptable materials, compositions or media, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is harmless to the patient. Some examples of materials that can be used as pharmaceutically 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil and corn oil. (10) Soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Atherless water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic and compatible substances used in pharmaceutical formulations.

[0056] In some embodiments, the term "prevent" or "preventing," which is related to a disease or ailment, may mean that, in a statistical sample, the compound reduces the occurrence of the disease or ailment in a treated sample relative to an untreated control sample, or that, relative to an untreated control sample, the compound delays the onset of one or more symptoms of the disease or ailment or reduces its severity.

[0057] As used herein, the term "treatment" may include relieving, reducing, or improving symptoms of a disease or condition; preventing additional symptoms; improving or preventing the underlying cause of symptoms; inhibiting the disease or condition, for example, preventing its progression; relieving the disease or condition; causing its remission; relieving symptoms caused by the disease or condition; or preventing and / or therapeutically stopping the symptoms of the disease or condition. B. Compounds of the Invention

[0058] In some embodiments, the present invention provides a compound represented by formula (A): (A); or a pharmaceutically acceptable salt thereof, wherein: Z is selected from 3 to 12-membered heterocycles that are substituted as desired and C3-C12 carbon rings that are substituted as desired, wherein the substituents thereon are independently selected each time they appear from one or more -N(R10)2, halogen, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-C10 alkyl, C3-12 carbon ring, 3 to 12-membered heterocycles; The C1-C10 alkyl group is substituted as required by one or more substituents selected independently each time from halogens, -OH, -CN, -NO2, -NH2, syloxy groups, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocyclic rings; The C3-12 carbon ring and the 3 to 12-membered heterocycle are each substituted as needed with one or more independent substituents selected from halogens, -OH, -CN, -NO2, -NH2, septyl groups, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12-membered heterocycles and C1-10 alkyl groups substituted as needed, wherein the optional substituents on the C1-10 alkyl group are each independently selected as one or more hydroxyl groups, halogens, septyl groups, -C1-10 haloalkyl groups, -NH2, -CN and -NO2; R10 is selected from C1-C6 alkyl groups that are substituted as desired, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocycles; The W group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as needed, wherein the substituents on each are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3- to 12-membered heterocycles, wherein the C3-12 carbon ring and the 3- to 12-membered heterocycles are each substituted as needed by one or more substituents that are independently selected from halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.The Y group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as desired, wherein the substituents on each are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon rings, and 3- to 12-membered heterocycles, wherein each of the C3-12 carbon rings and 3- to 12-membered heterocycles is substituted as desired by one or more substituents that are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.

[0059] In some states, the compound of formula (A) is represented by formula (A*).

[0060] In some embodiments, for compounds or salts of formula (A), Z is selected from 3 to 12-membered heterocycles that are to be substituted as desired and C3-C12 carbon rings that are to be substituted as desired, wherein the substituents thereon are independently selected each time they appear from one or more halogens, -OH, -CN, -NO2, -NH2, syloxy, =S, -C1-10 haloalkyl, -O-C1-10 alkyl. In some cases, for Z, the heterocycle includes at least one nitrogen atom. In some cases, Z is selected from phenyl groups that are to be substituted as desired and pyridine groups that are to be substituted as desired. In some cases, the optional substituents of the phenyl group that is to be substituted as desired in Z are selected from one or more substituents selected from halogens, -OH, -CN, -NO2, -NH2, syloxy, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl. In some cases, the optional substituent of the phenyl group to which Z is to be substituted is selected from one or more substituents selected from halogens and C1-10 alkyl groups. In some cases, the heterocycle is unsubstituted. In some cases, Z is selected from substituted phenyl groups 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 selected from [missing information - likely a specific type of phenyl group]. In some cases, the optional substituent of the phenyl group to which Z is to be substituted is halogen. In some cases, Z is selected from [missing information - likely a specific type of phenyl group]. In some cases, Z is a substituted phenyl group. In some cases, Z is a halogen-substituted phenyl group.

[0061] In some embodiments, the present invention provides a compound represented by formula (A*): (A*); R1 is selected from: -N(R5)2, wherein R5 is selected from hydrogen and C1-C6 alkyl groups that are substituted as desired, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbide ring, 3 to 12-membered heterocycles; The C1-C6 alkyl group is substituted as required, wherein the substituents on the C1-C6 alkyl group are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12 member heterocycles; The 3 to 8-membered heterocycles to be substituted as required; wherein the optional substituents on the 3 to 8-membered heterocycles are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12-membered heterocycles and C1-10 alkyl to be substituted as required, wherein the optional substituents on the C1-10 alkyl are independently selected each time from one or more hydroxyl groups, halogens, side oxygen, -C1-10 haloalkyl, -NH2, -CN and -NO2; The W group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as needed, wherein the substituents on each are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3- to 12-membered heterocycles, wherein the C3-12 carbon ring and the 3- to 12-membered heterocycles are each substituted as needed by one or more substituents that are independently selected from halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.The Y group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as desired, wherein the substituents on each are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon rings, and 3- to 12-membered heterocycles, wherein each of the C3-12 carbon rings and 3- to 12-membered heterocycles is substituted as desired by one or more substituents that are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.

[0062] In some states, the compound of formula (A) or formula (A*) is represented by formula (I).

[0063] In some embodiments, the present invention provides a compound represented by formula (A*): (A*); R1 is selected from: -N(R5)2, wherein R5 is selected from hydrogen and C1-C6 alkyl groups that are substituted as desired, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbide ring, 3 to 12-membered heterocycles; The C1-C6 alkyl group is substituted as required, wherein the substituents on the C1-C6 alkyl group are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12 member heterocycles; The 3 to 14-membered heterocycles may be substituted as required; wherein the optional substituents on the 3 to 8-membered heterocycles are each independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, -S(O2)NH2, -C1-10 heteroalkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12-membered heterocycles and C1-10 alkyl groups may be substituted as required, wherein the optional substituents on the C1-10 alkyl group are each independently selected from one or more hydroxyl groups, halogens, septyl group, -C1-10 haloalkyl, -NH2, -CN and -NO2; The W group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as needed, wherein the substituents on each are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3- to 12-membered heterocycles, wherein the C3-12 carbon ring and the 3- to 12-membered heterocycles are each substituted as needed by one or more substituents that are independently selected from halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.The Y group is selected from 5- to 8-membered heterocycles and C3- to C8 carbon rings that are substituted as desired, wherein the substituents on each are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon rings, and 3- to 12-membered heterocycles, wherein each of the C3-12 carbon rings and 3- to 12-membered heterocycles is substituted as desired by one or more substituents that are independently selected, each time they appear, from one or more halogens, -OH, -CN, -NO2, -NH2, oxy-peptide, =S, C1-10 alkyl, -C1-10 haloalkyl, and -O-C1-10 alkyl.

[0064] In some embodiments, the present invention provides a compound represented by formula (A*): (A*); R1 is selected from: -N(R5)2, wherein R5 is selected from hydrogen and C1-C6 alkyl groups that are substituted as desired; C1-C6 alkyl groups that are substituted as desired; 3 to 14-membered heterocycles or 3 to 14-membered carbon rings that are substituted as desired; W is selected from 5 to 8-membered heterocycles and C3-C8 carbon rings that are substituted as desired; and Y is selected from 5 to 8-membered heterocycles and C3-C8 carbon rings that are substituted as desired.

[0065] In some embodiments, the R-series may be replaced by 3 to 14 heterocyclic members as needed.

[0066] In some embodiments, the present invention provides a compound represented by formula (I): (I); or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: -N(R5)2, wherein R5 is selected from hydrogen and, if desired, substituted C1-C6 alkyl groups, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbide ring, 3 to 12-membered heterocycles; The substituted C1-C6 alkyl group, wherein the substituents on the C1-C6 alkyl group are independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12 member heterocycles; The 3 to 8-membered heterocycles to be substituted as required; wherein the optional substituents on the 3 to 8-membered heterocycles are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, 3 to 12-membered heterocycles and C1-10 alkyl to be substituted as required, wherein the optional substituents on the C1-10 alkyl are independently selected each time from one or more hydroxyl groups, halogens, side oxygen, -C1-10 haloalkyl, -NH2, -CN and -NO2; R3 is selected from C1-C6 alkyl groups that are substituted as desired, 3- to 10-membered heterocycles that are substituted as desired, and C3-10 carbon rings that are substituted as desired, wherein the optional substituents thereon are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, C1-6 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon rings, and 3- to 12-membered heterocycles; R4 is selected from: hydrogen; The C1-C6 alkyl group may be substituted as required, wherein the optional substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -O-C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocycles;The C3-10 carbon ring is substituted as desired, wherein the optional substituents on the C3-10 carbon ring are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocycles; and the W series is selected from 5 to 8-membered heteroaryl groups substituted as desired, wherein the substituents on the 5 to 8-membered heteroaryl groups substituted as desired are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring, and 3 to 12-membered heterocycles. ;

[0067] In some embodiments, the present invention provides a compound represented by formula (I): (I); or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: -N(R5)2, wherein R5 is selected from hydrogen and, if desired, substituted C1-C6 alkyl; substituted C1-C6 alkyl; and, if desired, substituted 3 to 14-membered heterocycles (such as 5 to 6-membered heterocyclic alkyl); R3 is selected from, if desired, substituted C1-C6 alkyl, substituted 3 to 10-membered heterocycles, and substituted C3-10 carbon rings; R4 is selected from: hydrogen; substituted C1-C6 alkyl or substituted C1-C6 heteroalkyl; substituted C3-10 carbon rings or substituted 3 to 12-membered heterocycles; and W is selected from, if desired, substituted 5 to 8-membered heteroaryl (such as 5 to 6-membered heteroaryl).

[0068] In some embodiments, R4 is a C1-C6 alkyl group that needs to be substituted. In some embodiments, R4 is a C3-10 carbon ring that needs to be substituted.

[0069] In some embodiments, for compounds or salts of formula (A), (A*), or (I), when R1 is a methylpiperazine and W is a pyridine, R4 is not methyl. In some cases, when R1 is a pyridine and W is a pyridine, R4 is not methyl.

[0070] In some embodiments, for compounds or salts of formula (A), (A*), or (I), when W is a furan, R4 is not ethyl-1-one. In some cases, when W is a furan and R4 is cyclopentyl or cyclohexyl, R1 is not ethyl-1-one. In some cases, when W is a furan and R4 is cyclopentyl or cyclohexyl, R1 is not ethyl-1-one. In some cases, R1 is not...

[0071] In some embodiments, for compounds or salts of formula (A), (A*), or (I), W is selected from 5- to 8-membered heterocycles as desired for substitution. 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 1 nitrogen atom and 1 oxygen atom.

[0072] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), the R1 group is optionally substituted. In some embodiments, the R1 group is optionally substituted with 1 to 4 substituents. In some embodiments, the R1 group is optionally substituted with 1 to 3 substituents. In some embodiments, the R1 group is optionally substituted with 1 to 2 substituents. In some embodiments, the R1 group is optionally substituted with 1 substituent. In some embodiments, the R1 group is optionally substituted with 2 substituents. In some embodiments, the R1 group is optionally substituted with 3 substituents. In some embodiments, the R1 group is a monocyclic ring. In some embodiments, the R1 group is a bicyclic ring. In some embodiments, the R1 group is a bridged ring. In some embodiments, the R1 group is a fused ring. In some embodiments, the R1 group is a spirocyclic ring. In some embodiments, the R1 group is optionally substituted with 3 to 12-membered rings. In some embodiments, the R1 group is optionally substituted with 5 to 8-membered rings.

[0073] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), the R1 series is substituted with oxides as needed.

[0074] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from substituted C1-C6 alkyl groups, wherein the substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbide ring and 3 to 12-membered heterocycles. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is selected from substituted C1-C6 alkyl groups, wherein the substituents on the C1-C6 alkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, =S, -C1-6 haloalkyl, -O-C1-6 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-6 alkyl), C2-6 alkenyl, C2-6 ynyl, C3-6 carbocyclic, and 3 to 12-membered heterocycles. In some embodiments, R1 is a substituted C1-C3 alkyl group as desired. In some embodiments, R1 is substituted as desired with one or more substituents selected from oxy groups, halogens, -O-C1-10 alkyl, -C1-10 haloalkyl, and -OH.

[0075] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 refers to a C1-C10 heteroalkyl group that needs to be substituted. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 refers to a C1-C6 heteroalkyl group that needs to be substituted, wherein the substituents on the C1-C6 heteroalkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, =S, -C1-10 haloalkyl, -C2-10 alkenyl, C2-10 alkynyl, C3-12 carbide rings, and 3 to 12-membered heterocycles. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 refers to a C1-C6 heteroalkyl group that is substituted as desired, wherein the substituents on the C1-C6 heteroalkyl group are independently selected each time from one or more halogens, -OH, -CN, -NO2, -NH2, =S, -C1-3 haloalkyl, -C2-6 alkenyl, C2-6 ynyl, C3-6 carbide ring, and 3 to 12 heterocyclic rings.

[0076] In some cases, when W is a furan, R1 is selected from substituted C1-C6 alkyl groups, wherein the substituents on the C1-C6 alkyl group are independently selected each time they appear from one or more halogens, -OH, -CN, -NO2, -NH2, side oxygen, =S, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl), C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring and 3 to 12 member heterocycles.

[0077] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from -N(R5)2, and in some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from -N(R5)2, wherein R5 is selected from C1-C6 alkyl groups that are to be substituted as desired, wherein optional substituents on the C1-C6 alkyl groups are selected from hydroxyl groups.

[0078] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from substituted C1-C6 alkyl groups and, as desired, substituted 3 to 8-membered heterocycles.

[0079] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a substituted C1-C6 alkyl group. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is selected from substituted C1-C6 alkyl groups, wherein the substituents are selected from hydroxyl, side-oxygen, and -O-C1-10 alkyl groups.

[0080] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a 3- to 8-membered heterocycle that needs to be substituted. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is selected from 5- to 6-membered heterocycles that need to be substituted. In some embodiments, R1 is a monocyclic ring. In some embodiments, R1 is a bicyclic ring. In some embodiments, R1 is a fused bicyclic group. In some embodiments, R1 is a bridged bicyclic group. In some embodiments, R1 is a 5-membered heterocycle that needs to be substituted. In some embodiments, R1 is a heteroaryl group that needs to be substituted. In some embodiments, R1 is a heterocyclic alkyl group that needs to be substituted. In some embodiments, the ring of R1 contains 0 to 3 nitrogen atoms and 0 to 1 oxygen atom. In some embodiments, the ring of R1 contains 1 to 2 nitrogen atoms and 0 to 1 oxygen atom. In some embodiments, R1 contains 1 to 2 cyclic nitrogen atoms. In some embodiments, R1 contains 2 cyclic nitrogen atoms. In some embodiments, R1 contains one cyclic nitrogen atom.

[0081] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is a 6-membered heterocycle that is substituted as needed.

