Method for producing kinase inhibitors

Abstract

In one aspect, the present disclosure provides methods for synthesizing TNIK and / or MAP4K4 kinase inhibitors for the treatment of disease. In one aspect, the present disclosure provides intermediates used in the synthetic methods described herein.

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international patent application claims the benefit of International Patent Application No. PCT / CN2022 / 114447, filed August 24, 2022, which is incorporated herein by reference in its entirety.

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

[0003] In one aspect, methods for producing kinase inhibitors (e.g., TNIK inhibitors) and intermediates used in the methods are described herein. TNIK is a serine / threonine kinase involved in various biological processes, including acting as an essential regulatory component of the Wnt signaling pathway. TNIK can directly bind to TCF4 and b-catenin and phosphorylate TCF4. Furthermore, TNIK can carry activators of Wnt target gene expression, regulate the actin cytoskeleton, and activate the c-Jun N-terminal kinase pathway, which responds to stress. It is also part of a signaling complex composed of NEDD4, RAP2A, and TNIK, which regulates neuronal dendrite outgrowth and branching during development. More generally, TNIK may be involved in regulating cytoskeletal reorganization and cell expansion. TNIK also attenuates Smad1 T322 phosphorylation, which is involved in TGF-b1 signaling.

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

[0005] TNIK activation of Wnt signaling may play an important role in carcinogenesis and embryonic development. Mutations in this gene are associated with an autosomal recessive form of cognitive impairment.

[0006] Furthermore, TNIK has been associated with cancer, including, for example, colorectal cancer, and therefore has been identified as an attractive candidate for drugs that target specific cancers.

[0007] The current data may suggest that TNIK is a potential target for the generation of small molecule inhibitors to specifically block the Wnt pathway in disease states such as colorectal cancer or autosomal recessive cognitive impairment.

[0008] Additionally, therapeutic targets associated with EMT, such as TNIK, which are targets for inhibition, may be used in therapies to treat and / or prevent EMT-based disorders, such as cancer metastasis and fibrosis.

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

[0010] In one aspect, provided herein is a method of producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0011] [ka] During the ceremony, R 1 But the following: N(R 5 ) 2, and each R 5 are independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-12 N(R) optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; 5 )2, Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted 3- to 8-membered heterocyclic rings, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 Alkyl is hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 Carbocyclic rings, such as C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (A), or a pharmaceutically acceptable salt thereof, with

[0012] [ka] In the formula, rings W, R 3 , and R 4 is defined above, R A1 , R A2 , and R A3 are halogen and -OC, respectively. 1-6 independently selected from alkyl, subjecting the compound to a hydrolysis step to produce a compound represented by formula (B) or a pharmaceutically acceptable salt thereof;

[0013] [ka] In the formula, rings W, R 3 , and R 4 is defined above.

[0014] In one aspect, provided herein is a method of producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0015] [ka] During the ceremony, R 1 But the following: N(R 5 ) 2, and each R 5 are independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 N(R) optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; 5 )2, Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted 3- to 8-membered heterocyclic rings, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 Alkyl is hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 Carbocyclic rings, such as C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (E), or a pharmaceutically acceptable salt thereof, with

[0016] [ka] During the ceremony, The ring W is defined above, En is 0 or 1, R EN is a protecting group, R E1 is C1-C6 alkyl (e.g., ethyl), C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; a compound represented by formula (F), or a pharmaceutically acceptable salt thereof,

[0017] [ka] In the formula, R 3 is defined above, and R F is a substituted or unsubstituted phenyl; reacting in the presence of a compound of formula (K) or a pharmaceutically acceptable salt thereof, R 4 -NH2(K), thereby producing a compound represented by formula (G), or a pharmaceutically acceptable salt thereof:

[0018] [ka] In the formula, R 3 , R 4 , Ring W, En, R EN , and R E1 is defined above.

[0019] In one aspect, provided herein is a method of producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0020] [ka] During the ceremony, R 1 But the following: N(R 5 ) 2, and each R 5are independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 N(R) optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; 5 )2, Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted 3- to 8-membered heterocyclic rings, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 Alkyl is hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 A carbocyclic ring, C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (E), or a pharmaceutically acceptable salt thereof, with

[0021] [ka] During the ceremony, The ring W is defined above, En is 0, R EN is a protecting group, R E1 is C1-C6 alkyl (e.g., ethyl), C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; reacting a compound represented by formula (F), or a pharmaceutically acceptable salt thereof,

[0022] [ka] In the formula, R 3 is defined above, R F is a substituted or unsubstituted phenyl; thereby producing a compound of formula (Ga), or a pharmaceutically acceptable salt thereof;

[0023] [ka] In the formula, R 3 , Ring W, En, R EN , and R E1 is defined above, and the process further comprises reacting a compound of formula (Ga) or a pharmaceutically acceptable salt thereof with a compound of formula (J) or a pharmaceutically acceptable salt thereof; R 4 -RJ (J) In the formula, R J is a leaving group and R 4 is defined above, thereby producing a compound represented by formula (G), or a pharmaceutically acceptable salt thereof,

[0024] [ka] In the formula, R 3 , R 4 , R EN , En, and R E1 is defined above.

[0025] In one aspect, provided herein is a method of producing a compound represented by formula (Ia), or a pharmaceutically acceptable salt thereof:

[0026] [ka] During the ceremony, R 1 is piperazine, which is an oxo, -S(O2)NH2, and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, which is optionally substituted with one or more halogens; R 4 is unsubstituted C1-C6 alkyl; The method comprises reacting a compound represented by formula (E-1), or a pharmaceutically acceptable salt thereof, with

[0027] [ka] During the ceremony, R EN’ is hydrogen or R EN and R ENis a protecting group, R E1 is C1-C6 alkyl (e.g., ethyl), C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; reacting a compound represented by formula (F), or a pharmaceutically acceptable salt thereof,

[0028] [ka] In the formula, R 3 is defined above, R F is a substituted or unsubstituted phenyl; thereby producing a compound of formula (G-1a) or a pharmaceutically acceptable salt thereof,

[0029] [ka] In the formula, R 3 , R EN’ , and R E1 is defined above, The method comprises reacting a compound of formula (G-1a), or a pharmaceutically acceptable salt thereof, with a compound of formula (J), or a pharmaceutically acceptable salt thereof; R 4 -R J (J) In the formula, R J is a leaving group, thereby producing a compound represented by formula (G-1), or a pharmaceutically acceptable salt thereof;

[0030] [ka] In the formula, R 3 , R 4 , R EN’ , and R E1 is defined above.

[0031] In one aspect, provided herein is a compound represented by Formula (A), or a pharmaceutically acceptable salt thereof:

[0032] [ka] During the ceremony, R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 Carbocyclic rings, such as C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R A1 , R A2 , and R A3 Each of the halogens and -OC 1-6 alkyl.

[0033] In certain embodiments, the present disclosure provides a compound represented by formula (I):

[0034] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 But the following: -N(R 5 )2, wherein R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, and the optional substituents on the C1-C6 alkyl are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 -N(R 5 )2, Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 substituted C1-C6 alkyl, independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; Optionally substituted 3- to 8-membered heterocycles, wherein the optional substituents on the 3- to 8-membered heterocycle are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —S(O2)NH2, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 independently selected at each occurrence from alkyl, C 1-10 The optional substituents on the alkyl are one or more of hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocyclic rings, each of which may optionally be substituted with one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, where any substituent on the C1-C6 alkyl is one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; Optionally substituted C 3-10 A carbocyclic ring, C 3-10 Optional substituents on the carbocyclic ring may be one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted C independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle 3-10 selected from carbocycles, W is selected from optionally substituted 5- to 6-membered heteroaryl, and the substituents on the optionally substituted 5- to 8-membered heteroaryl are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —S(O2)NH2, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 and independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle.

[0035] In some embodiments, the present disclosure provides a method for treating or preventing a disease, comprising administering to a subject in need thereof a compound synthesized by the methods described herein (e.g., a compound of Formula (Ia) or Formula (I), or a salt thereof) 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 psychiatric disorders. In some cases, the pharmaceutical composition can be used as an inhibitor of tumor immunosuppression in combination with chemotherapy or immune checkpoint inhibitor therapy for cancer. In some cases, the pharmaceutical composition can be used to treat fibrotic diseases or conditions, including, but not limited to, chronic renal fibrosis ("CKD"), liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, dermal fibrosis, systemic sclerosis ("SSc"), and graft-versus-host disease ("GVHD"). In some cases, the pharmaceutical composition can be used to treat renal fibrosis. In some cases, the pharmaceutical composition can be used to treat skin fibrosis. In some cases, the pharmaceutical composition can be used to treat idiopathic pulmonary fibrosis (IPF). In some cases, the pharmaceutical composition can be used to treat diseases associated with TNIK kinase.

[0036] In some aspects, the present disclosure provides a method for inhibiting TNIK kinase, comprising administering to a subject in need thereof a compound synthesized by the methods described herein (e.g., a compound of Formula (Ia) or Formula (I), or a salt thereof) and a pharmaceutically acceptable excipient.

[0037] In some aspects, the present disclosure provides a method for inhibiting MAP4K4 kinase, comprising administering to a subject in need thereof a compound synthesized by a method described herein (e.g., a compound of Formula (Ia) or Formula (I) or a salt thereof), and a pharmaceutically acceptable excipient.