[0082] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a piperazine that is substituted as desired. In some embodiments, R1 is a piperazine that is substituted as desired, wherein the piperazine is nitrogen-bound to the remainder of the compound (e.g., bound to a phenyl group). In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a piperazine that is substituted with one or more C1-6 alkyl groups as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a piperazine that is substituted with one or more substituents selected from methyl, ethyl, and propyl groups as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a piperazine that is substituted with one or more methyl groups as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 refers to piperazines that are optionally substituted with one or more C1-6 alkyl groups, wherein the alkyl group is optionally substituted with a hydroxyl group, a halogen group, a side oxygen group, or -NH2. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 refers to piperazines that are optionally substituted with an oxide.

[0083] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), the optional substituents on the piperazine of R1 that need to be substituted are selected from syloxy groups, -S(O2)NH2, and C1-10 alkyl groups that need to be substituted, wherein the optional substituents on the C1-10 alkyl group are independently selected each time they appear from one or more hydroxyl groups, halogens, syloxy groups, and -NH2. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), the optional substituents on the piperazine of R1 that need to be substituted are selected from syloxy groups, -S(O2)NH2, -S(O2)N(C1-6 alkyl)2, -S(O2)NH(C1-6 alkyl), and C1-6 alkyl groups that need to be substituted. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is substituted with a heteroalkyl group that needs to be substituted. In some embodiments, the R1 group may be substituted as required by one or more substituents selected from halogens, -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.

[0084] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a 3- to 10-membered heterocycle that is to be substituted as desired. In some cases, R1 is a 4- to 8-membered heterocycle that is to be substituted as desired. In some cases, R1 is a 4-membered heterocycle that is to be substituted as desired. In some cases, R1 is a 6-membered heterocycle that is to be substituted as desired. In some cases, when R1 is a piperazine, the piperazine is substituted. In some cases, R1 is not an unsubstituted piperazine. In some cases, R1 is a substituted 3- to 10-membered heterocycle.

[0085] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), for R1, the optional substituents of the heterocycle are independently selected each time from one or more substituents selected from halogens, -OH, -CN, -NO2, -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, side-oxygen, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl and C1-10 alkyl substituted as desired, wherein the optional substituents on the C1-10 alkyl are independently selected each time from one or more hydroxyl groups, halogens, side-oxygen groups, -C1-10 haloalkyl, -NH2, -CN, -O-C1-10 alkyl and -NO2.

[0086] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), the optional substituents of R1 are independently selected each time they appear from one or more substituents selected from -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, side oxygen and C1-10 alkyl that is substituted as desired, wherein the optional substituents on the C1-10 alkyl are independently selected each time they appear from one or more side oxygen and -O-C1-10 alkyl.

[0087] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), the optional substituents of R1 are independently selected each time they appear from one or more substituents selected from -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, side oxygen and C1-10 alkyl that is substituted as desired, wherein the optional substituents on the C1-10 alkyl are independently selected each time they appear from one or more side oxygen and -O-C1-10 alkyl.

[0088] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), the heterocycle has at least one nitrogen atom, phosphorus atom, or oxygen atom for R1. In some cases, the heterocycle has at least one nitrogen atom for R1. In some cases, the heterocycle has at least two nitrogen atoms for R1. In some cases, the heterocycle has at most two nitrogen atoms for R1. In some cases, the heterocycle has at most one nitrogen atom for R1. In some cases, the heterocycle has two nitrogen atoms for R1. In some cases, the heterocycle is a screwed heterocycle for R1. In some cases, the heterocycle is a bridged heterocycle for R1. In some cases, the heterocycle is unsaturated for R1. In some cases, the heterocycle is saturated for R1.

[0089] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , ...

[0090] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is selected from , ...

[0091] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , ...

[0092] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , ...

[0093] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , ...

[0094] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , , , , , , , , , , , , , , , , , , , , , , and .

[0095] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from (A), (I), and (IIB).

[0096] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a 6- to 10-membered heterocyclic alkyl group that is substituted as desired. In some cases, the optional substituent of the 6- to 10-membered heterocyclic alkyl group that is substituted as desired in R1 is selected from C1-6 alkyl groups. In some cases, the 6- to 10-membered heterocyclic alkyl group is a spirocyclic alkyl group. In some cases, R1 is selected from piperazine that is substituted as desired, diazabicyclo[3.2.1]octane that is substituted as desired, diazabicyclo[3.1.1]heptane that is substituted as desired, diazaspiro[3.5]nonane that is substituted as desired, and diazaspiro[3.3]heptane that is substituted as desired. In some cases, these optional groups are selected from C1-6 alkyl groups.

[0097] In some embodiments, the R3 group is substituted for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB). In some embodiments, the R3 group is substituted with 1 to 4 substituents. In some embodiments, the R3 group is substituted with 1 to 3 substituents. In some embodiments, the R3 group is substituted with 1 to 2 substituents. In some embodiments, the R3 group is substituted with 1 substituent. In some embodiments, the R3 group is substituted with 2 substituents. In some embodiments, the R3 group is substituted with 3 substituents.

[0098] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R3 is selected from C3-6 carbon rings that are to be substituted as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R3 is selected from C3-6 cycloalkyl groups that are to be substituted as desired.

[0099] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R3 is a phenyl group that is substituted as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R3 is a phenyl group that is substituted with one or more halogens as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R3 is a phenyl group that is substituted with 1 to 3 halogens as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R3 is a phenyl group that is substituted with 1 to 2 halogens as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R3 is a phenyl group that is substituted with one halogen as desired.

[0100] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), the optional substituents of the phenyl group of R3 are selected from halogens and -C1-10 haloalkyl groups. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), the optional substituents of the phenyl group of R3 are selected from halogens and -C1-3 haloalkyl groups.

[0101] In some embodiments, R4 is unsubstituted for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB). In some embodiments, R4 is substituted for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB). In some embodiments, R4 is substituted for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB) by one or more substituents selected from halogens, -OH, -CN, -NO2, -NH2, syloxy groups, =S, -O-C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbide rings, and 3 to 12-membered heterocycles. In some embodiments, R4 is substituted with one or more substituents selected from halogens, -OH, -CN, -NO2, -NH2, oxy-groups, =S, -O-C1-6 alkyl, -C1-6 haloalkyl, -O-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclic rings, and 3 to 12-membered heterocyclic rings. In some embodiments, R4 is substituted with one or more substituents selected from halogens, -OH, -CN, -NO2, -NH2, oxy-groups, =S, -O-C1-6 alkyl, -C1-6 haloalkyl, and -O-C1-6 alkyl. In some embodiments, R4 is substituted with one or more halogens. In some embodiments, R4 is substituted with one halogen. In some embodiments, R4 is substituted with two halogens. In some embodiments, the R4 group is substituted with three halogens.

[0102] In some embodiments, R4 is a hydrogen group for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB).

[0103] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R4 is selected from C1-C6 alkyl groups and C3-6 carbon rings that are substituted as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R4 is a cycloalkyl group that is substituted as desired. In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R4 is an aryl group that is substituted as desired.

[0104] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), the optional substituent group of the C1-C6 alkyl group of R4 is selected from halogens.

[0105] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), the optional substituents of the C3-C6 carbon ring of R4 are selected from hydroxyl groups.

[0106] In some embodiments, for compounds or salts of formula (A), (A*) or (I), W is selected from 5 to 6 heteroaryl groups.

[0107] In some embodiments, for compounds or salts of formula (A), (A*) or (I), the 5 to 6 heteroaryl groups of W are selected from imidazole, furan, thiophene, oxazole, isoxazole, thiazole, oxadiazole, thiadiazole, pyridine, pyrazine, pyrimidine and pyrazine.

[0108] In some embodiments, for compounds or salts of formula (A), (A*) or (I), the 5 to 6 heteroaryl groups of W are selected from imidazole, furan and pyridine.

[0109] In some embodiments, W is an imidazole for compounds or salts of formula (A), (A*), or (I). In some embodiments, W is a pyridine for compounds or salts of formula (A), (A*), or (I).

[0110] In some embodiments, for compounds or salts of formula (A), (A*) or (I), W is selected from 5 to 6 heteroaryl groups as desired to be substituted.

[0111] In some embodiments, for compounds or salts of formula (A), (A*) or (I), W is selected from pyridine, imidazole, thiazole and furan.

[0112] In some embodiments, for compounds or salts of formula (A), (A*) or (I), W is selected from pyridine and imidazole.

[0113] In some cases, the compound or salt of formula (I) is represented by formula (IIA): (IIA); or a pharmaceutically acceptable salt thereof.

[0114] In some cases, the compound or salt of formula (I) is represented by formula (IIB): (IIB); or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R3 is selected from C1-C6 alkyl groups and C6 carbon rings that are substituted as desired.

[0116] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R3 is selected from C1-C6 alkyl groups and wherein the C6 carbide ring is substituted by one or more substituents selected from halogens and -C1-10 haloalkyl groups.

[0117] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R3 is selected from , , , and .

[0118] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R3 is a C6 carbon ring substituted with one or more substituents selected from halogens.

[0119] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R3 is a phenyl group, wherein the phenyl group is substituted with one or more halogens as required.

[0120] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R3 is selected from (A), (I), and (IIB).

[0121] In some embodiments, the R3 system is used for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB).

[0122] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is selected from hydrogen, C1-C6 alkyl groups substituted with one or more substituents selected from halogens as needed, and C5-6 carbon rings substituted with one or more substituents selected from hydroxyl and amines as needed.

[0123] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is an unsubstituted C1-C6 alkyl group.

[0124] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is a substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted with one or more halogens.

[0125] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is selected from , , , , , and.

[0126] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is selected from C1-C6 alkyl groups substituted with one or more fluorine substituents as desired, and C6 cycloalkyl groups substituted with hydroxyl groups.

[0127] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is selected from , , and .

[0128] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), the R4 system is selected from [missing information]. In some embodiments, the R4 system is [missing information].

[0129] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is selected from , , , , , and.

[0130] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is selected from [1, 2, 3, 4, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ...

[0131] In some cases, R4 is selected from unsubstituted C1-10 alkyl groups, unsubstituted 3 to 6-membered heterocycles and, as needed, substituted C3-C6 carbon rings.

[0132] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), each R4 is selected from C1-10 alkyl, C3-12 carbon ring and 3 to 12-membered heterocycles each time it appears, wherein the C1-10 alkyl, C3-12 carbon ring and 3 to 12-membered heterocycle are each substituted as needed by one or more substituents selected independently each time from halogen, -OH, -CN, -NO2, -NH2, side oxygen, =S, C1-10 alkyl, -C1-10 haloalkyl and -O-C1-10 alkyl.

[0133] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R4 is selected from unsubstituted C1-10 alkyl groups, unsubstituted 3 to 6-membered heterocycles and, if necessary, substituted C3-C6 carbon rings, wherein such optional substituents are independently selected from one or more halogen-C1-10 haloalkyl groups.

[0134] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), each R4, in each occurrence, is selected from C1-10 alkyl groups, unsubstituted 4-membered heterocycles, and optionally substituted C3-C5 carbon rings, wherein these optional substituents are independently selected from one or more halogenated C1-10 haloalkyl groups. In some cases, R4 is selected from C1-10 alkyl groups. In some cases, R4 is selected from 4-membered heterocycles. In some cases, R4 is a 4-membered heterocycle. In some cases, R4 is a saturated 4-membered heterocycle.

[0135] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R4 is selected from [A*, B*, C*, D*, and E*]. In some cases, R4 is selected from [A*, B*, C*, and E*]. In some cases, R4 is selected from [A*, B*, C*, and E*].

[0136] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from: -N(R5)2, wherein R5 is selected from C1-C6 alkyl groups that are substituted as desired, wherein the substituents on the C1-C6 alkyl group are independently selected each time they appear from one or more halogens, -OH, -CN, -NO2, -NH2, sideoxy groups, -C1-10 haloalkyl, -O-C1-10 alkyl, substituted C1-C6 alkyl groups, wherein the substituents on the C1-C6 alkyl group are independently selected each time they appear from one or more halogens, -OH, -NH2, sideoxy groups, -C1-10 haloalkyl, -O-C1-10 alkyl, -O-C1-6 alkyl-OC(O)(O-C1-10 alkyl); The 6- to 8-membered heterocycles may be substituted as required; wherein the optional substituents on the 6- to 8-membered heterocycles are each independently selected from one or more septal oxygen groups, -S(O2)NH2, -NH2, -C1-10 haloalkyl, -O-C1-10 alkyl and C1-10 alkyl may be substituted as required, wherein the optional substituents on the C1-10 alkyl are each independently selected from one or more hydroxyl groups, halogens, septal oxygen groups, -C1-10 haloalkyl, -NH2, -CN and -NO2.

[0137] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , ...

[0138] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , , , , , , , , , , , , , and .

[0139] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from: , , , , , , , , , , , , and.

[0140] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from: substituted C1-C6 alkyl groups, wherein the substituents on the C1-C6 alkyl group are independently selected each time they appear from one or more halogens, -OH, side-oxygen groups, -C1-10 haloalkyl groups and -O-C1-10 alkyl groups; substituted 6 to 8-membered saturated heterocycles as desired; wherein the optional substituents are independently selected each time they appear from one or more -S(O2)NH2 groups and substituted C1-10 alkyl groups as desired, wherein the optional substituents on the C1-10 alkyl group are independently selected each time they appear from one or more hydroxyl groups, halogens, side-oxygen groups, -C1-10 haloalkyl groups and -NH2 groups.

[0141] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , , , , , , , and.

[0142] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from 6 to 8 saturated heterocycles that are substituted as desired; wherein the optional substituents are independently selected each time they appear from one or more -S(O2)NH2 and C1-10 alkyl groups that are substituted as desired, wherein the optional substituents on the C1-10 alkyl group are independently selected each time from one or more hydroxyl groups, halogens, side oxygen groups, -C1-10 haloalkyl groups and -NH2.

[0143] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , , , , , and.

[0144] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from substituted C1-C6 alkyl groups, wherein the substituents on the C1-C6 alkyl group are independently selected each time they appear from one or more halogens, -OH, side oxygen, -C1-10 haloalkyl and -O-C1-10 alkyl groups.

[0145] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from [1, 2, 3, 4, 5, 6, 7, 8, 9, 1 ...

[0146] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from: substituted C1-C6 alkyl groups, wherein the substituents on the C1-C6 alkyl group are independently selected from one or more -OH, side-oxygen, and -O-C1-10 alkyl groups each time they appear; substituted 6 to 8-membered saturated heterocycles as desired; wherein the optional substituents are independently selected from one or more C1-10 alkyl groups as desired each time they appear, wherein the optional substituents on the C1-10 alkyl group are independently selected from one or more hydroxyl, side-oxygen, -C1-10 haloalkyl, and -NH2 groups each time they appear.

[0147] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from: , , , , and.

[0148] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA), or (IIB), R1 is a piperazine, wherein the piperazine is substituted as desired with one or more substituents independently selected from hydroxyl, -S(O2)NH2, and C1-10 alkyl groups in each occurrence, wherein the C1-10 alkyl groups are substituted as desired with one or more substituents independently selected from hydroxyl, halogen, hydroxyl, and -NH2 groups in each occurrence. In some embodiments, R1 is a piperazine substituted with one or more C1-3 alkyl groups, wherein the C1-3 alkyl groups are substituted as desired with one or more substituents independently selected from hydroxyl, halogen, hydroxyl, and -NH2 groups in each occurrence.

[0149] In some embodiments, for compounds or salts of formula (A), (A*), (I), (IIA) or (IIB), R1 is selected from , , , , , , , , , and.

[0150] In some embodiments, the compound is not a compound or salt of formula (A), (A*), or (I). In some cases, the compound is not a compound.

[0151] In some embodiments, for compounds or salts of formula (A), (A*), or (I), R1 is selected from -N(R5)2, wherein R5 is selected from C1-C6 alkyl groups to be substituted as desired, wherein optional substituents on the C1-C6 alkyl group are selected from hydroxyl groups; substituted C1-C6 alkyl groups, wherein the substituents are selected from hydroxyl groups, side-oxy groups, and -O-C1-10 alkyl groups; and substituted 5- to 6-membered heterocycles to be substituted as desired, wherein the optional substituents are selected from side-oxy groups, -S(O2)NH2, and substituted C1-10 alkyl groups to be substituted as desired, wherein optional substituents on the C1-10 alkyl group are independently selected from one or more hydroxyl groups, halogens, side-oxy groups, and -NH2 groups each time they appear; R3 is a phenyl group to be substituted as desired, wherein optional substituents on the phenyl group of R3 are selected from halogens and -C1-10 haloalkyl groups; R4 is selected from C1-C6 alkyl groups and C3-6 carbon rings that are substituted as desired, wherein the optional substituents of the C1-C6 alkyl groups of R4 are selected from halogens and the optional substituents of the C3-C6 carbon rings of R4 are selected from hydroxyl groups; and W is selected from imidazole, furan and pyridine.

[0152] In some embodiments, for compounds or salts of formula (A), (A*), or (I), R1 is selected from -N(R5)2, wherein R5 is selected from C1-C6 alkyl groups to be substituted as desired, wherein optional substituents on the C1-C6 alkyl group are selected from hydroxyl groups; substituted C1-C6 alkyl groups, wherein the substituents are selected from hydroxyl groups, side-oxy groups, and -O-C1-10 alkyl groups; and substituted 5- to 6-membered heterocycles to be substituted as desired, wherein the optional substituents are selected from side-oxy groups, -S(O2)NH2, and substituted C1-10 alkyl groups to be substituted as desired, wherein optional substituents on the C1-10 alkyl group are independently selected from one or more hydroxyl groups, halogens, side-oxy groups, and -NH2 groups each time they appear; R3 is a phenyl group to be substituted as desired, wherein optional substituents on the phenyl group of R3 are selected from halogens and -C1-10 haloalkyl groups; R4 is selected from C1-C6 alkyl groups and C3-6 carbon rings that are substituted as desired, wherein the optional substituents of the C1-C6 alkyl groups of R4 are selected from halogens and wherein the optional substituents of the C3-C6 carbon rings of R4 are selected from hydroxyl groups; and W is selected from imidazoles.

[0153] In some embodiments, for compounds or salts of formula (A), (A*), (IIA), (IIB) or (I), the R1 series is selected from , , , , , , , , , , , , and; the R3 series; and the R4 series is selected from , , and.

[0154] This invention includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of this invention having sufficiently acidic, sufficiently basic, or both functional groups can react with any of a number of inorganic bases and inorganic and organic acids to form salts. Alternatively, inherently charged compounds (such as those having a quaternary nitrogen) can form salts with suitable relative ions (e.g., halide ions, such as bromide, chloride, or fluoride ions, particularly bromide ions).

[0155] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z or E forms (or cis or trans forms). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z, E, and tautomeric forms.

[0156] "Tautomer" refers to a molecule in which a proton can transfer from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist as tautomers. Where tautomerization is possible, a chemical equilibrium of such tautomers will exist. The precise ratio of such tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0157] In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, for example, enriched in 2H, 3H, 11C, 13C, and / or 14C content. In a particular embodiment, the compound is deuterated at at least one position. These deuterated forms can be manufactured 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, thereby increasing the duration of drug action.

[0158] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of the invention, except for hydrogen substitution by deuterium or tritium, or carbon substitution by 13C- or 14C enriched carbon.

[0159] The compounds of the present invention may contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds, as desired. For example, such compounds may be labeled with isotopes such as, for instance, deuterium (2H), tritium (3H), iodine-125 (125I), or carbon-14 (14C). Isotopic substitutions using 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, and 125I have been carefully considered. All isotopic variations (whether radioactive or not) of the compounds of the present invention are included within the scope of the present invention. In some embodiments illustrating isotopic variations, the remaining atoms of the compound may contain atomic isotopes in non-natural proportions, as desired.

[0160] In some embodiments, some or all of the 1H atoms of the compounds disclosed herein have been replaced with 2H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include (by means of non-limiting examples) the following synthetic methods.

[0161] The deuterated compounds were synthesized using various methods described in the following: Dean, Dennis C. (ed.); Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; 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.

[0162] Deuteration starting materials are readily available and can be synthesized using the methods described herein to provide for the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and building blocks are available from chemical suppliers such as Aldrich Chemical Co.

[0163] In some embodiments of the compounds disclosed herein, one or more of the R1, R3, R4, R5, W, Z, Y and R10 groups contain deuterium in a percentage higher than the natural abundance of deuterium.

[0164] In some embodiments of the compounds disclosed herein, one or more hydrogen atoms are replaced by one or more deuterium groups R1, R3, R4, R5, W, Z, Y and R10.

[0165] In some embodiments of the compounds disclosed herein, the abundance of deuterium in each of R1, R3, R4, R5, W, Z, Y and R10 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 amount of hydrogen and deuterium.

[0166] In some embodiments of the compounds disclosed herein, one or more hydrogen systems of ring W are replaced by one or more deuteriums.

[0167] The compounds of the present invention also include crystalline and amorphous forms of such compounds, pharmaceutically acceptable salts and active metabolites of such compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), configurational polymorphs and amorphous forms of such compounds, and mixtures thereof.

[0168] In some cases, the compounds described herein may exist as non-mirror image isomers, enantiomers, or other stereoisomers. Unless otherwise specified, the compounds presented herein include all non-mirror image isomers, enantiomers, and epimers, and suitable mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming non-mirror image isomers 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). Stereoisomers may also be obtained by stereoselective synthesis.

[0169] The methods and compositions described herein include the use of amorphous and 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 such compounds having the same type of activity are included within the scope of the invention. Furthermore, the compounds described herein may be present in both non-solventized and solvated forms in pharmaceutically acceptable solvents (such as water, ethanol, and the like). It is also considered that the solvated forms of the compounds presented herein are disclosed herein.

[0170] In some embodiments, the compound or a salt of such compounds may be a prodrug, for example, wherein the hydroxyl group in the parent compound is presented in the form of an ester or carboxylic acid ester, or the carboxylic acid present in the parent compound is presented in the form of an ester. The term "prodrug" is intended to include compounds that, under physiological conditions, are converted into the pharmaceutical agents of the present invention. A method for manufacturing a prodrug includes hydrolysis of one or more molecules under physiological conditions to reveal selected portions of the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal (such as specific target cells in the host animal). For example, esters or carbonates (e.g., esters of alcohols or carboxylic acids or esters of carbonates and phosphonates) are preferred prodrugs of the present invention.

[0171] The compounds described herein are in prodrug form, wherein the prodrug is metabolized in vivo to produce compounds as listed herein, and are included within the scope of the technical solutions. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0172] Prodrugs are often useful because, in some cases, they can be administered more easily than parent drugs. They may be bioavailable, for example, by oral administration, whereas parents are not. Prodrugs can help enhance the cellular permeability of compounds compared to parent drugs. Prodrugs may also have improved solubility in pharmaceutical compositions compared to parent drugs. Prodrugs can be engineered as reversible drug derivatives to act as modifiers to enhance drug delivery to site-specific tissues or increase drug retention within cells.

[0173] In some embodiments, the prodrug is designed to increase the lipophilicity of the agent. In some embodiments, the prodrug is designed to increase effective water solubility. See, for example, 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, ACS Symposium Series, Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (both incorporated herein by reference). According to another embodiment, the present invention provides a method for producing compounds as defined above. These compounds can be synthesized using known techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0174] The synthetic chemical transformations and methodologies applicable to the synthesis of the compounds described herein are known in this art and include, for example, those described in: R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd edition (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). C. Pharmaceutical Compositions

[0175] In some embodiments, this document provides a composition comprising a therapeutically effective amount of any compound or salt of any of formula (A), (A*), (I), (IIA) or (IIB) (also referred to herein as a "pharmaceutical").

[0176] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers (including excipients and adjuvants that facilitate the processing of the pharmaceutical composition into a pharmaceutically usable formulation). Appropriate formulations depend on the chosen route of administration. A summary of pharmaceutical compositions can be found (for example): 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).

[0177] The compositions and methods of the present invention can be used to treat individuals in need. In some embodiments, the system is a mammal (such as a human) or a non-human mammal. When administered to an animal (such as a human), the composition or agent is preferably administered in the form of a pharmaceutical composition comprising, for example, an 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 physiologically buffered saline or other solvents or mediators such as glycols, glycerol, oils (such as olive oil), or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are administered to humans, particularly via invasive routes of administration, such as those avoiding delivery or diffusion across the epithelial barrier, such as injection or implantation, the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipients may be selected, for example, to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units, such as tablets, capsules, granules, lyophilized formulations for reconstitution, powders, solutions, syrups, suppositories, injections, or the like. The composition may also be present in transdermal delivery systems (e.g., skin patches). The composition may also be present in solutions suitable for topical administration (e.g., eye drops).

[0178] The pharmaceutical composition may 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 may be used to treat fibrotic diseases or conditions, including (but not limited to) chronic renal fibrosis (“CKD”), cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, cutaneous fibrosis, systemic sclerosis (“SSc”), and graft-versus-host disease (“GVHD”). In some cases, the pharmaceutical composition may be used to treat renal fibrosis. In some cases, the pharmaceutical composition may be used to treat cutaneous fibrosis. In some cases, the pharmaceutical composition may be used to treat idiopathic pulmonary fibrosis (IPF). In some cases, the pharmaceutical composition may be used to treat diseases associated with TNIK kinase.

[0179] Pharmaceutically acceptable excipients may contain physiologically acceptable agents for, for example, stabilizing, increasing the solubility of compounds (such as pharmaceuticals), or increasing their absorption. Such physiologically acceptable agents include, for example, sugars (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 selection of pharmaceutically acceptable excipients (including physiologically acceptable agents) depends on, for example, the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix in which, for example, compounds of the present invention may be incorporated. Liposomes (e.g., those comprising phospholipids or other lipids) are relatively easy to manufacture and administer as non-toxic, physiologically acceptable, and metabolizable carriers.

[0180] The pharmaceutical composition (formulation) may be administered to a subject via any of a number of routes of administration, including, for example, oral administration, such as in the form of an aqueous or non-aqueous solution or suspension, tablets, capsules (including dispersible capsules and gelatin capsules), granules, powders, or pastes to the tongue; absorption through the oral mucosa, such as sublingually; anal, rectal, or vaginal administration, such as in the form of a pessary, cream, or foam; non-enteric administration, including intramuscular, intravenous, subcutaneous, or intrathecal administration, such as in the form of a sterile solution or suspension; nasal administration; intraperitoneal administration; subcutaneous administration; transdermal administration, such as in the form of a patch; and topical administration, such as in the form of a cream, ointment, or spray, or in the form of eye drops. The compound may also be formulated for inhalation. In some embodiments, the compound may be simply dissolved or suspended in sterile water.

[0181] The pharmaceutical composition may be a sterile aqueous or non-aqueous solution, a suspension or an emulsion, such as a microemulsion. The excipients described herein are examples and are not intended to limit the scope in any way. An effective amount or therapeutically effective amount means the amount of one or more pharmaceutical agents administered to a subject in the form of a single dose or a portion of a series of doses to effectively produce the desired therapeutic effect.

[0182] Subjects may be monitored for treatment effectiveness using analyses and methods generally applicable to the condition being treated, analyses familiar to those skilled in the art and described herein. The pharmacokinetics of a drug or one or more of its metabolites administered to a subject may be monitored by measuring the amount of the drug or metabolite in a biological fluid from the subject, such as blood, blood fractions (e.g., serum), and / or urine and / or other biological samples or tissues. Any method practiced in this art and described herein for detecting the drug may be used to measure the amount of the drug or metabolite during treatment.

[0183] The dosage of the pharmaceutical agent described herein for treating a disease or ailment may depend on the subject's condition (i.e., stage of disease, severity of symptoms caused by the disease, general health status), age, sex, weight, and other factors readily apparent to a person skilled in the medical field. The pharmaceutical composition may be administered in a manner appropriate for the disease to be treated, as determined by a person skilled in the medical field. In addition to the factors described herein and above regarding the use of the pharmaceutical agent to treat a disease or ailment, the appropriate duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dosage of the pharmaceutical agent may generally be determined using experimental models and / or clinical trials. This optimal dosage may depend on the subject's body mass, weight, or blood volume. Generally, the minimum dose sufficient to provide an effective therapy is preferred. The design and execution of preclinical and clinical studies of the pharmaceutical agent described herein (including when administered for preventative benefit) are entirely within the technical scope of a person skilled in the relevant field. When two or more agents are administered to treat a disease or ailment, the optimal dosage of each agent may be different, such as less than when any agent is administered alone as a monotherapy. In certain specific embodiments, the two agents in combination may act synergistically or additively, and each agent may be used in a smaller amount than when administered alone. The daily dosage of the agent may be, for example, between about 0.01 mg / kg and 100 mg / kg, such as between about 0.1 and 1 mg / kg, between about 1 and 10 mg / kg, between about 10 and 50 mg / kg, or between about 50 and 100 mg / kg body weight. In other embodiments, the daily dosage of the agent may be between about 0.01 mg / kg and 1000 mg / kg, between about 100 and 500 mg / kg, or between about 500 and 1000 mg / kg body weight. The optimal dosage for each day or each course of treatment may vary depending on the disease or ailment being treated, as well as the route of administration and treatment regimen.

[0184] A pharmaceutical composition containing a pharmaceutical agent can be formulated in a manner suitable for delivery methods using techniques routinely practiced in this art. The composition can be in the form of a solid (e.g., tablets, capsules), a semi-solid (e.g., gel), a liquid, or a gas (e.g., aerosol). In other embodiments, the pharmaceutical composition is administered by injection.