[0038]

[0013] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be understood, the present disclosure is capable of other and different embodiments, and its several details can be modified in various obvious respects without departing from the present disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

[0039] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION OF THE INVENTION

[0040] While various embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may be made by those skilled in the art without departing from the present disclosure. It will be appreciated that various alternatives to the embodiments of the present disclosure described herein may be employed.

[0041] A.Definition 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 disclosure belongs. All patents and publications mentioned herein are incorporated by reference.

[0042] "Alkyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having 1 to 15 carbon atoms (i.e., C1-C 15Alkyl refers to a straight or branched hydrocarbon chain radical having 1 to 13 carbon atoms (i.e., C1-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (i.e., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (i.e., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (i.e., C5-C 15 In certain embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Unless stated otherwise in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0043] When used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, "C x-y " is meant to include groups containing x to y carbons in the chain. For example, "C 1-6 The term "alkyl" refers to alkyl groups that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, including straight chain alkyl groups and branched chain alkyl groups.

[0044] "Alkoxy" refers to a radical attached through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above. Unless otherwise stated in the specification, an alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0045] "Alkenyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from 2 to 12 carbon atoms (i.e., C-C 12"Alkenyl" refers to a straight or branched hydrocarbon chain radical group having from 2 to 8 carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, alkenyl contains from 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, alkenyl contains from 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). An alkenyl is attached to the remainder of the molecule by a single bond, e.g., ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise in the specification, an alkenyl group may be optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0046] "Alkynyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from 2 to 12 carbon atoms (i.e., C-C 12"alkynyl" refers to a straight or branched hydrocarbon chain radical group having 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In certain embodiments, alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). An alkynyl is attached to the remainder of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless stated otherwise in the specification, an alkynyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0047] "C x-y alkenyl" and "C x-y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups similar in length and possibly substituted to the alkyls described above, but that contain at least one double or triple bond respectively. x-y The term alkenylene- refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the chain. For example, -C 2-6 Alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. The alkenylene chain may have one double bond or two or more double bonds in the alkenylene chain. -C x-y The term alkynylene- refers to a substituted or unsubstituted alkynylene chain having x to y carbon atoms in the chain. For example, -C 2-6Alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. The alkynylene chain may have one triple bond or two or more triple bonds in the alkynylene chain.

[0048] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having 1 to 12 carbon atoms, connecting a radical group to the rest of the molecule, such as methylene, ethylene, propylene, or n-butylene. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkylene contains 1 to 10 carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, alkylene contains 1 to 8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (i.e., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (i.e., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (i.e., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (i.e., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (i.e., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkylene). -C x-y The term alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms in the alkylene chain. For example, -C 1-6Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0049] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms, connecting the rest of the molecule to a radical group. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkenylene is an alkyl group having 2 to 10 carbon atoms (i.e., C2-C 10 In certain embodiments, alkenylene includes 2 to 8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, alkenylene includes 2 to 5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, alkenylene includes 2 to 4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, alkenylene includes 2 to 3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, alkenylene includes 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, alkenylene includes 5 to 8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, alkenylene includes 3 to 5 carbon atoms (i.e., C3-C5 alkenylene).

[0050] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from 2 to 12 carbon atoms, linking the rest of the molecule to a radical group. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkynylene is an alkyl group having from 2 to 10 carbon atoms (i.e., C2-C 10 In certain embodiments, alkynylene includes 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, alkynylene includes 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, alkynylene includes 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, alkynylene includes 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, alkynylene includes 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, alkynylene includes 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, alkynylene includes 3 to 5 carbon atoms (i.e., C3-C5 alkynylene).

[0051] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom, the ring system containing at least one aromatic ring. The aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon and 5 to 18 carbon atoms, and at least one ring in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, aryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0052] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH3, -CHCHOCH3, -CHCHOCHCHOCH3, -CH(CH3)OCH3, -CHNHCH3, -CHN(CH3)2, -CHCH2NHCH3, or -CHCH2N(CH3)2. Unless stated otherwise in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0053] "Aralkyl" is a group of the formula -R c -aryl radical, where R c is an alkylene chain as defined above, for example, methylene, ethylene, etc.

[0054] "Aralkenyl" refers to a group of the formula -R d -aryl radical, where R d is an alkenylene chain as defined above. "Aralkynyl" refers to a group of the formula -Re -aryl radical, where R e is an alkynylene chain as defined above.

[0055] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring system in which each ring atom of the ring system is carbon. Carbocycles can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, valence permitting, is included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. In some embodiments, a carbocycle is aryl. In some embodiments, a carbocycle is cycloalkyl. In some embodiments, a carbocycle is cycloalkenyl. In some embodiments, a carbocycle contains a triple bond. Unless stated otherwise in the specification, carbocycles may be optionally substituted.

[0056] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having 3 to 12 carbon atoms. In certain embodiments, cycloalkyls contain 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain 5 to 7 carbon atoms. A cycloalkyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0057] "Heterocycloalkyl" refers to a cycloalkyl group, as defined above, in which one or more ring carbons are replaced with one or more heteroatoms, such as N, O, P, and S. Heterocycloalkyls may be optionally substituted.

[0058] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having 3 to 12 carbon atoms and containing at least one double bond. In certain embodiments, a cycloalkenyl contains one double bond. In certain embodiments, a cycloalkenyl contains two or more double bonds. In certain embodiments, a cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, a cycloalkenyl contains 5 to 7 carbon atoms. A cycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0059] "Heterocycloalkenyl" refers to a cycloalkenyl group, as defined above, in which one or more ring carbons are replaced with one or more heteroatoms, such as N, O, P, and S. A heterocycloalkenyl may be optionally substituted.

[0060] "Cycloalkylalkyl" refers to a group of the formula -R c -cycloalkyl radical, where R c is an alkylene chain as defined above.

[0061] "Cycloalkylalkoxy" refers to a group of the formula -OR c -refers to a radical attached through an oxygen atom of a cycloalkyl, where R c is an alkylene chain as defined above.

[0062] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro, and iodo substituents.

[0063] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, substituted by one or more halogen radicals, such as, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with multiple halogen radicals, each halogen may be independently selected, e.g., 1-chloro, 2-fluoroethane.

[0064] "Fluoroalkyl" refers to an alkyl radical as defined above that is substituted with one or more fluoro radicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0065] A "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. Each ring in a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. A "heterocycle" refers to a divalent heterocycle that connects the remainder of the molecule to a radical group. Unless otherwise specified herein, heterocycles are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycles are optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen. In some embodiments, a heterocycle is a heteroaryl. In some embodiments, a heterocycle is a heterocycloalkyl. In some embodiments, a heterocycle is a heterocycloalkenyl. In some embodiments, a heterocycle contains one or more triple bonds.

[0066] In some embodiments, the heterocycle contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycle contains 1 to 3 nitrogens. In some embodiments, the heterocycle contains one or two nitrogens. In some embodiments, the heterocycle contains one nitrogen. In some embodiments, the heterocycle contains one nitrogen and one oxygen. Unless stated otherwise herein, a heterocycle radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused, spirocyclic, or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycle radical can be optionally oxidized, and the nitrogen atoms can be optionally quaternized. Representative heterocycles include the heteroaryl groups described below. Representative heterocycles also include heteroaryl groups containing 2 to 15 carbon atoms (C2-C3). 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), 2-8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2-7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2-6 carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2-5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2-4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocyclic radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, Examples of heterocyclic rings include, but are not limited to, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycle also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycles have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycle, it is understood that the number of carbon atoms in the heterocycle is not the same as the total number of atoms (including heteroatoms) that make up the heterocycle (i.e., the skeletal atoms of the heterocycle). In some embodiments, the heterocycle is 3 to 8 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 5-6 membered.

[0067] "Heteroaryl" or "heteroaromatic ring" refers to a radical derived from a heteroaromatic ring radical containing 1 to 13 carbon atoms, at least one heteroatom (each heteroatom may be selected from N, O, and S), and at least one aromatic ring. As used herein, heteroaryl rings may be selected from monocyclic or bicyclic rings, and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroatoms in a heteroaryl radical may be optionally oxidized. If present, one or more nitrogen atoms may be optionally quaternized. A heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl that allows valence, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzthiazole, and imdazopyridine. "X-membered heteroaryl" refers to the number of ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered heteroaromatic ring has 5 ring atoms, e.g., triazole, oxazole, thiophene, etc. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthlanyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and indophenyl. linyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0068] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbon or substitutable heteroatoms, e.g., NH, of the structure. It should be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permissible valences of the replacing atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0069] In some embodiments, a substituent can be any substituent described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a, -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(Ra )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle, wherein each R a is, if valence permits, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c-C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); b is independently selected from a direct bond, or a straight or branched chain alkylene, alkenylene, or alkynylene chain; and each R c is a straight or branched alkylene, alkenylene, or alkynylene chain.

[0070] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0071] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, etc. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0072] As used herein, the phrases "oral administration" and "parenteral administration" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0073] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0074] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not damaging to the patient. Some examples of materials that can function 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and corn starch. (10) oils such as soybean oil, (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0075] In certain embodiments, the terms "prevention" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0076] The terms "treat," "treating," or "treatment," as used herein, can include alleviating, alleviating, or ameliorating disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying cause of symptoms, inhibiting the disease or condition, e.g., halting the onset of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating symptoms caused by the disease or condition, or halting the symptoms of the disease or condition, either prophylactically and / or therapeutically.