[0185] Pharmaceutically acceptable excipients are well known in the pharmaceutical field and 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)). Exemplary pharmaceutically acceptable excipients include sterile saline at physiological pH and phosphate-buffered saline. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. Antioxidants and suspending agents may also be used. Generally, the type of excipient is selected based on the dosing method and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilized products. The compositions described herein may be lyophilized or further formulated as lyophilized products using one or more suitable excipient solutions to dissolve and / or dilute the pharmaceutical composition at dosing. In other embodiments, the agent may be encapsulated in liposomes using techniques known and practiced in this art. In certain specific embodiments, the agent is not formulated into liposomes for administration to stents used to treat highly but not completely occluded arteries. The pharmaceutical composition may be formulated for any suitable administration method described herein and in this art.

[0186] Pharmaceutical compositions (e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other methods) may be in liquid form. Liquid pharmaceutical compositions may include, for example, one or more of the following: sterile diluents, such as water, physiological saline, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils that can be used as solvents or suspension media, polyethylene glycol, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers; and agents for regulating tension, such as sodium chloride or glucose. Non-entericidal compositions may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Physiological 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. Liquid pharmaceutical compositions may be delivered orally.

[0187] For oral formulations, at least one of the pharmaceutical agents described herein may be used alone or in combination with suitable additives to manufacture tablets, powders, granules, or capsules, and, as needed, in combination with diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents. These pharmaceutical agents may be buffered to provide protection of the compound from the low pH of the gastric environment and / or to provide an enteric coating. Pharmaceutical agents included in the pharmaceutical composition may be flavored for oral delivery, (e.g.) as liquid, solid, or semi-solid formulations and / or with an enteric coating.

[0188] Pharmaceutical compositions comprising any of the agents described herein may be formulated for sustained or slow release, also known as timed or controlled release. These compositions may be prepared using generally known techniques and administered via, for example, oral, rectal, intradermal, or subcutaneous implantation, or implantation at a desired target site. Sustained-release formulations may contain compounds dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-controlled membrane. Excipients used in such formulations are biocompatible and may also be biodegradable; preferably, the formulation provides a relatively constant level of release of the active ingredient. The amount of agent contained in a sustained-release formulation depends on the implantation site, the rate of release and the expected duration, and the nature of the condition, disease, or ailment to be treated or prevented.

[0189] In some embodiments, the pharmaceutical composition containing the agent is formulated for transdermal, intradermal, or topical administration. These compositions can be administered using syringes, bandages, transdermal patches, inserts, or syringe-like applicators in the form of powders / talc or other solids, liquids, sprays, aerosols, ointments, foams, creams, gels, or pastes. Preferably, this is in the form of a controlled-release or continuously released formulation administered topically or directly into the skin (e.g., intradermal or subcutaneous) near or within the area to be treated. The active composition can also be delivered via iontophoresis. Preservatives may be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include (but are not limited to) benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate, sodium propionate, benzalkonium chloride, benzyl chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethanol, sodium ethylmercuric thiosalicylate, and combinations thereof.

[0190] Pharmaceutical compositions containing a pharmaceutical agent may be formulated into emulsions for topical application. The emulsion contains a liquid distributed within a bulk of a second liquid. The emulsion may be an oil-in-water emulsion or an oil-in-water emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oil-based pharmaceutically approved excipients. Suitable surfactants include (but are not limited to) anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, softener, or humectant.

[0191] Ointments and creams may be formulated, for example, with a water-based or oil-based formulation and the addition of suitable thickeners and / or modifiers. Lotions may be formulated with a water-based or oil-based formulation and generally will contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Liquid sprays may be delivered from pressurized packaging, for example, via specially shaped closures. Oil-in-water emulsions may also be used in compositions, patches, bandages, and articles. These systems are semi-solid emulsions, microemulsions, or foam emulsion systems.

[0192] In some embodiments, the pharmaceutical preparations described herein can be formulated as inhalers. Inhalation methods can deliver the medication directly to the airways. The pharmaceutical preparations can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical preparations can be formulated with solvents, gases, nitrates, or any combination thereof. The compositions described herein are formulated as needed to be delivered as liquid aerosols or inhalable dry powders. Liquid aerosol formulations are, as needed, primarily nebulized to a particle size deliverable to the terminal and respiratory bronchioles. Liquid aerosols and inhalable dry powder formulations are preferably delivered via the bronchial canal to the terminal bronchioles and ultimately to the parenchymal tissue.

[0193] The nebulizer formulations described herein are delivered as needed using an aerosol forming device (such as a jet injector, vibrating perforated plate, or ultrasonic nebulizer), preferably selected to allow the formation of aerosol particles with an average diameter primarily between 1 and 5 μm. Furthermore, the formulation preferably has a balanced osmotic pressure ionic strength and chloride concentration, and a minimum nebulizable volume for delivering an effective dose of medication. Additionally, the nebulizer formulation preferably does not negatively impair airway function and does not cause unwanted side effects.

[0194] Atomizing devices suitable for dispensing the aerosol formulations described herein include, for example, injectors, vibrating perforated plates, ultrasonic atomizers, and electrically heated dry powder inhalers capable of atomizing the formulations into aerosol particles with a primary size range of 1 to 5 μm. In this application, it is primarily meant that at least 70%, but preferably greater than 90%, of all generated aerosol particles are in the range of 1 to 5 μm. Injector atomizers operate by means of air pressure to break down liquid solutions into aerosol droplets. Vibrating perforated plate atomizers operate by using sonic vacuum generated by a rapidly vibrating perforated plate to force solvent droplets through the perforated plate. Ultrasonic atomizers operate by means of piezoelectric crystals that shear liquids into small aerosol droplets. A variety of suitable devices are available for purchase, including (for example) AeroNeb™ and AeroDose™ vibrating perforated plate atomizers (AeroGen, Inc., Sunnyvale, California), Sidestream® atomizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet atomizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany), and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic atomizers.

[0195] In some embodiments, the agent may be formulated with an oily matrix or ointment to form a semi-solid composition having the desired shape. In addition to the agent, such semi-solid compositions may contain dissolved and / or suspended bactericides, preservatives, and / or buffer systems. The petrolatum component may be any paraffin with a viscosity ranging from mineral oils incorporating isobutylene, colloidal silica, or stearates to paraffin waxes. An absorbent base may be used with the oily system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, lanolin alcohol, low HLB (hydrophobic-oleophobic balance) emulsifiers), and a variety of ionic and nonionic surfactants, alone or in combination.

[0196] Controlled or sustained release of transdermal or local formulations can be achieved by adding timed-release additives (such as polymeric structures, matrices) available in this technology. For example, the composition can be administered using a hot-melt extrusion article (such as a bioadhesive hot-melt extrusion film). The formulation may contain a cross-linked polycarboxylic acid polymer formulation. The cross-linking agent can provide a sufficient amount of adhesion to allow the system to remain bound to the surface of the target epithelial or endothelial cells for a sufficient duration to allow the desired release of the compound.

[0197] Inserts, transdermal patches, bandages, or articles may comprise mixtures or coatings of polymers that provide drug release at a constant rate over an extended time period. In some embodiments, the article, transdermal patch, or insert comprises a water-soluble pore-forming agent, such as polyethylene glycol (PEG), which may be mixed with a water-insoluble polymer to increase the durability of the insert and prolong the release of the active ingredient.

[0198] Transdermal devices (insertions, patches, bandages) may also contain water-insoluble polymers. Rate-controlled polymers are suitable for administration to sites where pH changes can affect release. These rate-controlled polymers can be applied using a continuous coating film during the spraying and drying process with an active compound. In one embodiment, a coating formulation is used to coat aggregates containing an active ingredient compressed to form a solid, biodegradable insert.

[0199] Polymer formulations can also be used to provide controlled or sustained release. Bioadhesive polymers described in this art can be used. By way of example only, sustained-release gels and compounds can be incorporated into a polymer matrix (such as a hydrophobic polymer matrix). Examples of polymer matrices include microparticles. These microparticles can be microspheres, and the core can be a material different from the polymer shell. Alternatively, the polymer can be cast into sheets or films, produced as powders or gels (such as hydrogels) by grinding or other standard techniques. The polymer can also be in the form of coatings or portions of bandages, stents, catheters, vascular grafts, or other devices that facilitate drug delivery. The matrix can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0200] Kits are provided containing one or more of the pharmaceutical agents described herein in unit doses, typically in oral or injectable doses. Such kits may include a container containing the unit dose, an informational insert describing the use of the drug in treating a disease and its associated benefits, and, if necessary, an apparatus or device for delivering the composition. D. Treatment Methods

[0201] The compounds described herein can be used to prepare medicaments for the prevention or treatment of diseases or conditions. Additionally, a method for treating any of the diseases or conditions described herein in a subject requiring such treatment involves administering to the subject a pharmaceutical composition containing a therapeutically effective amount of at least one of the compounds described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0202] Compositions containing the compounds described herein may be administered for preventative and / or therapeutic treatment. In therapeutic use, the compositions are administered to a patient suffering from the disease or condition in an amount sufficient to cure or at least partially suppress the symptoms of the disease or condition. The effective amount for this purpose will depend on the severity and course of the disease or condition, prior therapy, the patient's health status, weight and response to the drug, and the judgment of the attending physician.

[0203] In prophylactic use, compositions containing the compounds described herein are administered to patients who are susceptible to or otherwise at risk of a particular disease, ailment, or condition. This amount is defined as a "prophylactic effective amount or dose." In this use, the precise amount also depends on the patient's health status, weight, and the like. When used on a patient, the effective amount for this purpose will depend on the severity and course of the disease, ailment, or condition, prior therapy, the patient's health status and response to the drug, and the judgment of the attending physician.

[0204] In cases where the patient’s condition does not improve, the compound may be administered for an extended period of time, as determined by the physician, including the entire lifespan of the patient, to improve or otherwise control or limit the symptoms of the patient’s disease or condition.

[0205] If the patient's symptoms have improved, a maintenance dose may be administered as needed. Subsequently, the dose or frequency, or both, may be reduced to maintain the improved level of the disease, ailment, or condition, depending on the symptoms. However, if symptoms recur, the patient may require long-term intermittent treatment.

[0206] The amount of a given agent corresponding to this quantity will vary depending on factors such as the specific compound, the disease or condition and its severity, and the identity (e.g., weight) of the subject or host to be treated. However, it may be determined in a manner recognized in the art based on the specific circumstances surrounding the case, including (e.g.) the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated. Generally, however, the dose for adult treatment will 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 required dose may be conveniently administered as a single dose or as fractions administered simultaneously (or over short periods) or at appropriate intervals, for example, as two, three, four, or more sub-dose per day. In some embodiments, the compounds and pharmaceutical compositions described herein are administered once daily. In some embodiments, the compounds and pharmaceutical compositions described herein are administered twice daily. In some embodiments, the compounds and pharmaceutical compositions described herein are administered three times daily. In some embodiments, the compounds and pharmaceutical compositions described herein are administered once weekly. In some embodiments, the compounds and pharmaceutical compositions described herein are administered twice weekly. In some embodiments, the compounds and pharmaceutical compositions described herein are administered 3 to 7 times weekly. 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 may be administered topically at doses from 0.001% to 10%.

[0207] The pharmaceutical compositions described herein may be unit dosage forms suitable for single-dose administration of precise dosages. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dose 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 containers that cannot be resealed. Alternatively, multi-dose resealable containers may be used, in which case the composition typically includes a preservative. By way of example only, formulations intended for non-enteric injection may be presented in unit dosage forms, including (but not limited to) ampoules, or in multi-dose containers with added preservatives.

[0208] The toxicity and therapeutic efficacy of these treatment regimens can be determined in cell culture or laboratory animals using standard pharmaceutical procedures, including (but not limited to) the determination of LD50 (the dose that is lethal to 50% of the population) and ED50 (the dose that is effective in 50% of the population). The dose-to-toxicity ratio is a therapeutic index and can be expressed as the ratio between LD50 and ED50. Compounds exhibiting a high therapeutic index are preferred. Data obtained from cell culture analysis and animal studies can be used to formulate doses within a certain range for human use. The doses of these compounds are preferably within a range that includes the circulating concentration of the ED50 with minimal toxicity. This dose can vary within this range depending on the dosage form and route of administration.

[0209] In the embodiments provided herein, the present invention provides an inhibitor of TNIK kinase. Therefore, these TNIK kinase inhibitors can be used to inhibit downstream biological pathways of TNIK. In some embodiments, the TNIK inhibitor can inhibit collagen fibers, thereby inhibiting biological activities related to the regulation and remodeling of the extracellular matrix. The TNIK inhibitor can inhibit the regulation of cell growth, differentiation, cell migration, proliferation, and metabolism.

[0210] In some embodiments, inhibiting TNIK can inhibit certain TNIK-related biological pathways. In some cases, this TNIK inhibitor inhibits the Wnt pathway.

[0211] In some embodiments, TNIK inhibition suppresses cytoskeleton rearrangement. This TNIK inhibition may inhibit the c-Jun N-terminal kinase pathway. This TNIK inhibition may inhibit the phosphorylation of colloid proteins. This TNIK inhibition may inhibit cytoskeleton regulation, such as cytoskeleton rearrangement.

[0212] In some embodiments, TNIK inhibitors suppress carcinogenesis. In some embodiments, the TNIK inhibitor is administered in 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.

[0213] In some embodiments, the present invention provides a method for treating or preventing a disease, state, or symptom in a patient in need, comprising administering to the patient an effective amount of any of the compounds of the present invention or a pharmaceutically acceptable salt thereof. The disease, state, or symptom may be selected from the group consisting of: colorectal cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, chronic myeloid leukemia, cancer metastasis, fibrosis, and mental 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 myeloid leukemia. In some embodiments, the cancer is cancer metastasis.

[0214] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is not a solid tumor.

[0215] In some embodiments, TNIK inhibitors suppress embryonic development. Therefore, TNIK inhibitors can inhibit pregnancy progression and thereby be used to terminate pregnancy.

[0216] In some embodiments, TNIK inhibitors suppress TGF β signaling. This TGF β signaling pathway is involved in various processes, and inhibiting this pathway can suppress these processes, some of which are described herein. This may include inhibiting embryonic development as described herein to suppress pregnancy progression. This may include inhibiting cell growth and differentiation, which can be used to suppress pregnancy progression and cancer.

[0217] In some embodiments, inhibition of TGF β signaling can be used to inhibit the formation or excessive formation of the extracellular matrix and related problems (e.g., fibrosis). In some embodiments, TGF β signaling is inhibited by inhibiting TNIK, thus inhibiting glycosaminoglycan formation. In some embodiments, collagen formation is inhibited by inhibiting TGF β with TNIK. In some embodiments, the TNIK inhibition inhibits fibrosis. In some categories, suppressed fibrosis is selected from pulmonary fibrosis (e.g., idiopathic or radiation-induced), cystic fibrosis, liver fibrosis (e.g., cirrhosis), myocardial fibrosis (e.g., atrial fibrosis, endocardial myocardial fibrosis, old myocardial infarction), renal fibrosis, cerebral fibrosis (e.g., glial scars), arterial fibrosis, joint fibrosis (e.g., knee, shoulder, other joints), intestinal fibrosis (e.g., Crohn's disease), Dupytren's contracture fibrosis (e.g., hand, fingers), keloid fibrosis (e.g., skin), mediastinal fibrosis (e.g., mediastinal soft tissue), myelofibrosis (e.g., bone marrow), and Peyronie's disease. Fibrosis of the skin (e.g., penis), progressive massive fibrosis (e.g., lungs, a complication of pneumoconiosis in coal miners), retroperitoneal fibrosis (e.g., retroperitoneal soft tissue), sclerodermatic fibrosis (e.g., skin, lungs), adhesive bursitis fibrosis (e.g., shoulder), or combinations thereof. In some cases, the fibrosis is skin fibrosis.