[0077] B. Synthetic Methods and Compounds In one aspect, provided herein is a method of producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0078] [ka] During the ceremony, R 1 But the following: N(R 5 )2, where each R 5 are independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 N(R) optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; 5 )2, Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted 3- to 8-membered heterocyclic rings, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 Alkyl is hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 Carbocyclic rings, such as C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (A), or a pharmaceutically acceptable salt thereof, with

[0079] [ka] In the formula, rings W, R3 , and R 4 is defined above, R A1 , R A2 , and R A3 are halogen and -OC, respectively. 1-6 independently selected from alkyl, subjecting the compound to a hydrolysis step to produce a compound represented by formula (B) or a pharmaceutically acceptable salt thereof;

[0080] [ka] In the formula, rings W, R 3 , and R 4 is defined above.

[0081] In one aspect, provided herein is a method of producing a compound represented by formula (B), or a pharmaceutically acceptable salt thereof:

[0082] [ka] During the ceremony, R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 Carbocyclic rings, such as C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (A), or a pharmaceutically acceptable salt thereof, with

[0083] [ka] In the formula, rings W, R 3 , and R 4 is defined above, R A1 , R A2 , and R A3 are halogen and -OC, respectively. 1-6independently selected from alkyl, subjecting the compound to a hydrolysis step, thereby producing a compound represented by formula (B), or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments of Formula (A), R A1 , R A2 , and R A3 are halogen and -OC, respectively. 1-3 In some embodiments, R A1 , R A2 , and R A3 are each independently selected from halogen. A1 , R A2 , and R A3 are respectively -OC 1-6 In some embodiments, R A1 , R A2 , and R A3 are each independently selected from F, Cl, Br, OMe, and OEt.

[0085] [ka] is CBr, CCl, CF, CFCl, CFCl, CFBr, CFBr, C(OMe), or C(OEt).

[0086] [ka] is CF3. In some embodiments, the hydrolysis step is carried out in a solvent selected from ether, alcohol, water, and mixtures thereof (e.g., MeOH / water). In some embodiments, the hydrolysis step is carried out in a solvent selected from 1,4-dioxane, MeOH, EtOH, i-PrOH, n-PrOH, THF, water, or mixtures thereof. In some embodiments, the hydrolysis step is carried out in a mixture of methanol and water. In some embodiments, the hydrolysis step is carried out under alkaline conditions. In some embodiments, the hydrolysis step is carried out in the presence of a base, and the base is an alkali, an alkali salt, or a mixture thereof. In some embodiments, the alkali salt is a carbonate, bicarbonate, or phosphate (e.g., phosphate, hydrogen phosphate, and dihydrogen phosphate). In some embodiments, the base is selected from NaOH, KOH, LiOH, Ca(OH), KCO, KHCO, NaCO, NaHCO, KPO, KHPO, KHPO, NaPO, NaHPO, NaHPO, or a combination thereof. In some embodiments, the base is NaOH.

[0087] In some embodiments, the method further comprises subjecting the compound represented by Formula (B), or a pharmaceutically acceptable salt thereof, to a condensation reaction with a compound of Formula (C), or a pharmaceutically acceptable salt thereof;

[0088] [ka] In the formula, R 1 is in formula (I). In some embodiments, the condensation step is carried out in the presence of a base (e.g., DIEA), a coupling agent (HATU), or both. In some embodiments, the condensation reaction is carried out in a polar solvent. In some embodiments, the condensation reaction is carried out in either: In some embodiments, the condensation reaction is carried out in THF. In some embodiments, the condensation reaction is carried out at a temperature between 15 and 25°C. In some embodiments, the condensation reaction is carried out at a temperature between 0 and 40°C.

[0089] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia):

[0090] [ka] During the ceremony, R 1 is piperazine, and piperazine is oxo and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, which is optionally substituted with one or more halogens; R 4 is a substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more halogens.

[0091] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia):

[0092] [ka] During the ceremony, R 1 is piperazine, which is an oxo, -S(O2)NH2, and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, which is optionally substituted with one or more halogens; R 4 is unsubstituted C1-C6 alkyl.

[0093] In one aspect, provided herein is a method of producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0094] [ka] During the ceremony, R 1 But the following: N(R 5 )2, where each R 5 are independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 N(R) optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; 5 )2, Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted 3- to 8-membered heterocyclic rings, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 Alkyl is hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 A carbocyclic ring, C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (E), or a pharmaceutically acceptable salt thereof, with

[0095] [ka] During the ceremony, The ring W is defined above, En is 0 or 1, R EN is a protecting group, R E1 is C1-C6 alkyl (e.g., ethyl), C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; a compound represented by formula (F), or a pharmaceutically acceptable salt thereof,

[0096] [ka] In the formula, R 3 is defined above, R F is a substituted or unsubstituted phenyl; reacting in the presence of a compound of formula (K) or a pharmaceutically acceptable salt thereof, R4 -NH2(K), thereby producing a compound represented by formula (G), or a pharmaceutically acceptable salt thereof:

[0097] [ka] In the formula, R 3 , R 4 , Ring W, En, R EN , and R E1 is defined above.

[0098] In one aspect, provided herein is a method of producing a compound represented by formula (G), or a pharmaceutically acceptable salt thereof:

[0099] [ka] During the ceremony, R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 Carbocyclic rings, such as C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO, -NH, oxo, =S, -S(O)NH, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; En is 0 or 1, R EN is a protecting group, R E1 is C1-C6 alkyl (e.g., ethyl), C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; The method comprises reacting a compound represented by formula (E), or a pharmaceutically acceptable salt thereof, with

[0100] [ka] During the ceremony, Ring W, En, REN , and R E1 is defined above, a compound represented by formula (F), or a pharmaceutically acceptable salt thereof,

[0101] [ka] In the formula, R 3 is defined above, R F is a substituted or unsubstituted phenyl; reacting in the presence of a compound of formula (K) or a pharmaceutically acceptable salt thereof, R 4 -NH2(K), thereby producing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments of formulas (E), (E-1), (G), (Ga), (G-1), and (G-1a), R E1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl. E1 is ethyl. In some embodiments, R E1 is phenyl, benzyl, or p-methoxybenzyl. In some embodiments, R E1 is substituted or unsubstituted phenyl. In some embodiments, R E1 is substituted or unsubstituted heteroaryl. In some embodiments, R E1is halogen, -NH2, CN, NO2, -OH, -SH, SF5, C1-C6 alkyl, -OC1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 and optionally substituted with one or more substituents selected from —NHC(═O)OC-C alkyl, —C(═O)C-C alkyl, —C(═O)OH, —C(═O)OC-C alkyl, —C(═O)NH, —C(═O)N(C-C alkyl), —C(═O)NHC-C alkyl, C-C hydroxyalkyl, C-C aminoalkyl, and C-C heteroalkyl. In some embodiments, R E1 is optionally substituted with one or more substituents selected from halogen, —NH, CN, NO, —OH, —C(═O)OH, —SH, SF, C-C alkyl, —O—C alkyl, C-C haloalkyl, and —O—C alkyl.

[0103] In some embodiments, En is 0. In some embodiments, En is 1.

[0104] In some embodiments, the compound of Formula (E) has the structure of Formula (E-1):

[0105] [ka] In the formula, R EN’ is hydrogen or R EN In some embodiments, the compound of formula (E-1) is

[0106] [ka] In some embodiments, the compound of formula (E-1) has the structure:

[0107] [ka] In some embodiments, the compound of formula (E-1) has the structure:

[0108] [ka] It has the following structure.

[0109] In some embodiments of formulas (E), (G), (Ga), and (H), R EN is selected from (trimethylsilicon)ethoxymethyl (SEM), methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl (CBz), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), para-toluenesulfonyl (Tos), 2,2,2-trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (Pmb), and benzyl (Bn). In some embodiments, R EN is SEM.

[0110] In some embodiments of Formula (F), R F is one or more R F1 and each R F1is halogen, -NH2, CN, NO2, -OH, -SH, SF5, C1-C6 alkyl, -OC1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, independently selected from —N(C1-C6 alkyl)2, —NHC(═O)OC1-C6 alkyl, —C(═O)C1-C6 alkyl, —C(═O)OH, —C(═O)OC1-C6 alkyl, —C(═O)NH2, —C(═O)N(C1-C6 alkyl)2, —C(═O)NHC1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and C1-C6 heteroalkyl.

[0111] In some embodiments of Formula (F), R F is one or more R F1 and each R F1 are independently selected from F, Cl, Br, methyl, and methoxy.

[0112] In some embodiments, the compound of Formula (F) has the structure of Formula (F-1):

[0113] [ka] where Fn is 0, 1, 2, 3, 4, or 5, and each R F1is halogen, -NH2, CN, NO2, -OH, -SH, SF5, C1-C6 alkyl, -OC1-C6 alkyl, C1-C6 haloalkyl, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, In some embodiments, the compound of Formula (F) is independently selected from: -N(C-C alkyl), -NHC(=O)OC-C alkyl, -C(=O)C-C alkyl, -C(=O)OH, -C(=O)OC-C alkyl, -C(=O)NH, -C(=O)N(C-C alkyl), -C(=O)NHC-C alkyl, C-C hydroxyalkyl, C-C aminoalkyl, and C-C heteroalkyl.

[0114] [ka] is.

[0115] In some embodiments, the compound represented by Formula (E), Formula (E-1) or a salt thereof, and the compound represented by Formula (F) or a salt thereof are reacted in a commercially available solvent. In some embodiments, the commercially available solvent is THF, 2-MeTHF, toluene, 1,4-dioxane, 1,2-DCE, DCM, DMF, DMAc, NMP, DMSO, acetone, acetonitrile, EtOH, MeOH, i-PrOH, t-BuOH, etc., or a combination thereof.