[0218] In some embodiments, TNIK inhibitors can be used to inhibit the development of epithelial-mesenchymal transition and / or fibrosis in cancer cells. In some embodiments, this may include inhibition of the Smad signaling pathway. In some embodiments, this may include inhibition of non-Smad signaling pathways. In some embodiments, this may include inhibition of Wnt, NF-KB, FAC-Src-pile protein-associated punctate adhesion, and MAP kinase (e.g., ERK and JNK) signaling pathways.

[0219] In some embodiments, the present invention provides a method for treating or preventing fibrotic diseases or conditions. 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, joint fibrosis, intestinal fibrosis, Dupuytrum contracture fibrosis, keloid fibrosis, mediastinal fibrosis, myelofibrosis, Peroni disease fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma fibrosis, adhesive bursitis fibrosis, or combinations thereof. In some embodiments, the fibrotic disease is selected from 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.

[0220] In some embodiments, the present invention provides a method for treating kidney disease. In some embodiments, the kidney disease is chronic renal fibrosis (CKD). In some embodiments, the kidney disease is renal fibrosis.

[0221] In some embodiments, the fibrotic disease is cirrhosis of the liver. In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0222] In some embodiments, the fibrotic disease is renal fibrosis, which may be chronic or acute. In some embodiments, the renal fibrosis causes glomerular sclerosis or tubulointerstitial fibrosis. In some embodiments, the fibrotic disease is renal interstitial fibrosis. In some embodiments, the fibrotic disease is acute interstitial nephritis (AIN).

[0223] 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 scar (HTS).

[0224] In some embodiments, this document provides a method for inhibiting fibrosis markers (such as α-smooth muscle actin or α-SMA and collagen) in subjects by administering the compounds and pharmaceutical compositions of the present invention.

[0225] In some embodiments, this document provides a method for antagonizing fibroblast-to-myofibroblast transformation (FMT) in primary human pulmonary fibroblasts. In some embodiments, this document provides a method for antagonizing epithelial-mesenchymal transition (EMT) in primary human epithelial cells.

[0226] In some embodiments, this document provides a method for reducing collagen and hydroxyproline in the skin by administering (e.g., via oral or topical administration) the compounds and pharmaceutical compositions of the present invention.

[0227] In some embodiments, the compounds and pharmaceutical compositions described herein are administered together 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 together with a subtherapeutic dose of pirfenidone.

[0228] The compounds and pharmaceutical compositions described herein may be administered to subjects for about 1 day to about 30 years or longer. In some embodiments, the compounds and pharmaceutical compositions described herein may be administered to subjects for more than one year. In some embodiments, the compounds and pharmaceutical compositions described herein are administered to subjects for 3 months to 5 years. In some embodiments, the compounds and pharmaceutical compositions described herein are administered to subjects for 1 month to 1 year or any amount or range therebetween (e.g., 2 to 3 months, 1 to 6 months, 6 to 12 months, 1 to 3 months, etc.). E. Other Examples

[0229] In one state, this document provides a compound represented by formula (IIA): (IIA), or a pharmaceutically acceptable salt thereof, wherein: R1 is a piperazine, wherein the piperazine is substituted as desired by one or more substituents independently selected in each occurrence from hydroxyl, halogen, hydroxyl and -NH2; R3 is a phenyl, wherein the phenyl is substituted as desired by one or more halogens; and R4 is an unsubstituted C1-C6 alkyl.

[0230] In some embodiments, R4 is selected from , , , , , and.

[0231] In some embodiments, R3 is selected from [missing information], [missing information], and [missing information].

[0232] In some embodiments, R1 is a piperazine substituted with one or more C1-3 alkyl groups, wherein the C1-3 alkyl group is substituted as needed with one or more substituents selected independently of hydroxyl, halogen, side oxygen and -NH2 each time it appears.

[0233] In some embodiments, R1 is selected from , , , , , , , , , and.

[0234] In some embodiments, the compound is: , , , , , , , or, or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0244] In another embodiment, this article provides a method for treating fibrotic diseases or conditions, comprising administering to a subject in need the compound described herein, or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the fibrotic disease or condition is idiopathic pulmonary fibrosis (IPF).

[0246] In some embodiments, the fibrotic disease or condition is skin fibrosis.

[0247] In another embodiment, this document provides a pharmaceutical composition comprising (i) a compound represented by formula (IIA): (IIA), or a pharmaceutically acceptable salt thereof, wherein: R1 is a piperazine, wherein the piperazine is substituted as desired by one or more substituents independently selected in each occurrence from syl groups, -S(O2)NH2 and C1-10 alkyl groups, wherein the C1-10 alkyl groups are substituted as desired by one or more substituents independently selected in each occurrence from hydroxyl groups, halogens, syl groups and -NH2 groups; R3 is a phenyl group, wherein the phenyl group is substituted as desired by one or more halogens; and R4 is an unsubstituted C1-C6 alkyl group; and (ii) a pharmaceutically acceptable excipient.

[0248] In some embodiments, R1 is selected from , , , , , , , , , and ; R3 is selected from , and ; and R4 is selected from , and .

[0249] In some embodiments, the compound represented by formula (IIA) is: , , , , , , , or, or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, the compound system represented by formula (IIA) is a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0254] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0259] In one state, this document provides a compound represented by formula (IIA): (IIA), or a pharmaceutically acceptable salt thereof, wherein: R1 is a piperazine, wherein the piperazine is substituted as desired by one or more substituents independently selected from syloxy and C1-10 alkyl groups in each occurrence, wherein the C1-10 alkyl groups are substituted as desired by one or more substituents independently selected from hydroxyl, halogen, syloxy and -NH2 groups in each occurrence; R3 is a phenyl, wherein the phenyl is substituted as desired by one or more halogens; and R4 is a substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by one or more halogens.

[0260] In some embodiments, the R4 system is substituted with two or three fluorines.

[0261] In some embodiments, R4 is selected from […].

[0262] In some embodiments, R3 is selected from [missing information] and [missing information].

[0263] In some embodiments, R1 is a piperazine substituted with one or more C1-3 alkyl groups, wherein the C1-3 alkyl groups are substituted with one or more halogens as needed.

[0264] In some embodiments, R1 is selected from , , , , , , , , and.

[0265] In some embodiments, R1 is selected from , , , , and .

[0266] In some embodiments, the compound is selected from: , , , , , and, or a pharmaceutically acceptable salt thereof.

[0267] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the compound is a pharmaceutically acceptable salt thereof.

[0273] In another embodiment, this article provides a method for treating fibrotic diseases or conditions, comprising administering to a subject in need a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the fibrotic disease or condition is renal fibrosis.

[0275] In some embodiments, the fibrotic disease or condition is associated with TNIK kinase.

[0276] In another embodiment, this document provides a pharmaceutical composition comprising (i) a compound represented by formula (IIA): (IIA), or a pharmaceutically acceptable salt thereof, wherein: R1 is a piperazine, wherein the piperazine is substituted as desired by one or more substituents independently selected from syloxy and C1-10 alkyl groups in each occurrence, wherein the C1-10 alkyl groups are substituted as desired by one or more substituents independently selected from hydroxyl, halogen, syloxy and -NH2 in each occurrence; R3 is a phenyl, wherein the phenyl is substituted as desired by one or more halogens; and R4 is a substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted by one or more halogens; and (ii) a pharmaceutically acceptable excipient.

[0277] In some embodiments, R1 is a piperazine substituted with one or more C1-3 alkyl groups, wherein the C1-3 alkyl groups are substituted with one or more halogens as needed.

[0278] In some embodiments, R1 is selected from , , , , and ; R3 is selected from , and ; and R4 is selected from and .

[0279] In some embodiments, the compound represented by formula (IIA) is selected from: , , , , , and, or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the compound system represented by formula (IIA) is a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the compound system represented by formula (IIA) or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the compound system represented by formula (IIA), or a pharmaceutically acceptable salt thereof, is used. Examples

[0287] The following examples are provided to illustrate (but not limit) the invention. These examples further illustrate the invention, but should not be construed as limiting its scope in any way.

[0288] The following synthetic schemes are provided for illustrative purposes (but not as limiting). The following examples illustrate various methods for preparing the compounds described herein. It should be 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. It should also be understood that those skilled in the art can prepare these compounds by using appropriate starting materials and modifying the synthetic route as needed, in a manner similar to that described below. Generally, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein. Illustrative Synthetic Schemes

[0289] Compounds of formula (A), (A*), (I), (IIA) or (IIB) and their salts can be synthesized according to one or more of the illustrative schemes herein and / or techniques known in this art. The materials used herein are commercially available or prepared by synthetic methods generally known in this art. These schemes are not limited to the compounds listed in the examples or any particular substituents, which are used for illustrative purposes. Although various steps are described and illustrated in the synthetic schemes below, in some cases these steps may be performed in a different order than shown below. The numbers or R groups in each scheme do not necessarily correspond to the technical schemes herein or other schemes or the numbers or R groups in their tables.

[0290] In some embodiments, the compounds in Table 1 can be prepared according to the synthetic protocols described below. Example 1: Synthesis of compound 102 Example 2: General procedure for the preparation of 4-(4-fluorophenyl)-5-iodo-1-isopropyl-1H-imidazolium (compound B)

[0291] TFA (5.86 g, 51.41 mmol, 3.81 mL, 0.3 equivalents) was added to a solution of compound A (35 g, 171.36 mmol, 1 equivalent) and NIS (115.66 g, 514.09 mmol, 3 equivalents) in DCM (210 mL) at 20 °C. The mixture was stirred at 20 °C for 16 h. TLC (PE:EA = 1:1) showed the consumption of reactant 1 (Rf = 0.4) and detected a new spot (Rf = 0.6). The mixture was poured into an aqueous solution of NaNO2 (1000 mL). The mixture was extracted with EA (500 mL × 3). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, PE:EA = 5:1 to 1:1) to provide the desired compound. Compound B (14 g, 37.74 mmol, 22.02% yield, 89% purity) was obtained as a yellow solid and identified by 1H NMR and LCMS. LCMS: Retention time: 0.743 min, (M+H) = 331.1. 1H NMR: (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). Example 3: General procedure for the preparation of 4-(4-fluorophenyl)-1-isopropyl-5-(tributyltinyl)-1H-imidazolium (compound C).

[0292] n-BuLi (2.5 M, 3.15 mL, 1.3 equivalent) and tributyl(chloro)stanne (2.96 g, 9.09 mmol, 2.44 mL, 1.5 equivalent) were slowly added to a solution of compound B (2 g, 6.06 mmol, 1 equivalent) in THF (20 mL) 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 100 mL of NH4Cl aqueous solution and 100 mL of KF aqueous solution. The mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, PE:EA = 50:1 to 3:1) to provide the desired compound. Compound C (2 g, 4.05 mmol, 66.93% yield), present as a colorless oil, was obtained and identified by ¹H NMR. 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). Example 4: General procedure for preparing ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-4-carboxylate (compound I)

[0293] A mixture of compound H (20 g, 142.71 mmol, 1 equivalent) in THF (100 mL) was added to a solution of NaH (8.56 g, 214.07 mmol, 60% purity, 1.5 equivalent) in THF (200 mL) at 0 °C. The mixture was stirred at 0 °C for 20 min, and then at 20 °C for 30 min. SEM-Cl (35.69 g, 214.07 mmol, 37.89 mL, 1.5 equivalent) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 16 h. TLC (PE:EA = 1:1) showed the consumption of reactant 1 (Rf = 0.1) and observed a new point (Rf = 0.2). 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 × 2), dried over Na₂SO₄, filtered, and concentrated under vacuum to produce a residue. This 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), present as a yellow oil, was obtained and identified by ¹H NMR. 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). Example 5: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-4-carboxylate (compound J).

[0294] NBS (9.54 g, 53.62 mmol, 1 equivalent) and AIBN (880.56 mg, 5.36 mmol, 0.1 equivalent) were added to a solution of compound I (14.5 g, 53.62 mmol, 1 equivalent) in CHCl3 (150 mL) at 20 °C. The mixture was stirred at 60 °C for 5 hours. TLC (PE:EA = 1:1) showed the consumption of reactant I (Rf = 0.2) and observed a new spot (Rf = 0.5). The mixture was concentrated under vacuum to produce 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 given as a yellow solid, which was identified by ¹H NMR. ¹H 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). 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-carboxylic acid (compound D).

[0295] A solution of compound C (300 mg, 608.17 µmol, 1 equivalent) and compound J (318.64 mg, 912.25 µmol, 1.5 equivalent) in toluene (2 mL) was added to [2-(2-aminophenyl)phenyl]chloropalladium; bis(1-adamantyl)-butylphosphine (120.00 mg, 179.47 µmol, 2.95e-1 equivalent) at N2 and 20 °C. The mixture was stirred at 110 °C for 16 h. LCMS showed consumption of reactant 1 and detected 58% of the desired mass. The mixture was concentrated under vacuum to provide the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 54% to 64%, 14 min) to provide the desired compound. Compound D (60 mg, 125.68 µmol, 20.67% yield, 99% purity), present as a brown oil, was obtained, identified by 1H NMR and LCMS. Compound D (100 mg, 84.63 µmol, 13.92% yield, 40% purity), present as a brown oil, was obtained, identified 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). 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)

[0296] LiOH·H2O (8.88 mg, 211.58 µmol, 2 equivalents) was added to a solution of compound D (50.00 mg, 105.79 µmol, 1 equivalent) in THF (1 mL) and H2O (1 mL) 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. 1N HCl (10 mL) was added to the mixture. The mixture was extracted 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 produce a crude product. Compound E (50 mg, crude) was given as a colorless oil. LCMS: Retention time: 0.778 min, (M+H) = 445.3. Example 8: General procedure for preparing methyl 3-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)propionate (compound F)

[0297] HATU (64.15 mg, 112.47 µmol, 1 equivalent) and DIPEA (43.61 mg, 337.40 µmol, 58.77 µL, 3 equivalent) were added to a solution of compound E (50 mg, 112.47 µmol, 1 equivalent) and compound GG (30.23 mg, 168.70 µmol, 1.5 equivalent) in DMF (2 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. LCMS showed that reactant 1 was consumed and detected 82% of the desired mass. The mixture was poured into H2O (20 mL). The mixture was extracted with EA (20 mL * 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a crude product. Compound F (65 mg, crude) was obtained as a colorless oil. LCMS: Retention time: 0.978 min, (M+H) = 606.1. Example 9: General procedure for the preparation of methyl 3-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)propionate (compound G).

[0298] TFA (1.54 g, 13.51 mmol, 1 mL, 136.36 equivalents) was added to a solution of compound F (60 mg, 99.05 µmol, 1 equivalent) in DCM (2 mL) 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 an aqueous solution of NaHCO3 (20 mL). The mixture was extracted with EA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a crude product. Compound G (50 mg, crude) was given as a colorless oil. LCMS: Retention time: 0.748 min, (M+H) = 476.3. Example 10: General procedure for the preparation of 3-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)propionic acid (compound 102)

[0299] LiOH·H2O (35.30 mg, 841.20 µmol, 1 equivalent) was added to a solution of compound G (40 mg, 84.12 µmol, 1 equivalent) in THF (1 mL) and H2O (1 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. LCMS showed that reactant 1 was consumed and detected 74% of the desired mass. The mixture was poured into 1N HCl (100 mL). The mixture was extracted with EA (20 mL*3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 µm; mobile phase: [water (0.225% FA)-ACN]; B%: 18% to 38%, 10 min) to provide the desired compound. Compound 102 (14.8 mg, 31.59 µmol, 37.55% yield, 98.5% purity) was obtained as a yellow solid and identified by 1H NMR, LCMS, 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. 1HNMR: (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). Example 11: Synthesis of Compound 112 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)

[0300] HATU (8.34 g, 21.93 mmol, 1 equivalent) and DIEA (5.67 g, 43.86 mmol, 7.64 mL, 3 equivalent) were added to a mixture of compound E (6.5 g, 14.62 mmol, 1 equivalent) and compound 3A (4.19 g, 21.93 mmol, 1.5 equivalent) in DMF (50 mL). The mixture was stirred at 20 °C for 3 hours. LCMS was used to detect the consumption of compound E and the desired mass. 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 under vacuum. 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. 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-carboxylamine (compound 112).

[0301] TFA (30.80 g, 270.12 mmol, 20.00 mL, 18.54 equivalents) was added to a mixture of compound K (9 g, 14.57 mmol, 1 equivalent) in CH2Cl2 (2 mL). The mixture was stirred at 20 °C for 5 hours. LCMS showed the consumption of compound K and detected the desired mass. The mixture was alkalized to pH = 8 with saturated NaHCO3 and extracted with ethyl acetate (200 mL × 4). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by reversed-phase HPLC (0.1% NH3•H2O). Compound 112 (3.04 g, 6.20 mmol, 42.58% yield, 99.492% purity) was given as a grayish-white solid, which was examined by HNMR, LCMS, and HPLC. LCMS: Retention time: 0.683 min, (M+H) = 488.2. HPLC: Retention time: 1.157 min. HPLC: Retention time: 1.155 min. 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). Example 14: Synthesis of Compound 113

[0302] 4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)benzoic acid (compound 113) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, 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. ¹H NMR: (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). Example 15: Synthesis of Compound 111

[0303] 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 via the same synthetic route as compound 112, and its composition was determined by 1H NMR, 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. ¹H NMR: (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). Example 16: Synthesis of Compound 116

[0304] N-(4-(bis(2-hydroxyethyl)amino)phenyl)-5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 116) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, 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. ¹H NMR: (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). Example 17: Synthesis of compound 117

[0305] 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 via the same synthetic route as compound 112, and its composition was determined by 1H NMR, 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). Example 18: Synthesis of Compound 99

[0306] N-(4-(4-aminomethoxypiperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 99) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, F NMR, LCMS, and HPLC. LCMS: Retention time: 1.298 min, (M+H) = 474.2. HPLC: Retention time: 0.732 min. ¹H NMR (400 MHz, 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). ¹⁹F NMR (376 MHz, methanol-d⁴) δ = -116.70 (br s, ¹F). Example 19: Synthesis of Compound 97

[0307] 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-aminosulfonylopiropiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxyamine (compound 97) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, F NMR, LCMS, and HPLC. LCMS: Retention time: 0.956 min, (M+H) = 553.3. HPLC: Retention time: 1.854 min. 1H NMR (400 MHz, 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). 19F NMR (376 MHz, DMSO-d6) δ = -115.64 (br s, 1F). Example 20: Synthesis of compound 181

[0308] 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(piperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 181) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, F NMR, LCMS, and HPLC. LCMS: Retention time: 0.825 min, (M+H) = 474.2. HPLC: Retention time: 0.693 min. 1H NMR (400 MHz, 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). 19F NMR (376 MHz, DMSO-d6) δ = -115.66 (br s, 1F). Example 22: Synthesis of compound 119

[0309] 5'-(4-fluorophenyl)-3'-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 119) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, F NMR, LCMS, and HPLC. LCMS: Retention time: 0.851 min, (M+H) = 460.4. HPLC: Retention time: 0.981 min. 1H NMR (400 MHz, 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). 19F NMR (377 MHz, DMSO-d6) δ = -115.52 (s, 1F). Example 23: Synthesis of compound 135

[0310] 5'-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3'-neopentyl-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 135) was synthesized as a white solid via the same synthetic route as compound 102, and its composition was determined by 1H NMR, 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. 1HNMR: (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). Example 24: Synthesis of compound 130. 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-carboxylic acid (compound BB).

[0311] NaH (46.45 mg, 1.16 mmol, 60% purity, 1 equivalent) was added to a solution of compound AA (500 mg, 1.16 mmol, 1 equivalent) in ACN (5 mL) 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 equivalent) and Zn (9.80 mg, 149.81 µmol, 1.29e-1 equivalent) were added to the mixture at -15 °C. The mixture was stirred at 20 °C for 16 h. LCMS showed 42% of compound BB remaining and detected 17% of the desired mass. The mixture was poured into an aqueous solution of 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 produce the residue. The residue was purified by column chromatography (SiO2, PE:EA = 5:1~0:1) to provide the desired compound and recover 200 mg of reactant 1. Compound BB (40 mg, 72.42 µmol, 6.24% yield, 87% purity), a yellow oil, was obtained, as determined by LCMS. Ethyl 5'-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylic acid was recovered (200 mg, 464.53 µmol, 40.00% yield). LCMS: Retention time: 0.958 min, (M+H) = 481.3. LCMS: Retention time: 0.968 min, (M+H) = 481.3.

[0312] 3'-(difluoromethyl)-5'-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 130) was synthesized from BB as an oil via the same synthetic route as compound 112, and its composition was determined by 1H NMR, 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). Example 26: Synthesis of Compound 120. Example 27: General Procedure for the Preparation of Ethyl 2-cresyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-4-carboxylate (Compound M).

[0313] i-PrMgCl (2 M, 120.24 mL, 3 equivalents) was added to a solution of compound J (28 g, 80.16 mmol, 1 equivalent) in THF (300 mL) at -40 °C. The mixture was stirred at -40 °C for 10 min. DMF (35.16 g, 480.97 mmol, 37.01 mL, 6 equivalents) was added to the mixture at -70 °C. The mixture was stirred at 20 °C for 1 h. The required mass was detected by LCMS. The mixture was poured into 1N HCl (500 mL). The mixture was extracted with EA (300 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to produce 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), present as a yellow oil, was obtained and examined by ¹H NMR. LCMS: Retention time: 0.955 min, (M+H) = 299.2. HPLC: Retention time: 2.170 min. ¹H NMR: (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). Example 28: General procedure for preparing ethyl 5'-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylic acid (compound N)

[0314] NH3•H2O (582.40 mg, 4.15 mmol, 640.00 µL, 25% purity, 3.87 equivalents) was added to a solution of compound M (320 mg, 1.07 mmol, 1 equivalent) in THF (12 mL) at 20 °C. The mixture was stirred at 20 °C for 3.5 h. Compound 1A (372.31 mg, 1.29 mmol, 1.2 equivalents) and DIEA (415.78 mg, 3.22 mmol, 560.35 µL, 3 equivalents) were added to the mixture 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 produce a residue. This residue was purified by column chromatography (SiO2, PE:EA = 1:1 to 0:1) to provide 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. 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-carboxylic acid (compound O).

[0315] K₂CO₃ (240.75 mg, 1.74 mmol, 3 equivalents) and compound 2A (404.31 mg, 1.74 mmol, 3 equivalents) were added to a solution of ethyl compound N (250 mg, 580.66 µmol, 1 equivalent) in DMF (5 mL) 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 produce a residue. The residue was purified by preparative TLC (PE:EA = 1:1, product Rf = 0.5) to provide 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. 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-carboxylamine (compound 120).

[0316] 5'-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 120) was synthesized from compound O via the same synthetic route as compound 112 to a white solid, which was determined by 1H NMR, 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). Example 31: Synthesis of Compound 167. 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-carboxylamine (Compound 167).

[0317] A solution of 2-[5-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)imidazol-4-yl]-N-[4-(4-methylpiperazin-1-yl)phenyl]-1H-imidazol-4-carboxamide (50 mg, 77.94 µmol, 1 equivalent, TFA salt) in DCE (1 mL) was added to 1-chloroethyl chloroformate (55.71 mg, 389.69 µmol, 5 equivalents) and TEA (31.55 mg, 311.75 µmol, 43.39 µL, 4 equivalents). The mixture was stirred at 40 °C for 4 hours. LCMS showed the consumption of reactant 1 and detected the main peak. Then, MeOH (1.5 mL) was added to the reaction mixture, and the mixture was stirred at 60 °C for 1 hour. LCMS showed 66% of the desired mass. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 µm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 12% to 42%, 8 min). Compound 167 was obtained as a grayish-white solid (2.99 mg, 5.24 µmol, 6.72% yield, 90% purity). The structure was confirmed by LCMS, HPLC, ¹H NMR, and FNMR. 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 min. ¹H 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). ¹⁹F NMR: (377 MHz, methanol-d⁴) δ = -73.58 (s, ¹F). Example 33: Synthesis of Compound 166 Example 34: General Procedure for the Preparation of 1-Oxy-4-(4-(5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)-1-methylpiperazine (Compound 166)

[0318] m-CPBA (14.24 mg, 70.14 µmol, 85% purity, 1 equivalent) and pyridine (16.65 mg, 210.43 µmol, 16.98 µL, 3 equivalent) were added to a solution of 2-[5-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)imidazol-4-yl]-N-[4-(4-methylpiperazin-1-yl)phenyl]-1H-imidazol-4-carboxamide (45 mg, 70.14 µmol, 1 equivalent, TFA salt) in DCM (0.3 mL) at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. LCMS showed 23% of the desired mass remaining and detected 35% of the desired mass. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (10 mm NH4HCO3)-ACN]; B%: 10% to 40%, 8 min). Compound 166 was given as a white solid (3.81 mg, 6.31 µmol, 8.99% yield, 89.98% purity). The structure was confirmed by LCMS, HPLC, ¹H NMR, and FNMR. 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 min. ¹H NMR: (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). ¹⁹F NMR: (377 MHz, methanol-d⁴) δ = -73.57 (s, ¹F). Example 35: Synthesis of Compound 121 Example 36: General Procedure for the Preparation of Methyl 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)furan-2-carboxylic acid (Compound FF)

[0319] Methylchloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (20 mg, 60.91 µmol, 0.3 equivalents)) was added to a solution of compound C (100 mg, 202.72 µmol, 1 equivalent) and compound EE (83.12 mg, 405.44 µmol, 2 equivalents) in toluene (2 mL) under N2 and at 20 °C. The mixture was stirred at 110 °C for 16 h. TLC showed the consumption of compound GG and detected new spots. The mixture was concentrated under vacuum to provide a residue. The residue was purified by preparative TLC (PE:EA=1:1) to provide the desired compound. Compound FF (65 mg, 181.54 µmol, 89.55% yield, 91.7% purity) was obtained as a colorless oil, which was determined by LCMS. LCMS: Retention time: 0.715 min, (M+H) = 329.2. 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-carboxyamine (121).

[0320] Compound 125 was synthesized from compound FF via the same synthetic route as compound 112 to form an oil, which was determined by 1H NMR, 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). Example 38: Synthesis of compound 102. Example 39: Synthesis of compound 132.

[0321] 5-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)valeric acid (compound 132) was synthesized as a white solid via a similar synthetic route to compound 102, and its composition was determined by ¹H NMR, 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 min. 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). Example 40: Synthesis of Compound 126

[0322] 5-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(4-(2-hydroxyethyl)phenyl)furan-2-carboxyamine (compound 126) was synthesized as a white solid via the same synthetic route as compound 121, and its concentration was determined by ¹H NMR, F NMR, 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 min. HPLC: Retention time: 1.494 min. 1H 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). 19F NMR (400 MHz, DMSO-d6) δ = 74.404. Example 41: Synthesis of Compound 162

[0323] 6-(4-(4-fluorophenyl)-1-isopropyl-1H-imidazol-5-yl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)pyridinamide (compound 162) was synthesized as a yellow solid via a similar synthetic route to compound 121, and its composition was determined by ¹H NMR, 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 min. 1H 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). Example 42: Synthesis of compound 133

[0324] 3-(4-(3'-isopropyl-5'-(4-(trifluoromethyl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)propionic acid (compound 133) was synthesized as a white solid via a similar synthetic route to compound 102, and its composition was determined by ¹H NMR, 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&254.1 cm. HPLC: Retention time: 2.301 min. 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). Example 43: Synthesis of Compound 137

[0325] 3-(4-(5'-(4-chlorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)propionic acid (compound 137) was synthesized as a white solid via a similar synthetic route to compound 102, and its composition was determined by ¹H NMR, 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. ¹H 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). Example 44: Synthesis of compound 134

[0326] 3-(4-(5'-(4-chlorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)propionic acid (compound 134) was synthesized as a yellow oil via a similar synthetic route to compound 102, and its composition was determined by ¹H NMR, LCMS, and HPLC. LCMS: Retention time: 0.671 min, (M+H) = 568.3, 5-95AB_R_220&254.1 cm. LCMS: Retention time: 0.755 min, (M+H) = 568.2. HPLC: Retention time: 1.869 min. 1H 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). Example 45: Synthesis of Compound 139

[0327] 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 via a similar synthetic route to compound 137, and its composition was determined by ¹H NMR, 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 = 6.8 Hz, 6H). Example 46: Synthesis of Compound 146

[0328] 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 via a similar synthetic route to compound 102, and its composition was determined by ¹H NMR, 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 min. 1H 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). Example 47: Synthesis of compound 158

[0329] 5'-(4-fluorophenyl)-3'-((1r,4r)-4-hydroxycyclohexyl)-N-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 158) was synthesized as a white solid via a similar synthetic route to compound 120, and its composition was determined by ¹H NMR, LCMS, and HPLC. LCMS: Retention time: 0.683 min, (M+H) = 574.3. HPLC: Retention time: 1.600 min. 1H 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). Example 48: Synthesis of compound 156

[0330] 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 via a similar synthetic route to compound 102, and its composition was determined by ¹H NMR, 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). Example 49: Synthesis of Compound 159