[0116] In some embodiments, the compound represented by formula (G) has the structure of formula (G-1):

[0117] [ka] In the formula, R EN’ is hydrogen or R EN is.

[0118] In some embodiments, the compound represented by formula (G-1) is

[0119] [ka] In some embodiments, the compound represented by formula (G-1) has the structure:

[0120] [ka] In some embodiments, the compound represented by formula (G-1) has the structure:

[0121] [ka] It has the following structure.

[0122] In some embodiments, the method further comprises subjecting the compound represented by formula (G) or a pharmaceutically acceptable salt thereof to a hydrolysis reaction, thereby producing a compound of formula (H) or a pharmaceutically acceptable salt thereof.

[0123] [ka] In some embodiments, the compound represented by formula (H) has the structure of formula (H-1):

[0124] [ka] In some embodiments, the compound represented by formula (H-1) is

[0125] [ka] It has the following structure.

[0126] In some embodiments, the method further comprises subjecting the compound represented by Formula (H) or a pharmaceutically acceptable salt thereof to a condensation reaction with a compound of Formula (C) or a pharmaceutically acceptable salt thereof.

[0127] [ka]

[0128] In some embodiments, the deprotection reaction further comprises a deprotection reaction. In some embodiments, the deprotection reaction further comprises a deprotection reaction of R EN with hydrogen. In some embodiments, the deprotection reaction occurs after the condensation reaction. In some embodiments, the deprotection reaction occurs before the condensation reaction.

[0129] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia):

[0130] [ka] During the ceremony, R 1 is piperazine, and piperazine is oxo and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, which is optionally substituted with one or more halogens; R 4 is a substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more halogens.

[0131] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia):

[0132] [ka] During the ceremony, R 1 is piperazine, which is an oxo, -S(O2)NH2, and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, which is optionally substituted with one or more halogens; R 4 is unsubstituted C1-C6 alkyl.

[0133] In one aspect, provided herein is a method of producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:

[0134] [ka] During the ceremony, R 1 But the following: N(R 5 ) 2, and each R 5 are independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 N(R) optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; 5 )2, Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted 3- to 8-membered heterocyclic rings, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 Alkyl is hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 A carbocyclic ring, C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (E), or a pharmaceutically acceptable salt thereof, with

[0135] [ka] During the ceremony, The ring W is defined above, En is 0, R EN is a protecting group, R E1is C1-C6 alkyl (e.g., ethyl), C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; reacting a compound represented by formula (F), or a pharmaceutically acceptable salt thereof,

[0136] [ka] In the formula, R 3 is defined above, R F is a substituted or unsubstituted phenyl; thereby producing a compound of formula (Ga), or a pharmaceutically acceptable salt thereof;

[0137] [ka] In the formula, R 3 , Ring W, En, R EN , and R E1 is defined above, The method comprises reacting a compound of formula (Ga), or a pharmaceutically acceptable salt thereof, with a compound of formula (J), or a pharmaceutically acceptable salt thereof; R 4 -R J (J) In the formula, R J is a leaving group and R 4 is defined above, thereby producing a compound represented by formula (G), or a pharmaceutically acceptable salt thereof;

[0138] [ka] In the formula, R 3 , R 4 , R EN , En, and R E1 is defined above.

[0139] In some embodiments, a compound represented by Formula (E), or a pharmaceutically acceptable salt thereof, is reacted with a compound represented by Formula (F), or a pharmaceutically acceptable salt thereof, in the presence of NH gas or NH in a solvent, such as NH·H O, NH in MeOH, NH in EtOH, and other NH solutions, to produce a compound of Formula (Ga), or a pharmaceutically acceptable salt thereof. In some embodiments, NH is present in a solvent such as alcohol and water.

[0140] In some embodiments, the compound of formula (E) is

[0141] [ka] It has the following structure.

[0142] In some embodiments, the compound of formula (Ga) is

[0143] [ka] It has the following structure.

[0144] In some embodiments, the compound of formula (G) is

[0145] [ka] It has the following structure.

[0146] In some embodiments of Formula (J), R J is a halogen (e.g., Br, Cl, I). In some embodiments, R J is an alkyl sulfonate (e.g., trifluoromethanesulfonate (triflate or TfO) - )) or arylsulfonate (e.g., 4-methylbenzenesulfonate). In some embodiments, R J is Br. In some embodiments, R Jis Cl. In some embodiments, R J is I. In some embodiments, R J is a triflate. In some embodiments, R J is 4-methylbenzenesulfonate.

[0147] In some embodiments, R 4 -R J is 2-bromopropane. In some embodiments, R 4 -R J is 2-chloropropane. In some embodiments, R 4 -R J is 2-iodopropane. In some embodiments, R 4 -R J is isopropyl trifluoromethanesulfonate. In some embodiments, R 4 -R J is isopropyl 4-methylbenzenesulfonate.

[0148] In some embodiments, R 4 -R J is 2-chloro-1,1,1-trifluoroethane. In some embodiments, R 4 -R J is 2-bromo-1,1,1-trifluoroethane. In some embodiments, R 4 -R J is 2-iodo-1,1,1-trifluoroethane. In some embodiments, R 4 -R J is 2,2,2-trifluoroethyl p-toluenesulfonate.

[0149] In some embodiments, the method further comprises a deprotection reaction. In some embodiments, the deprotection reaction occurs before the reaction of the compound represented by Formula (E) with the compound represented by Formula (F). In some embodiments, the compound represented by Formula (E) is deprotected.

[0150] In some embodiments, the method further comprises subjecting the compound represented by formula (G) or a pharmaceutically acceptable salt thereof to a hydrolysis reaction, thereby producing a compound of formula (H) or a pharmaceutically acceptable salt thereof.

[0151] [ka]

[0152] In some embodiments, the compound of formula (H) is

[0153] [ka] It has the following structure.

[0154] In some embodiments, the method further comprises subjecting the compound represented by Formula (H) or a pharmaceutically acceptable salt thereof to a condensation reaction with a compound of Formula (C) or a pharmaceutically acceptable salt thereof.

[0155] [ka]

[0156] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia):

[0157] [ka] During the ceremony, R 1 is piperazine, and piperazine is oxo and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3is phenyl, which is optionally substituted with one or more halogens; R 4 is a substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more halogens.

[0158] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia):

[0159] [ka] During the ceremony, R 1 is piperazine, which is an oxo, -S(O2)NH2, and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, which is optionally substituted with one or more halogens; R 4 is unsubstituted C1-C6 alkyl.

[0160] In one aspect, provided herein is a method of producing a compound represented by formula (Ia), or a pharmaceutically acceptable salt thereof:

[0161] [ka] During the ceremony, R 1 is piperazine, which is an oxo, -S(O2)NH2, and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3is phenyl, which is optionally substituted with one or more halogens; R 4 is unsubstituted C1-C6 alkyl; The method comprises reacting a compound represented by formula (E-1), or a pharmaceutically acceptable salt thereof, with

[0162] [ka] During the ceremony, R EN’ is hydrogen or R EN and R EN is a protecting group, R E1 is C1-C6 alkyl (e.g., ethyl), C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; reacting a compound represented by formula (F), or a pharmaceutically acceptable salt thereof,

[0163] [ka] In the formula, R 3 is defined above, R F is a substituted or unsubstituted phenyl; thereby producing a compound of formula (G-1a) or a pharmaceutically acceptable salt thereof,

[0164] [ka] In the formula, R 3 , R EN’ , and R E1 is defined above, The method comprises reacting a compound of formula (G-1a), or a pharmaceutically acceptable salt thereof, with a compound of formula (J), or a pharmaceutically acceptable salt thereof; R 4 -R J(J) In the formula, R J is a leaving group, thereby producing a compound represented by formula (G-1), or a pharmaceutically acceptable salt thereof;

[0165] [ka] In the formula, R 3 , R 4 , R EN’ , and R E1 is defined above.

[0166] In some embodiments, a compound represented by Formula (E-1), or a pharmaceutically acceptable salt thereof, and a compound represented by Formula (F), or a pharmaceutically acceptable salt thereof, are reacted in the presence of NH gas or NH in a solvent, such as NH·H O, NH in MeOH, NH in EtOH, and other NH solutions, to produce a compound of Formula (G-1a), or a pharmaceutically acceptable salt thereof. In some embodiments, NH is present in a solvent such as alcohol and water.

[0167] In some embodiments, the method further comprises subjecting the compound represented by formula (G-1), or a pharmaceutically acceptable salt thereof, to a hydrolysis reaction, thereby producing a compound of formula (H-1), or a pharmaceutically acceptable salt thereof.

[0168] [ka]

[0169] In some embodiments, the method further includes subjecting the compound represented by formula (H-1) or a pharmaceutically acceptable salt thereof to a condensation reaction with a compound of formula (C) or a pharmaceutically acceptable salt thereof.

[0170] [ka]

[0171] In some embodiments, R EN’ is hydrogen. In some embodiments, R EN’ is R EN In some embodiments, R EN’ is selected from (trimethylsilicon)ethoxymethyl (SEM), methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl (CBz), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), para-toluenesulfonyl (Tos), 2,2,2-trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (Pmb), and benzyl (Bn). In some embodiments, R EN’ is SEM.