[0331] 5'-(4-fluorophenyl)-3'-((1r,4r)-4-hydroxycyclohexyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 159) was synthesized as a yellow solid via a similar synthetic route to 158, and its composition was determined by ¹H NMR, 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). Example 50: Synthesis of compound 142

[0332] 3'-Isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-5'-(4-(trifluoromethyl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 142) was synthesized as a white solid via a similar synthetic route to compound 102, and its composition was determined by ¹H NMR, 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

[0333] 5'-(4-chlorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[4,4'-biimidazole]-2-carboxylamine (compound 150) was synthesized as a white solid via the same synthetic route as compound 120, and its composition was determined by 1H NMR, LCMS, and HPLC. LCMS: Retention time: 0.714 min, [M+H+] = 504.3. HPLC: Retention time: 1.992 min. ¹H 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). Example 52: Synthesis of compound 153

[0334] 1-Oxy-4-(4-(5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxyamino)phenyl)-1-methylpiperazine (compound 153) was synthesized as a white solid via the same synthetic route as compound 166, and its composition was determined by 1H NMR, 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. 1H 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). Example 53: Synthesis of compound 205

[0335] 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 via the same synthetic route as compound 120, and its composition was determined by 1H NMR, 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 min. 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). Example 54: Synthesis of compound 196

[0336] 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(3,4,5-trimethylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 196) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, 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·cm, 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 = 8.9 Hz, 2H). 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). Example 55: Synthesis of compound 185

[0337] 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methyl-3-sideoxypiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 185) was synthesized as a white solid via the same synthetic route as compound 112, and its composition 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. 1H 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 = 6.8 Hz, 6H). Example 56: Synthesis of Compound 188

[0338] N-(4-(4-acetylopiperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 188) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, 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 min. 1H 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). Example 57: Synthesis of compound 189

[0339] 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 189) was synthesized as a white solid via the same synthetic route as compound 112, and its composition 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. ¹H NMR: (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). Example 58: Synthesis of Compound 186

[0340] 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 186) was synthesized as a white solid via the same synthetic route as compound 112, and its composition was determined by 1H NMR, 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). Example 59: Synthesis of compound 190

[0341] 5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-N-(4-(3,4,5-trimethylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 190) was synthesized as a white solid via the same synthetic route as compound 120, and its composition was determined by 1H NMR, LCMS, and HPLC. LCMS: Retention time: 0.937 min, (M+H) = 556.5. HPLC: Retention time: 1.519 min. 1H 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 = 6.1 Hz, 6H). Example 60: Synthesis of compound 194

[0342] 5'-(4-fluorophenyl)-N-(4-(4-methyl-3-t-oxypiperazin-1-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 194) was synthesized as a white solid via the same synthetic route as compound 120, and its composition was determined by 1H NMR, LCMS, and HPLC. LCMS: Retention time: 0.832 min, (M+H) = 542.4. HPLC: Retention time: 1.704 min. ¹H 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). Example 61: Synthesis of compound 191

[0343] N-(4-(4-acetylopiperazin-1-yl)phenyl)-5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 191) was synthesized as a white solid via the same synthetic route as compound 120, and its composition 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). Example 62: Synthesis of compound 192

[0344] 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-carboxylamine (compound 192) was synthesized as a white solid via the same synthetic route as compound 120, and its composition was determined by 1H NMR, LCMS, and HPLC. LCMS: Retention time: 0.943 min, (M+H) = 596.5. HPLC: Retention time: 1.965 min. 1H 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). Example 63: Synthesis of Compound 193

[0345] 5'-(4-fluorophenyl)-N-(4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylamine (compound 193) was synthesized as a white solid via the same synthetic route as compound 120, and its composition was determined by 1H NMR, LCMS, and HPLC. LCMS: Retention time: 1.036 min, (M+H) = 554.5. HPLC: Retention time: 1.544 min, 10⁻⁸ AB⁻⁴ min·1 cm. 1H 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).

[0346] Some of the compounds in Table 1 can be prepared using alternative reagents as described in the examples above. Illustrative compounds may include (but are not limited to) compounds selected from Table 1 or their salts, which can be prepared using the examples described herein and the accompanying procedures. Table 1: Compounds and Analytical Information Compound numbering Compound Structure Human liver microsomes (µM / min / mg) TNIK (IC50, nM) MAP4K4 (IC50, nM) 172 +++ ++ 175 +++ 128 + +++ +++ 186 +++ +++ 131 +++ +++ ++ 127 + +++ +++ 125 + +++ +++ 188 +++ ++ 159 ++ +++ ++ 158 +++ +++ ++ 97 + ++ ++ 121 + +++ ++ 196 ++ ++ 193 ++ ++ 112 ++ ++ ++ 181 ++ ++ ++ 126 + ++ ++ 117 ++ ++ ++ 132 +++ ++ ++ 189 ++ ++ 116 +++ ++ ++ 153 +++ ++ ++ 190 +++ ++ 185 ++ ++ 191 ++ ++ 167 ++ ++ + 111 ++ ++ + 156 ++ ++ + 194 ++ + 146 ++ ++ + 102 +++ ++ + 150 ++ ++ + 99 ++ + + 166 +++ + + 139 ++ ++ + 120 ++ ++ + 113 +++ +++ + 192 ++ + 135 + ++ + 119 ++ + + 137 +++ +++ + 130 ++ ++ + 142 + + + 134 ++ + + 133 +++ + + 164 168 171 198 199 200 205 Example 64: Metabolic stability in human and mouse liver microsomes Table 1.1: Compound Information Compound number Compound ID Batch number Precise quality Reserve fluid Concentration (mM) 172 172 10 Comparison testosterone 288.42 10 Comparison diclofenac 295.14 10 Comparison propafenone 341.44 10

[0347] 2.1. Preparation of test compound and control working solution: Working solution: 5 μL of compound and control stock solution (10 mM in dimethyl sulfoxide (DMSO)) was diluted with 495 μL of acetonitrile (ACN) (intermediate solution concentration: 100 μM, 99% ACN).

[0348] 2.2. Preparation of NADPH cofactor

[0349] 2.2.1. Material: NADPH powder: reduced form of β-nicotinamide adenine dinucleotide phosphate, tetrasodium salt; NADPH·4Na (supplier: Chem-Impex International, catalog number 00616).

[0350] 2.2.2. Preparation procedure: Weigh an appropriate amount of NADPH powder and dilute it in 10 mM MgCl2 solution (working solution concentration: 10 units / mL; final concentration in the reaction system: 1 unit / mL).

[0351] 2.3. Preparation of liver microsomes:

[0352] 2.3.1. Materials: Table 2.1: Liver microsomal information Species Product Information supplier abbreviation Humans Catalog Number 452117 Corning HLM batch number 38295 CD-1 mice Catalog Number M00501 BioIVT MLM Batch number WQP

[0353] 2.3.2. Preparation procedure: Prepare a microsomal working solution of appropriate concentration in 100 mM potassium phosphate buffer.

[0354] 2.4. Preparation of the termination solution: Cold (4°C) acetonitrile (ACN) containing 200 ng / mL tolbutamide as an internal standard (IS) and 200 ng / mL labetalol was used as the termination solution.

[0355] 2.5. Analysis Procedure:

[0356] 2.5.1. Preheat the empty “culture” trays T60 and NCF60 for 10 minutes.

[0357] 2.5.2. Dilute liver microsomes to 0.56 mg / mL in 100 mM phosphate buffer.

[0358] 2.5.3. Transfer 445 µL of microsomal working solution (0.56 mg / mL) to preheated culture plates T60 and NCF60, and then pre-incubate the culture plates T60 and NCF60 at 37°C with continuous shaking for 10 min. Transfer 54 µL of liver microsomes to a blank plate, then add 6 µL of NAPDH cofactor to the blank plate, and then add 180 µL of quenching solution to the blank plate.

[0359] 2.5.4. Add 5 μL of the compound working solution (100 μM) to the “culture” dish (T60 and NCF60) containing microsomes and mix thoroughly 3 times.

[0360] 2.5.5. For NCF60 discs, add 50 μL of buffer and mix thoroughly three times. Start timing; incubate the discs at 37°C for 60 min with shaking.

[0361] 2.5.6. In the "quenching" pan T0, add 180 μL of quenching solution and 6 μL of NAPDH cofactor. Ensure the pan is frozen to prevent evaporation.

[0362] 2.5.7. For the T60 disc, thoroughly mix three times, and immediately remove 54 μL of the mixture at the 0-min time point to "quench" the disc. Then add 44 μL of NAPDH cofactor to the culture disc (T60). Start timing; incubate the disc at 37°C for 60 min with shaking. Table 2.2: Final concentrations of each component in the culture medium Components concentration microparticles 0.5 mg protein / mL Test compounds 1 μM control compound 1 μM Acetonitrile 0.99% DMSO 0.01%

[0363] 2.5.8. At 5, 10, 20, 30 and 60 min, add 180 μL of quenching solution to the "quenching" tray, mix once, and at each time point continuously transfer 60 μL of sample from the T60 tray to the "quenching" tray. Table 2.3: Reaction tray culture Time point Start time End time blank 1:00:00 0:00:00 T60 1:00:00 0:00:00 T30 0:30:00 0:00:00 T20 0:20:00 0:00:00 T10 0:10:00 0:00:00 T5 0:05:00 0:00:00 T0 Mix three times and remove to the "quenching" plate.

[0364] 2.5.9. For NCF60: Mix once and at the 60-min time point, transfer 60 µL of sample from NCF60 culture to a "quenching" dish containing quenching solution. Table 2.4: NCF60 culture Time point Start time End time NCF60 1:00:00 0:00:00

[0365] 2.5.10. Shake all sampling disks for 10 min, then centrifuge at 4000 rpm for 20 min at 4℃.

[0366] 2.5.11. Transfer 80 µL of supernatant to 240 µL of HPLC water and mix with a plate shaker for 10 min.

[0367] 2.5.12. Seal each bioanalytical disc and shake for 10 minutes before LC-MS / MS analysis.

[0368] 3.1. Use first-order kinetic equations to calculate T1 / 2 and intrinsic clearance (CLint mic) in (μL / min / mg).

[0369] First-order dynamic equation.

[0370] Table 1 includes the μM / min / mg values ​​of selected compounds; compounds with an LM Clint of 1 to 10 μM / min / mg are denoted as +++, compounds with an LM Clint of 10 to 100 μM / min / mg are denoted as ++, and compounds with an LM Clint > 100 μM / min / mg are denoted as +. Example 65: TNIK Human STE Kinase Enzymatic Radioactivity Assay Analysis

[0371] Analysis Information

[0372] Analysis type: Biochemistry

[0373] Analyze subtypes; Enzyme-catalyzed

[0374] Functional mode: Antagonist

[0375] Detection method: Radiation determination

[0376] Measurement response: Scintillation

[0377] Summary of the procedure: TNIK (h) was cultured with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM RLGRDKYKTLRQIRQ, 10 mM magnesium acetate and [γ-33P-ATP] (specific activity and concentration as required). The reaction was initiated by the addition of Mg / ATP mixture. After incubation for 40 min at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%. Then 10 ul of the reactant was dotted onto the P30 filter mat and washed four times in 0.425% phosphoric acid over a period of 4 min and once in methanol before drying and scintillation counting.

[0378] Receptor: 250 μM RLGRDKYKTLRQI

[0379] Tracer: 33P

[0380] ATP concentration: 70 μM

[0381] Culture: 40 min at room temperature

[0382] Control inhibitor: 1-NM-PP1

[0383] Compound concentrations: 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 protocol: All compounds supplied were made in 100% DMSO as a working reservoir of 50x final analytical concentration. The more concentrated reserve solution was manually diluted to 50x using 100% DMSO as needed. The compounds supplied as powders were reconstituted in 100% DMSO to a 10 mM reservoir and then further diluted to 50x. Analysis Procedure: A 50x reserve solution of the required volume of the test compound was added to the analysis, followed by the addition of the reaction mixture containing the enzyme and acceptor. The reaction was initiated by the addition of selected concentrations of ATP. The compound was not precultured with an enzyme / acceptor mixture prior to ATP addition. Other details for each individual analysis are provided on the website or in the accompanying protocol files. Data Analysis: Process data using custom built-in analysis software. The results were expressed as the remaining kinase activity as a percentage of the DMSO control. This was calculated using the following equation: Data were analyzed for the IC50 assay using XLFit version 5.3 (ID Business Solutions). S-type dose-response (variable slope) curves were fitted based on the mean results of each tested concentration using nonlinear regression analysis. In cases where the top and / or bottom of the curve fall >10% by 100 and 0, respectively, either or both of these limits may be limited to 100 and 0, provided that the QC criterion of R2 is satisfied.

[0384] Table 1 includes the IC50 values ​​of TNIK for selected compounds;+++ for compounds with IC50 values ​​from 1 to 12 nM, ++ for compounds with IC50 values ​​from 12 to 120 nM, and + for compounds with IC50 values ​​>120 nM. These IC50 values ​​can be found in Table 1 . Example 66: MAP4K4 human STE kinase enzymatic radiometric analysis

[0385] Type of analysis: Biochemistry

[0386] Analytical subtype;enzymatic

[0387] Functional mode: antagonist

[0388] Method of detection: Radiological assay

[0389] Measurement response: flashing

[0390] Summary of the procedure: MAP4K4 was cultured with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μM RLGRDKYKTLRQIRQ, 10 mM magnesium acetate and [γ-33P-ATP] (specific activity and concentration as required) (h). The reaction was initiated by the addition of Mg / ATP mixture. After incubation for 40 min at room temperature, the reaction was stopped by the addition of phosphoric acid to a concentration of 0.5%. Then 10 ul of the reactant was dotted onto the P30 filter mat and washed four times in 0.425% phosphoric acid over a period of 4 min and once in methanol before drying and scintillation counting.

[0391] Receptor: 250 μM RLGRDKYKTLRQI

[0392] Tracer: 33P

[0393] ATP concentration: 200 μM

[0394] Culture: 40 min at room temperature

[0395] Control inhibitor: staurosporine

[0396] Compound concentrations: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM.

[0397] Compound dilution protocol: Prepare a working stock solution of all supplied compounds to a final analytical concentration of 50x in 100% DMSO. If necessary, manually dilute the stock solution to 50x using 100% DMSO. Reconstitute compounds supplied as powder into a 10 mM stock solution in 100% DMSO, and then further dilute to 50x.

[0398] Analytical Procedure: Add the required volume of 50x stock solution of the test compound to the assay, followed by the addition of the reaction mixture containing the enzyme and acceptor. Initiate the reaction by adding the selected concentration of ATP. The compound is not pre-cultured with the enzyme / acceptor mixture prior to the addition of ATP. For further details regarding individual assays, please refer to the website or the accompanying protocol file.

[0399] Data Analysis: Data was processed using custom built-in analysis software. Results are expressed as a percentage of remaining kinase activity compared to the DMSO control. This was calculated using the following equation:

[0400] For IC50 determination, data were analyzed using XLFit version 5.3 (ID Business Solutions). Nonlinear regression analysis was used to fit an S-shaped dose-response (variable slope) curve based on the average results for each test concentration. If the top and / or bottom of the curve decrease by >10% from 100 and 0 respectively, either or both of these limits can be limited to 100 and 0, provided that the QC standard of R2 is met.