[0172] In some embodiments, the method further comprises a deprotection reaction. In some embodiments, the deprotection reaction occurs after the condensation reaction, and the deprotection reaction is EN with hydrogen. In some embodiments, the deprotection reaction occurs before the reaction of the compound represented by Formula (E-1) with the compound represented by Formula (F). In some embodiments, the compound represented by Formula (E-1) is deprotected. In some embodiments, the compound of Formula (C) or a pharmaceutically acceptable salt thereof is

[0173] [ka] It has the following structure.

[0174] In one aspect, provided herein is a compound represented by Formula (A), or a pharmaceutically acceptable salt thereof:

[0175] [ka] During the ceremony, R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocycle, wherein each of the alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO, —NH, oxo, ═S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; and Optionally substituted C 3-10 A carbocyclic ring, C 3-10 Carbocyclic rings are halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. 3-10 selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, and the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R A1 , R A2 , and R A3 Each of the halogens and -OC 1-6 alkyl.

[0176] In some embodiments, the compound of Formula (A) is

[0177] [ka] It has the following structure.

[0178] In certain embodiments, the present disclosure provides a compound represented by formula (I):

[0179] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 But the following: -N(R 5 )2, wherein R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, and the optional substituents on the C1-C6 alkyl are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12-N(R 5 )2, Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 substituted C1-C6 alkyl, independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; Optionally substituted 3- to 8-membered heterocycles, wherein the optional substituents on the 3- to 8-membered heterocycle are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —S(O2)NH2, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 independently selected at each occurrence from alkyl, C 1-10 The optional substituents on the alkyl are one or more of hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocyclic rings, each of which may optionally be substituted with one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-6 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; R 4 But the following: hydrogen, Optionally substituted C1-C6 alkyl, where any substituent on the C1-C6 alkyl is one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; Optionally substituted C 3-10 A carbocyclic ring, C 3-10 Optional substituents on the carbocyclic ring may be one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Optionally substituted C independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle 3-10 selected from carbocycles, Ring W is selected from optionally substituted 5- to 8-membered (e.g., 5- or 6-membered) heteroaryl, and the substituents on the optionally substituted 5- to 8-membered heteroaryl are one or more of halogen, —OH, —CN, —NO, —NH, oxo, ═S, —S(O)NH, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 and independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle.

[0180] In certain embodiments, the present disclosure provides a compound represented by formula (I):

[0181] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 But the following: -N(R 5 )2, wherein R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, -N(R 5 )2, substituted C1-C6 alkyl, and optionally substituted 3- to 14-membered heterocycles (e.g., 5- to 6-membered heterocycloalkyl); R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 selected from carbocycles, R 4 But the following: hydrogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; Optionally substituted C 3-10 selected from a carbocycle or an optionally substituted 3- to 12-membered heterocycle; Ring W is selected from optionally substituted 5- to 6-membered heteroaryls.

[0182] In some embodiments of formulas (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (K), and (J), R 4 is an optionally substituted C1-C6 alkyl. In some embodiments, R 4 is an arbitrarily substituted C 3-10 It is a carbocyclic ring.

[0183] In some embodiments, for a compound or salt of formula (X), (X*), or (I), R 1 is methylpiperazine and W is pyridine, R 4 is not methyl. In some cases, R 1 but

[0184] [ka] and when W is pyridine, R 4 is not methyl.

[0185] In some embodiments, for compounds or salts of Formula (X), (X*), or (I), when W is furan, R 4 is not ethan-1-one. In some cases, W is furan and R 4 is cyclopentyl or cyclohexyl, R 1 is not ethan-1-one. In some cases, W is furan and R 4 is cyclopentyl or cyclohexyl, R 1 is not ethan-1-one. In some cases, R 1 teeth

[0186] [ka] isn't it.

[0187] In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), W is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, the heterocycle of W is a 5- to 6-membered heteroaryl. In some cases, the heterocycle of W is an unsubstituted 5- to 6-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 two heteroatoms. In some cases, the heterocycle of W has up to two heteroatoms. In some cases, the heterocycle of W has only two heteroatoms. In some cases, the heterocycle of W is unsubstituted. In some cases, the heterocycle of W has two heteroatoms selected from nitrogen, sulfur, and oxygen. In some cases, the heterocycle of W has at least two different heteroatoms. In some cases, the heterocycle of W has two nitrogen atoms. In some cases, the heterocycle of W has one nitrogen atom and one oxygen atom.

[0188] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is optionally substituted. In some embodiments, R 1 is optionally substituted with 1 to 4 substituents. In some embodiments, R 1 is optionally substituted with 1 to 3 substituents. In some embodiments, R 1 is optionally substituted with 1 to 2 substituents. In some embodiments, R 1 is optionally substituted with 1 substituent. In some embodiments, R 1 is optionally substituted with two substituents. In some embodiments, R 1 is optionally substituted with 3 substituents. In some embodiments, R 1 is monocyclic. In some embodiments, R 1 is bicyclic. In some embodiments, R 1 is a bridged ring. In some embodiments, R 1 is a fused ring. In some embodiments, R 1 is a spiro ring. In some embodiments, R 1 is an optionally substituted 3- to 12-membered ring. In some embodiments, R 1 is an optionally substituted 5- to 8-membered ring.

[0189] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is optionally substituted with an oxide.

[0190] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is selected from substituted C1-C6 alkyl, the substituents on the C1-C6 alkyl being one or more halogen, -OH, -CN, -NO2, -NH2, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is selected from substituted C1-C6 alkyl, the substituents on the C1-C6 alkyl being one or more halogen, -OH, -CN, -NO2, -NH2, =S, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-6 alkyl), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 In some embodiments, R is independently selected at each occurrence from a carbocycle, and a 3- to 12-membered heterocycle. 1 is an optionally substituted C1-C3 alkyl. In some embodiments, R 1 is oxo, halogen, -OC 1-10 Alkyl, -C 1-10 It is optionally substituted with one or more substituents selected from haloalkyl, and -OH.

[0191] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is an optionally substituted C1-C 10 In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is an optionally substituted C1-C6 heteroalkyl, wherein the substituents on the C1-C6 heteroalkyl are one or more halogen, —OH, —CN, —NO2, —NH2, ═S, —C 1-10 Haloalkyl, -C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is an optionally substituted C1-C6 heteroalkyl, wherein the substituents on the C1-C6 heteroalkyl are one or more halogen, —OH, —CN, —NO2, —NH2, ═S, —C 1-3 Haloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 and independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle.

[0192] In some cases, when W is furan, R 1 is selected from substituted C1-C6 alkyl, the substituents on the C1-C6 alkyl being one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 and independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle.

[0193] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is -N(R 5 )2, and in some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is -N(R 5 )2, wherein R 5 is selected from optionally substituted C1-C6 alkyl, and the optional substituents on the C1-C6 alkyl are selected from hydroxy.

[0194] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is selected from substituted C1-C6 alkyl and optionally substituted 3- to 8-membered heterocycle.

[0195] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is substituted C1-C6 alkyl. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is selected from substituted C1-C6 alkyl, the substituents being hydroxy, oxo, and -OC 1-10 alkyl.

[0196] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is an optionally substituted 3- to 8-membered heterocycle. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is selected from optionally substituted 5- to 6-membered heterocycles. 1 is monocyclic. In some embodiments, R 1 is bicyclic. In some embodiments, R 1 is a fused bicyclic group. In some embodiments, R 1 is a bridged bicyclic group. In some embodiments, R 1 is an optionally substituted 5-membered heterocycle. In some embodiments, R 1 is an optionally substituted heteroaryl. In some embodiments, R 1 is an optionally substituted heterocycloalkyl. In some embodiments, R 1 contains 0-3 nitrogen atoms and 0-1 oxygen atoms on the ring. In some embodiments, R 1contains 1-2 nitrogen atoms and 0-1 oxygen atoms on the ring. In some embodiments, R 1 contains 1 to 2 ring nitrogen atoms. In some embodiments, R 1 contains two ring nitrogen atoms. In some embodiments, R 1 contains one ring nitrogen atom.

[0197] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is an optionally substituted 6-membered heterocycle.

[0198] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is an optionally substituted piperazine. In some embodiments, R 1 is an optionally substituted piperazine, wherein the piperazine is attached to the remainder of the compound through the nitrogen (e.g., attached to the phenyl). In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is one or more 1-6 In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is piperazine optionally substituted with one or more substituents selected from methyl, ethyl, and propyl. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is piperazine optionally substituted with one or more methyl. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is one or more 1-6In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R is a piperazine optionally substituted with alkyl, wherein alkyl is optionally substituted with hydroxy, halogen, oxo, and -NH. 1 is piperazine optionally substituted with an oxide.

[0199] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 The optional substituents on the optionally substituted piperazine are oxo, —S(O2)NH2, and optionally substituted C 1-10 alkyl, C 1-10 Optional substituents on alkyl are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, and -NH. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 The optional substituents on the optionally substituted piperazine are oxo, -S(O2)NH2, -S(O2)N(C 1-6 alkyl)2, -S(O2)NH(C 1-6 alkyl), and optionally substituted C 1-6 In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is optionally substituted with heteroalkyl. In some embodiments, R 1 is optionally substituted with one or more substituents selected from halogen, —CN, —OH, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, and C3-C6 cycloalkyl.

[0200] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is an optionally substituted 3- to 10-membered heterocycle. In some instances, R 1 is an optionally substituted 4- to 8-membered heterocycle. In some instances, R 1 is an optionally substituted 4-membered heterocycle. In some instances, R 1 is an optionally substituted 6-membered heterocycle. In some instances, R 1 When R is a piperazine, the piperazine is substituted. 1 is not an unsubstituted piperazine. In some cases, R 1 is a substituted 3- to 10-membered heterocycle.

[0201] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 For the formula (I), optional substituents on the heterocycle are halogen, —OH, —CN, —NO2, —NH2, —N(H)C1-C6 alkyl, —N(C1-C6 alkyl)2 oxo, ═S, —S(O2)NH2, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, and optionally substituted C 1-10 and one or more substituents independently selected at each occurrence from alkyl, C 1-10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1-10 Haloalkyl, -NH2, -CN, -OC 1-10 and -NO2, independently selected at each occurrence from alkyl, -N-, and -NO2.

[0202] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 The optional substituents are -NH, -N(H)C-C alkyl, -N(C-C alkyl), oxo, and optionally substituted C 1-10and one or more substituents independently selected at each occurrence from alkyl, C 1-10 Optional substituents on alkyl include one or more oxo and -OC 1-10 and independently selected at each occurrence from alkyl.

[0203] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 The optional substituents are -NH, -N(H)C-C alkyl, -N(C-C alkyl), oxo, and optionally substituted C 1-10 and one or more substituents independently selected at each occurrence from alkyl, C 1-10 Optional substituents on alkyl include one or more oxo and -OC 1-10 and independently selected at each occurrence from alkyl.

[0204] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 For R, the heterocycle has at least one nitrogen atom, phosphorus atom, or oxygen atom. 1 In some cases, the heterocycle has at least one nitrogen atom. 1 In some cases, R 1 For R, the heterocycle has at most two nitrogen atoms. 1 For R, the heterocycle has at most one nitrogen atom. 1 In some cases, R 1 In some cases, R 1 In some cases, R 1 In some cases, R 1 For the heterocycle, the heterocycle is saturated.

[0205] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0206] [ka] and any of which is optionally substituted.

[0207] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0208] [ka] any of which is selected from -NH, -N(H)C-C alkyl, -N(C-C alkyl), oxo, and optionally substituted C 1-10 optionally substituted with one or more substituents selected from alkyl, C 1-10 Optional substituents on alkyl include one or more oxo and -OC 1-10 In some embodiments, R 1 is -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, oxo, optionally substituted C 1-10 Heteroalkyl, and optionally substituted C 1-10 and optionally substituted with one or more substituents selected from alkyl.

[0209] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0210] [ka] is selected from.

[0211] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0212] [ka] is selected from.

[0213] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0214] [ka] is selected from.

[0215] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0216] [ka] is selected from.

[0217] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0218] [ka] is selected from.

[0219] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is an optionally substituted 6-10 membered heterocycloalkyl. In some instances, R 1The optional substituents of the optionally substituted 6- to 10-membered heterocycloalkyl are C 1-6 In some cases, the 6- to 10-membered heterocycloalkyl is a spiroheterocycloalkyl. In some cases, R 1 is selected from optionally substituted piperazine, optionally substituted diazabicyclo[3.2.1]octane, optionally substituted diazabicyclo[3.1.1]heptane, optionally substituted diazaspiro[3.5]nonane, and optionally substituted diazaspiro[3.3]heptane. In some cases, any is selected from C 1-6 alkyl.

[0220] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is optionally substituted. In some embodiments, R 3 is optionally substituted with 1 to 4 substituents. In some embodiments, R 3 is optionally substituted with 1 to 3 substituents. In some embodiments, R 3 is optionally substituted with 1 to 2 substituents. In some embodiments, R 3 is optionally substituted with 1 substituent. In some embodiments, R 3 is optionally substituted with two substituents. In some embodiments, R 3 is optionally substituted with three substituents.

[0221] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is an arbitrarily substituted C 3-6In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is an arbitrarily substituted C 3-6 cycloalkyl.

[0222] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), or (IIB), R 3 is an optionally substituted phenyl. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is phenyl optionally substituted with one or more halogens. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is phenyl optionally substituted with 1 to 3 halogens. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is phenyl optionally substituted with 1 to 2 halogens. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is phenyl optionally substituted with one halogen.

[0223] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 The optional substituents on the phenyl are halogen and -C 1-10 In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 The optional substituents on the phenyl are halogen and -C 1-3 haloalkyl.

[0224] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 are halogens, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 In some embodiments, R is substituted with one or more substituents selected from a carbocycle, a 3- to 12-membered heterocycle, and a 4 are halogens, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, -OC1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 In some embodiments, R is substituted with one or more substituents selected from a carbocycle, a 3- to 12-membered heterocycle, and a 4 are halogens, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, and -OC 1-6 In some embodiments, R is substituted with one or more substituents selected from alkyl. 4 are halogens, -OH, -NO2, -NH2, oxo, -C 1-6 Haloalkyl, and -OC 1-6 In some embodiments, R is substituted with one or more substituents selected from alkyl. 4 is substituted with one or more halogens. In some embodiments, R 4 is substituted with one halogen. In some embodiments, R 4 is substituted with two halogens. In some embodiments, R 4 is substituted with three halogens.

[0225] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 is hydrogen.

[0226] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 is an optionally substituted C1-C6 alkyl and an optionally substituted C 3-6 In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4is an optionally substituted cycloalkyl. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 is optionally substituted aryl.

[0227] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 The optional substituents of the C1-C6 alkyl are selected from halogen.

[0228] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 The optional substituents on the C3-C6 carbocyclic ring of are selected from hydroxy.

[0229] In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), W is selected from 5-6 membered heteroaryl.

[0230] In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), the 5- to 6-membered heteroaryl of W is selected from imidazole, furan, thiophene, oxazole, isoxazole, thiazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0231] In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), the 5- to 6-membered heteroaryl of W is selected from imidazole, furan, and pyridine.

[0232] In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), W is imidazole. In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), W is pyridine.

[0233] In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), W is selected from optionally substituted 5-6 membered heteroaryl.

[0234] In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), W is selected from pyridine, imidazole, thiazole, and furan.

[0235] In some embodiments, for a compound or salt of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), W is selected from pyridine and imidazole.

[0236] In some embodiments, the compound or salt of Formula (I) has the formula (Ia):

[0237] [ka] or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the compound or salt of formula (I) has formula (IIB):

[0239] [ka] or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is selected from optionally substituted C1-C6 alkyl and optionally substituted C6 carbocycle.

[0241] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is selected from C1-C6 alkyl, and the C6 carbocycle is selected from halogen and -C 1-10 and substituted with one or more substituents selected from haloalkyl.

[0242] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 teeth

[0243] [ka] is selected from.

[0244] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is a C6 carbocycle substituted with one or more substituents selected from halogen.

[0245] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 is phenyl, which is optionally substituted with one or more halogens.

[0246] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 teeth

[0247] [ka] is selected from.

[0248] In some embodiments, for a compound or salt of formula (X), (X*), (I), (Ia), (A), (B), (F), (F-1), (G), (Ga), (G-1), (G-1a), (H), (H-1), or (IIB), R 3 teeth,

[0249] [ka] is.

[0250] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 is hydrogen, C1-C6 alkyl optionally substituted with one or more substituents selected from halogen, and C optionally substituted with one or more substituents selected from hydroxy and amine. 5-6 Carbocycles are selected from:

[0251] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 is unsubstituted C1-C6 alkyl.

[0252] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 is a substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more halogens.

[0253] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), or (A), (B), (G), (G-1), (H), (H-1), (J), (K), (IIB), R 4 teeth

[0254] [ka] is selected from.

[0255] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 is selected from C1-C6 alkyl optionally substituted with one or more substituents selected from fluorine, and C6 cycloalkyl substituted with hydroxy.

[0256] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 teeth

[0257] [ka] is selected from.

[0258] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 teeth

[0259] [ka] In certain embodiments, R 4 teeth,

[0260] [ka] is.

[0261] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 teeth,

[0262] [ka] is selected from.

[0263] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 teeth,

[0264] [ka] is selected from.

[0265] In some cases, R 4 is the unsubstituted C 1-10It is selected from alkyl, unsubstituted 3- to 6-membered heterocycle, and optionally substituted C3-C6 carbocycle.

[0266] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), each R 4 is C 1-10 Alkyl, C 3-12 carbocyclic ring, and 3- to 12-membered heterocyclic ring; 1-10 Alkyl, C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings are each substituted with halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, C 1-10 Alkyl, -C 1-10 Haloalkyl, and -OC 1-10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0267] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 is the unsubstituted C 1-10 alkyl, unsubstituted 3- to 6-membered heterocycle, and optionally substituted C3-C6 carbocycle, the optional substituents being one or more halogen -C 1-10 haloalkyl.

[0268] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), each R 4 is C 1-10 at each occurrence selected from alkyl, unsubstituted 4-membered heterocycle, and optionally substituted C-C carbocycle, and the optional substituents are one or more halogen -C 1-10 In some instances, R is independently selected from haloalkyl. 4 is C 1-10In some cases, R 4 is selected from a 4-membered heterocycle. 4 is a four-membered heterocycle. In some cases, R 4 is a saturated four-membered heterocycle.

[0269] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (J), (K), or (IIB), R 4 teeth,

[0270] [ka] In some cases, R 4 teeth,

[0271] [ka] In some cases, R 4 teeth,

[0272] [ka] is selected from.