[0401] Table 1 includes the IC50 values ​​of selected compounds for MAP4K4; compounds with IC50 values ​​of 1 to 12 nM are marked +++, compounds with IC50 values ​​of 12 to 120 nM are marked ++, and compounds with IC50 values ​​> 120 nM are marked +. Example 67: Masson's Trichrome (M&T) staining and Ashcroft scoring

[0402] Mason's Tricolor (M&T) Staining Protocol: Lung sections were cut into 4 μm thick pieces, dried in an oven for 1 hour, and stained with M&T using the standard staining protocol. These sections were then briefly stained with Weigert's iron hematoxylin working solution for 10 minutes. Subsequently, they were stained with Biebrich scarlet acid fuchsin solution for 10 minutes and differentiated in phosphomolybdic phosphotungstic acid solution for 5 minutes or until the collagen was no longer red. The samples were then transferred to aniline blue solution and stained for 1 minute, followed by dedifferentiation in 1% acetic acid solution. The samples were then dehydrated and placed on coverslips for subsequent image analysis.

[0403] For image analysis of collagen deposition, the Aperio scan range model: CS2 (Leica) was used to scan slides stained with Mason chromatogram at 200X magnification. Fibrotic areas stained with Mason chromatogram were quantified using the HALO® image analysis platform from Indica Labs. The entire left lung slice was selected as the annotation layer.

[0404] Fibrotic modification was morphologically assessed and semi-quantitatively graded according to the 0 to 8 scale defined by Ashcroft et al. and modified by Hübner et al., as described in Table 3 below. The final score is expressed as the average of individual scores observed across all microscopic fields of view. Table 3: Modified Ashcroft Score score Feature-corrected Ashcroft score 0 Alveolar septa: Some of the weakest small fibers in the alveolar walls are free from fibrotic burden. Lung structure: normal lung 1 Alveolar septum: Isolated mild fibrotic changes (septum ≤3x thicker than normal). Lung structure: The alveoli are partially enlarged and thin, but there are no fibrotic masses. 2 Alveolar septa: marked fibrotic changes (septa are thicker than normal by >3x), and nodules formed but not connected to each other. Lung structure: The alveoli are partially enlarged and thinned, but there are no fibrotic masses. 3 Alveolar septa: Continuous fibrotic walls mainly visible throughout the entire microscope field of view (septa are >3x thicker than normal). Lung structure: The alveoli are partially enlarged and thin, but there are no fibrotic masses. 4 Alveolar septa: variable Lung structure: Single fibrotic mass (≤10% of the microscopic field of view) 5 Alveolar septa: variable Lung structure: Confluent fibrotic masses (>10% and ≤50% of the microscopic field). The lung structure is severely damaged but still well-preserved. 6 Alveolar septa: variable, mostly absent Lung structure: Large, continuous fibrotic mass (>50% of the microscopic field of view). Most of the lung structure was not preserved. 7 Alveolar septa: Not present Lung structure: The alveoli were almost completely eliminated by fibrotic masses, but there were still up to five alveoli in each alveolus. 8 Alveolar septa: Not present Lung structure: Completely eliminated under microscope, with fibrotic masses present. Example 68: α-SMA IHC Analysis

[0405] Protocol: For immunohistochemical staining, 4 μm thick sections were placed on glass slides and dried overnight, followed by paraffin removal with xylene. These sections were then placed in a series of graded ethanol solutions and immersed in distilled water. After demasking with heat-induced citrate antigen (pH=6.0), the sections were immersed in 3% hydrogen peroxide solution for 5 min. To avoid nonspecific staining, the sections were then cultured in blocking serum at room temperature for 15 min, followed by the addition of a 1:400 dilution of primary rabbit multi-line anti-α-SMA antibody for 1 hour. Subsequently, secondary goat multi-line antibody bound to HRP was added.

[0406] For image analysis of fibrosis, α-SMA stained sections were scanned using an Aperio CS2 scanner. Fibrosis areas were quantified using the HALO® image analysis platform from Indica Labs. The entire left lung section was selected as the annotation layer. Bronchial tissue was excluded from this annotation layer. The area occupied by collagen fibers was measured using the "Area Quantification v2.1.3" module. The percentage of positive areas in the selected annotation was then calculated using a program. The fibrosis is expressed as a percentage per lung section. Example 69: Bleomycin-induced pulmonary fibrosis mouse model

[0407] Protocol: Eight-week-old male C57BL / 6 mice were anesthetized with pentobarbital (60 mg / kg body weight, ip) and administered bleomycin intratracheally on day 1 at a dose of 0.66 mg / kg (equivalent to 1 U / kg). Compound treatment began on day 7 after induction of pulmonary fibrosis, at which point initial lung injury and inflammation had subsided. Example 70: Bleomycin-induced rat model of skin fibrosis.

[0408] Procedure: Five- to six-week-old male Sprague Dawley rats were briefly anesthetized with isoflurane and their dorsal areas were shaved using a Wahl pet trimmer. Bleomycin (BLM) was diluted to 1 mg / ml with sterile phosphate-buffered saline (PBS). Using a 1 ml syringe with a 27-gauge needle, 100 μl of BLM solution was subcutaneously injected into two sites on the shaved area once daily for 4 weeks. The blank control group was injected with the same volume of sterile PBS daily. Example 71: Unilateral ureteral obstruction renal fibrosis model

[0409] Procedure: On day 0, seven-week-old female C57BL / 6 mice underwent UUO surgery under a mixture of three types of anesthetics (medetomidine, midazolam, and butorphanol). After shaving, the abdomen was incised and the left ureter was removed from the abdomen. The ureter was sutured at two points with 4 to 0 silk sutures. The peritoneum and skin were sutured, and the mice were transferred to clean cages and held until recovery from anesthesia. Mice were divided into two equal-weight groups before the day of surgery. The compound was administered orally from day 0 to day 13. On day 14, the weight of the ligated left and right kidneys was measured at sacrifice. Example 72: Collagen and α-SMA in LX-2

[0410] Method: The culture medium was prepared using DMEM supplemented with 2% FBS and 1% P / S. The medium was removed from the culture flask containing the confluence layer of LX-2 cells. Then, 3 ml of 0.25% trypsin-EDTA solution was added, and the cells were cultured at 37°C for 5 min in each T150 flask. 7 ml of medium was added to stop trypsinization. The cells were centrifuged at 300 xg for 5 min. The supernatant was discarded, and the cells were resuspended in fresh medium. The cells were counted using a cell viability analyzer. 5.0E+05 cells / well were seeded into 6-well plates containing 2.0 mL of medium. The cells were cultured overnight at 37°C. The next day, the complete medium was replaced with medium containing 0.4% FBS for starvation. After culturing in medium with reduced serum for 24 h, LX-2 cells were treated with two copies of the compound (8 concentrations, 3-fold dilution) for 30 min, followed by restimulation with 4 ng / ml TGF-β for 48 h. Meanwhile, media containing only DMSO and TGF-β were used as blank and positive controls, respectively. TGF-β induction was used as a positive control for maximum induction. The culture medium was discarded at the end of induction. Cells were washed once with ice-cold DPBS. RIPA buffer was added to lyse the cells for 20 min. Cells were then scraped from the culture dish, collected in tubes, and centrifuged. The supernatant was stored at -80°C. The total protein content in the lysate was determined using the BCA protein analysis kit. Cell processing for fibrosis analysis was performed in three separate experiments for each compound.

[0411] After BCA analysis, all lysate samples were adjusted to the same protein concentration using RIPA buffer. Samples with the same protein content were mixed with 4x LDS sample buffer and boiled at 95°C for 5 min. Denatured samples were used for electrophoresis. Western ink dot method was performed according to standard protocol. Equal volumes of protein were loaded onto 4 to 12% Bis-Tris gels. Repeated lysates of the samples were loaded onto two gels. These gels were run at 80 V for 0.5 h and then again at 120 V for 1 h. When electrophoresis was complete, the gel containing the target protein collagen I (COL1A1) was transferred to an NC membrane using a Trans-Blot electrophoresis transfer tank at 100 V for 90 min. α-SMA and GAPDH were transferred using an iBlot™ 2 gel transfer device at 20 V for 7 min. All membranes were blocked in TBST buffer with 5% skim milk for 1 h at room temperature, and then incubated overnight at 4°C with primary antibodies against COL1A1 and α-SMA in TBST buffer containing 5% BSA. For GAPDH detection, membranes with α-SMA immunospots were peeled off using Restore™ Western ink dot stripping buffer after detection. These membranes were then re-blocked and re-detected at room temperature (RT) with primary antibody against GAPDH for 2 h. After incubation with primary antibody, the membranes were washed with TBST and then incubated with secondary antibody at room temperature for 1 h. Ink dots were visualized using the ImageQuant LAS-4000 instrument. Chemiluminescence signals from ECL Western ink dot reagent were captured. The band integration intensity from the 16-bit ink dot image was used for quantification using software (ImageQuant TL 1D component). Raw quantification data for two replicate gels were obtained from ImageQuant TL. For each gel, collagen I and α-SMA protein expression levels were normalized to GAPDH. The average normalized data from two replicate gels were calculated and used to calculate IC50 using the S-shaped dose-response (variable slope) equation in GraphPad™ Prism software. The equation is: Y = bottom + (top - bottom) / (1 + 10^((LogIC50 - X) * slope)). Note: X is the logarithm of the compound concentration, and Y is the average normalized data.

[0412] Table 4 includes the IC50 values ​​of selected collagen compounds; compounds with an IC50 value < 0.1 nM are denoted as +++, compounds with an IC50 value between 0.1 and 1.0 nM are denoted as ++, and compounds with an IC50 value > 1.0 nM are denoted as +. Table 4: IC50 data for collagen in LX-2 cells Compound numbering Collagen in LX-2 (IC 50 ,nM) 172 +++ 128 ++ 131 ++ 127 ++ 125 ++ 188 ++ 159 ++ 121 +++ 196 +++ 193 +++ 112 +++ 126 ++ 117 ++ 189 ++ 116 ++ 153 ++ 190 +++ 185 ++ 191 ++ 167 +++ 111 ++ 156 +++ 194 ++ 146 ++ 150 ++ 139 ++ 120 +++ 192 +++ 130 ++ 1 + 4 + 39 +

[0413] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or variations thereof will be made to those skilled in the art and are included within the spirit and scope of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, wherein: (I); R1 refers to 3 to 8-membered heterocycles that need to be substituted, wherein the 3 to 8-membered heterocycles are substituted as needed by one or more substituents that are independently selected each time from halogens, -OH, -CN, -NO2, -NH2, lateral oxygen, =S, -S(O2)NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl and C1-10 alkyl that need to be substituted, wherein the C1-10 alkyl is substituted as needed by one or more substituents that are independently selected each time from hydroxyl, halogen, lateral oxygen, -C1-10 haloalkyl, -NH2, -CN and -NO2; R3 is selected from C1-C6 alkyl groups that are substituted as needed, 3- to 10-membered heterocycles that are substituted as needed, and C3-10 carbon rings that are substituted as needed, wherein each of the alkyl, heterocycle, and carbon ring is substituted as needed by one or more substituents independently selected each time from halogens, -OH, -CN, -NO2, -NH2, septyl groups, =S, C1-6 alkyl groups, -C1-10 haloalkyl groups, -O-C1-10 alkyl groups, C2-10 alkenyl groups, C2-10 alkynyl groups, C3-12 carbon rings, and 3- to 12-membered heterocycles; R4 is selected from: hydrogen; The C1-C6 alkyl group to be substituted as required, wherein the C1-C6 alkyl group is substituted as required by one or more substituents selected independently each time from halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, -O-C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring and 3 to 12-membered heterocycles; and the C3-10 carbon ring to be substituted as required, wherein the C3-10 carbon ring is substituted as required by one or more substituents selected independently each time from halogens, -OH, -CN, -NO2, -NH2, septyl group, =S, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbon ring and 3 to 12-membered heterocycles; W is an imidazole or pyridine; and when R1 is a methylpiperazine or W is a pyridine, then R4 is not methyl.

2. The compound of claim 1 or its pharmaceutically acceptable salt, hydrate or stereoisomer, wherein R3 is selected from a C3-6 carbon ring that is substituted as desired.

3. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, hydrate or stereoisomer, wherein R3 is a substituted phenyl group as desired, wherein the optional substituent of the phenyl group is selected from halogens and -C1-10 haloalkyl groups.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof, is a compound represented by formula (IIA): (IIA); or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof, is a compound represented by formula (IIB): (IIB); or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, hydrate or stereoisomer, wherein R4 is selected from hydrogen, C1-C6 alkyl groups substituted with one or more substituents selected from halogens as needed, and C5-6 carbon rings substituted with one or more substituents selected from hydroxyl and amines as needed.

7. The compound of claim 6 or its pharmaceutically acceptable salt, hydrate or stereoisomer, wherein R4 is selected from C1-C6 alkyl groups substituted with one or more fluorine substituents as desired, and C6 cycloalkyl groups substituted with hydroxyl groups.

8. A compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, wherein R1 is a 6- to 8-membered heterocycle that is substituted as desired, wherein the optional substituents on the 6- to 8-membered heterocycle are independently selected each time from one or more septal oxygen groups, -S(O2)NH2, -NH2, -C1-10 haloalkyl, -O-C1-10 alkyl, and C1-10 alkyl that is substituted as desired, wherein the optional substituents on the C1-10 alkyl are independently selected each time from one or more hydroxyl groups, halogens, septal oxygen groups, -C1-10 haloalkyl, -NH2, -CN, and -NO2.

9. A compound of claim 1 or 2 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof, wherein R1 is selected from 6 to 8 saturated heterocycles that are substituted as desired; wherein each optional substituent is independently selected from one or more -S(O2)NH2 and C1-10 alkyl groups that are substituted as desired, wherein each optional substituent on the C1-10 alkyl group is independently selected from one or more hydroxyl groups, halogens, side oxygen groups, -C1-10 haloalkyl groups and -NH2 groups that are substituted as desired.

10. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or stereoisomer thereof is selected from the following compounds: , ...

11. If the compound of claim 1 or its pharmaceutically acceptable salt, hydrate or stereoisomer is a compound or its pharmaceutically acceptable salt, it is a compound or its pharmaceutically acceptable salt.

12. If the compound of claim 1 or its pharmaceutically acceptable salt, hydrate or stereoisomer is a compound or its pharmaceutically acceptable salt, it is a compound or its pharmaceutically acceptable salt.

13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

14. Use of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, or a pharmaceutical composition of claim 13, for the preparation of a medicament for treating diseases associated with TNIK kinase.

15. As used in claim 14, wherein the disease is a fibrotic disease or condition.

16. As claimed in claim 14 or 15, wherein the disease is selected from cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc), and graft-versus-host disease (GVHD).