[0273] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth, -N(R 5 )2, wherein R 5 is selected from optionally substituted C1-C6 alkyl, the substituents on the C1-C6 alkyl being one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 -N(R 5 )2, Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are one or more of halogen, —OH, —NH2, oxo, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 substituted C-C alkyl, independently selected at each occurrence from An optionally substituted 6- to 8-membered heterocycle, wherein the optional substituents on the 6- to 8-membered heterocycle are one or more of oxo, -S(O2)NH2, -NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, and optionally substituted C 1-10 independently selected at each occurrence from alkyl, C 1-10 The optional substituents on the alkyl are one or more of hydroxy, halogen, oxo, -C 1-10 an optionally substituted 6-8 membered heterocycle independently selected at each occurrence from haloalkyl, -NH2, -CN, and -NO2;

[0274] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0275] [ka] is selected from.

[0276] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0277] [ka] is selected from.

[0278] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R1 teeth,

[0279] [ka] is selected from.

[0280] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth, Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are one or more of halogen, —OH, oxo, —C 1-10 Haloalkyl, and -OC 1-10 substituted C1-C6 alkyl, independently selected at each occurrence from alkyl; An optionally substituted 6- to 8-membered saturated heterocycle, the optional substituents being one or more of -S(O2)NH2 and optionally substituted C 1-10 independently selected at each occurrence from alkyl, C 1-10 The optional substituents on the alkyl are one or more of hydroxy, halogen, oxo, -C 1-10 haloalkyl, and -NH2, independently selected at each occurrence from an optionally substituted 6-8 membered saturated heterocycle.

[0281] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0282] [ka] is selected from.

[0283] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is selected from optionally substituted 6- to 8-membered saturated heterocycles, the optional substituents being one or more -S(O2)NH2, and optionally substituted C 1-10independently selected at each occurrence from alkyl, C 1-10 Optional substituents on alkyl include one or more of hydroxy, halogen, oxo, -C 1-10 and -NH2, independently selected at each occurrence from haloalkyl, and -NH2.

[0284] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0285] [ka] is selected from.

[0286] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is selected from substituted C1-C6 alkyl, the substituents on the C1-C6 alkyl being one or more of halogen, —OH, oxo, —C 1-10 Haloalkyl, and -OC 1-10 and independently selected at each occurrence from alkyl.

[0287] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0288] [ka] is selected from.

[0289] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth, Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are one or more of -OH, oxo, and -OC 1-10 substituted C1-C6 alkyl, independently selected at each occurrence from alkyl; An optionally substituted 6- to 8-membered saturated heterocycle, wherein the optional substituents are one or more optionally substituted C 1-10 independently selected at each occurrence from alkyl, C 1-10 Optional substituents on alkyl include one or more of hydroxy, oxo, -C 1-10 haloalkyl, and -NH2, independently selected at each occurrence from an optionally substituted 6-8 membered saturated heterocycle.

[0290] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0291] [ka] is selected from.

[0292] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 is piperazine, which is an oxo, -S(O2)NH2, and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH. In some embodiments, R 1 is one or more C 1-3 Alkyl-substituted piperazine, C 1-3 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH2.

[0293] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 teeth,

[0294] [ka] is selected from.

[0295] In some embodiments, for a compound or salt of formula (X), (X*), (C), or (I), the compound is

[0296] [ka] In some cases, the compound

[0297] [ka] isn't it.

[0298] In some embodiments, for a compound or salt of Formula (I): R 1 is -N(R 5 )2, wherein R 5 is selected from optionally substituted C1-C6 alkyl, and the optional substituents on the C1-C6 alkyl are selected from hydroxy; 5 )2, Substituted C1-C6 alkyl, where the substituents are hydroxy, oxo, and -OC 1-10 substituted C1-C6 alkyl selected from alkyl, and Optionally substituted 5-6 membered heterocycles, the optional substituents being oxo, -S(O2)NH2, and optionally substituted C 1-10 alkyl, C 1-10 the optional substituents on the alkyl are selected from one or more of hydroxy, halogen, oxo, and -NH2, independently at each occurrence, selected from an optionally substituted 5- to 6-membered heterocycle; R 3 is an optionally substituted phenyl, where R 3 The optional substituents on the phenyl are halogen and -C 1-10 haloalkyl; R 4is an optionally substituted C1-C6 alkyl and an optionally substituted C 3-6 carbocyclic rings, R 4 the optional substituents of the C1-C6 alkyl are selected from halogen; 4 the optional substituents on the C3-C6 carbocycle are selected from hydroxy; W is selected from imidazole, furan, and pyridine.

[0299] In some embodiments, for a compound or salt of Formula (I): R 1 is -N(R 5 )2, wherein R 5 is selected from optionally substituted C1-C6 alkyl, and the optional substituents on the C1-C6 alkyl are selected from hydroxy; 5 )2, Substituted C1-C6 alkyl, where the substituents are hydroxy, oxo, and -OC 1-10 substituted C1-C6 alkyl selected from alkyl, and Optionally substituted 5-6 membered heterocycles, the optional substituents being oxo, -S(O2)NH2, and optionally substituted C 1-10 alkyl, C 1-10 the optional substituents on the alkyl are selected from one or more of hydroxy, halogen, oxo, and -NH2, independently at each occurrence, selected from an optionally substituted 5- to 6-membered heterocycle; R 3 is an optionally substituted phenyl, where R 3 The optional substituents on the phenyl are halogen and -C 1-10 haloalkyl; R 4 is an optionally substituted C1-C6 alkyl and an optionally substituted C 3-6 carbocyclic rings, R 4 the optional substituents of the C1-C6 alkyl are selected from halogen; 4 the optional substituents on the C3-C6 carbocycle are selected from hydroxy; W is selected from imidazole.

[0300] In some embodiments, for a compound or salt of Formula (X), (X*), (Ia), (IIB), or (I), R 1 teeth,

[0301] [ka] Selected from R 3 teeth

[0302] [ka] and R 4 teeth,

[0303] [ka] is selected from.

[0304] In one aspect, provided herein is a compound represented by formula (Ia):

[0305] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is piperazine, which is an oxo, -S(O2)NH2, and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, which is optionally substituted with one or more halogens; R 4 is unsubstituted C1-C6 alkyl.

[0306] In some embodiments of formulas (I), (A), (B), (Ia), (K), (G), (H), (Ga), (J), (G-1), (H-1), and (K), R 4 teeth,

[0307] [ka] is selected from.

[0308] In some embodiments of formulas (I), (A), (B), (Ia), (F), (G), (H), (Ga), (G), (H), (G-1a), (G-1), and (H-1), R 3 teeth,

[0309] [ka] is selected from.

[0310] In some embodiments of Formulas (I), (Ia), and (C), R 1 is one or more C 1-3 alkyl-substituted piperazine, wherein C 1-3 The alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH2.

[0311] In some embodiments of Formulas (I), (Ia), and (C), R 1 teeth,

[0312] [ka] is selected from.

[0313] In some embodiments of Formulas (I), (Ia), and (C), R 1 teeth,

[0314] [ka] is selected from R 3 teeth,

[0315] [ka] is selected from R 4 teeth,

[0316] [ka] is selected from.

[0317] In some embodiments, provided herein are methods for synthesizing a compound, the compound comprising:

[0318] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0319] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0320] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0321] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0322] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0323] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0324] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0325] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0326] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0327] [ka] or a pharmaceutically acceptable salt thereof.

[0328] In one aspect, provided herein is a compound represented by formula (Ia):

[0329] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is piperazine, and piperazine is oxo and C 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl, C 1-10alkyl is optionally substituted with one or more substituents independently selected at each occurrence from hydroxy, halogen, oxo, and -NH; R 3 is phenyl, which is optionally substituted with one or more halogens; R 4 is a substituted C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more halogens.

[0330] In some embodiments of formulas (I), (A), (B), (Ia), (K), (G), (H), (Ga), (J), (G-1), (H-1), and (K), R 4 is substituted with two or three fluorines.

[0331] In some embodiments of formulas (I), (A), (B), (Ia), (K), (G), (H), (Ga), (J), (G-1), (H-1), and (K), R 4 teeth,

[0332] [ka] is selected from.

[0333] In some embodiments of formulas (I), (A), (B), (Ia), (F), (G), (H), (Ga), (G), (H), (G-1a), (G-1), and (H-1), R 3 teeth,

[0334] [ka] is selected from.

[0335] In some embodiments of Formulas (I), (Ia), and (C), R 1 is one or more C 1-3 alkyl-substituted piperazine, wherein C 1-3 The alkyl is optionally substituted with one or more halogens.

[0336] In some embodiments of Formulas (I), (Ia), and (C), R 1 teeth,

[0337] [ka] In some embodiments, R 1 teeth,

[0338] [ka] is selected from.

[0339] In some embodiments, R 1 teeth,

[0340] [ka] is selected from R 3 teeth,

[0341] [ka] is selected from R 4 teeth,

[0342] [ka] is selected from.

[0343] In some embodiments, provided herein are methods for synthesizing a compound, the compound comprising:

[0344] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0345] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0346] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0347] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0348] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0349] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0350] [ka] or a pharmaceutically acceptable salt thereof.

[0351] In certain embodiments, the present disclosure provides a compound represented by formula (X):

[0352] [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is an optionally substituted 3- to 12-membered heterocycle and an optionally substituted C3-C 12 carbocyclic rings, each substituent being selected from one or more -N(R 10)2, halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C1-C 10 Alkyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; C1-C 10 Alkyl is halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted with one or more substituents independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings are each substituted with halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 optionally substituted at each occurrence with one or more substituents independently selected from alkyl, C 1-10 The optional substituents on the alkyl are one or more of hydroxy, halogen, oxo, -C 1-10 independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; R 10 is selected from optionally substituted C1-C6 alkyl, and any substituents on the C1-C6 alkyl are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle; W is selected from an optionally substituted 5- to 8-membered (e.g., 5- or 6-membered) heterocycle and an optionally substituted C3-C8 carbocycle, wherein each substituent is selected from one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are not substituted with halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, C 1-10 Alkyl, -C 1-10 Haloalkyl, and -OC 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl; Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein each substituent is selected from one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings are each substituted with halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, C 1-10 Alkyl, -C 1-10 Haloalkyl, and -OC 1-10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0353] In some embodiments, the compound of formula (X) is represented by formula (X*).

[0354] In some embodiments, for the compound or salt of Formula (X), Z is an optionally substituted 3- to 12-membered heterocycle and an optionally substituted C3-C 12 carbocycle, each substituent being selected from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10 In some cases, for Z, the heterocycle contains at least one nitrogen atom. In some cases, Z is selected from optionally substituted phenyl and optionally substituted pyridine. In some cases, the optional substituents on the optionally substituted phenyl of Z are halogen, —OH, —CN, —NO, —NH, oxo, ═S, C, or the like. 1-10 Alkyl, -C 1-10 Haloalkyl, and -OC 1-10 In some cases, the optional substituents on the optionally substituted phenyl of Z are selected from one or more substituents selected from halogen and C 1-10 In some cases, Z is selected from one or more substituents selected from alkyl. In some cases, the heterocycle is unsubstituted. In some cases, Z is selected from substituted phenyl and unsubstituted pyridine. In some cases, the heterocycle has one or two nitrogen atoms. In some cases, the heterocycle has only one nitrogen atom. In some cases, the heterocycle has only two nitrogen atoms. In some cases, the heterocycle is a 6-membered heterocycle. In some cases, Z is

[0355] [ka] In some cases, an optional substituent of the optionally substituted phenyl of Z is halogen. In some cases, Z is selected from

[0356] [ka] In some cases, Z is substituted phenyl. In some cases, Z is phenyl substituted with a halogen.

[0357] In some aspects, the present disclosure provides a method of synthesizing a compound represented by formula (X*):

[0358] [ka] R 1 But the following: -N(R 5 )2, wherein R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, and the optional substituents on the C1-C6 alkyl are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 -N(R 5 )2, Optionally substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; Optionally substituted 3- to 8-membered heterocycles, wherein the optional substituents on the 3- to 8-membered heterocycle are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —S(O2)NH2, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 independently selected at each occurrence from alkyl, C 1-10 The optional substituents on the alkyl are one or more of hydroxy, halogen, oxo, -C 1-10 an optionally substituted 3- to 8-membered heterocycle independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; W is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein each substituent is selected from one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, C 1-10 Alkyl, -C 1-10 Haloalkyl, and -OC 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl; Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein each substituent is selected from one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings are each substituted with halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, C 1-10 Alkyl, -C 1-10 Haloalkyl, and -OC 1-10 Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0359] In some embodiments, the compound of formula (X) or formula (X*) is represented by formula (I):

[0360] In some aspects, the present disclosure provides a method of synthesizing a compound represented by formula (X*):

[0361] [ka] R 1 But the following: -N(R 5 )2, wherein R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, and the optional substituents on the C1-C6 alkyl are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 -N(R 5 )2, Optionally substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 optionally substituted C1-C6 alkyl, independently selected at each occurrence from carbocycle, 3- to 12-membered heterocycle; Optionally substituted 3- to 14-membered heterocycles, wherein the optional substituents on the 3- to 8-membered heterocycle are one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —S(O2)NH2, —C 1-10 Heteroalkyl, -C 1-10 Haloalkyl, -OC1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C 1-10 independently selected at each occurrence from alkyl, C 1-10 The optional substituents on the alkyl are one or more of hydroxy, halogen, oxo, -C 1-10 independently selected at each occurrence from haloalkyl, —NH, —CN, and —NO; W is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein each substituent is selected from one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each selected from halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, C 1-10 Alkyl, -C 1-10 Haloalkyl, and -OC 1-10 optionally substituted with one or more substituents independently selected at each occurrence from alkyl; Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein each substituent is selected from one or more of halogen, —OH, —CN, —NO2, —NH2, oxo, ═S, —C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 independently selected at each occurrence from a carbocycle, a 3- to 12-membered heterocycle, 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings are each substituted with halogen, -OH, -CN, -NO2, -NH2, oxo, ═S, C 1-10 Alkyl, -C 1-10 Haloalkyl, and -OC 1-10Optionally substituted with one or more substituents independently selected at each occurrence from alkyl.

[0362] In some aspects, the present disclosure provides a method of synthesizing a compound represented by formula (X*):

[0363] [ka] R 1 But the following: -N(R 5 )2, wherein R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, -N(R 5 )2, optionally substituted C1-C6 alkyl; selected from an optionally substituted 3- to 14-membered heterocycle or an optionally substituted 3- to 14-membered carbocycle; W is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles; Y is selected from optionally substituted 5- to 8-membered heterocycles and optionally substituted C3-C8 carbocycles.

[0364] In some embodiments, R is an optionally substituted 3-14 membered heterocycle.

[0365] In some embodiments, provided herein is a method of synthesizing a compound, or a salt thereof, wherein the compound is

[0366] [ka]

[0367] [ka] is.

[0368] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0369] [ka]

[0370] [ka] is.

[0371] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0372] [ka] is.

[0373] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0374] [ka] is.

[0375] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0376] [ka] is.

[0377] In some embodiments, provided herein are methods of synthesizing a compound or salt thereof, wherein the compound is selected from Table 1.

[0378] [Table 1-1]

[0379] [Table 1-2]

[0380] [Table 1-3]

[0381] The salts of the compounds described herein, particularly pharmaceutically acceptable salts, are included in the present disclosure.The compounds of the present disclosure that have sufficient acidity, sufficient basicity, or both functional groups can react with any of a large number of inorganic bases, inorganic acids, and organic acids to form salts.Alternatively, compounds that are essentially charged, such as those that have quaternary nitrogen, can form salts with suitable counterions, for example, halides such as bromide, chloride, or fluoride, especially bromide.

[0382] Chemical substances having carbon-carbon or carbon-nitrogen double bonds may exist in Z- or E-forms (or cis- or trans-forms). Additionally, some chemical substances may exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z-, E-, and tautomeric forms.

[0383] "Tautomer" refers to a molecule in which a proton shift from one atom of the molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0384] [ka]

[0385] In some embodiments, the compounds disclosed herein are, for example, 2 H, 3 H, 11 C. 13 C, and / or 14The compound is used in different enriched isotopic forms, enriched in C content. In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared 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, and thus prolong the duration of action of the drug.

[0386] 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, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0387] The compounds of the present disclosure may optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It may be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81Br, and 125 Isotopic substitutions with I are all contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. In some embodiments, where an isotopic variation is indicated, the remaining atoms of the compound may optionally contain unnatural portions of atomic isotopes.

[0388] In certain embodiments, the compounds disclosed herein comprise: 2 Substituted with H atoms 1 Having some or all of the H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0389] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; 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.

[0390] Deuterated starting materials are readily available and are subject to the synthetic methods described herein to provide for the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical vendors such as Aldrich Chemical Co.

[0391] In some embodiments of the compounds disclosed herein, R 1 , R 3 , R 4 , R 5 , R A1 , R A2 , R A3 , R EN , R EN’ , R F , R F1 , R E1 , R J , W, Z, Y, and R 10 One or more of the groups contains deuterium at a percentage higher than the natural abundance of deuterium.

[0392] In some embodiments of the compounds disclosed herein, one or more 1 H is the following group R 1 , R 3 , R 4 , R 5 , R A1 , R A2 , R A3 , R EN , R EN’ , R F , R F1 , R E1 , R J , W, Z, Y, and R 10 is substituted with one or more deuterium atoms in one or more of:

[0393] In some embodiments of the compounds disclosed herein, R 1 , R 3 , R 4 , R 5 , R A1 , R A2 , R A3 , R EN , R EN’ , R F , R F1 , R E1 , R J , W, Z, Y, and R 10The abundance of deuterium in each of is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0394] In some embodiments of the compounds disclosed herein, one or more of rings W 1 H is replaced by one or more deuterium atoms.

[0395] The compounds of the present disclosure also include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity.

[0396] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomers. When absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers may be carried out by chromatography, or by forming diastereomers and separating them by recrystallization, chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, the disclosure of which is incorporated herein by reference.) Stereoisomers may also be obtained by stereoselective synthesis.

[0397] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0398] In certain embodiments, a compound or a salt of a compound may be a prodrug, for example, a hydroxyl in the parent compound is presented as an ester or carbonate, or a carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted to the pharmaceuticals of the present disclosure under physiological conditions. One method for creating a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, such as a specific target cell in the host animal. For example, esters or carbonates (e.g., esters of alcohols or carboxylic acids or esters of carbonates and phosphonic acids) are preferred prodrugs of the present disclosure.

[0399] Prodrug forms of the compounds described herein, where the prodrug is metabolized in vivo to produce the compounds described herein, are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0400] Prodrugs are often useful because in some situations they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs can help enhance the cell permeability of the compound compared to the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs are designed as reversible drug derivatives and can be used as modifiers to enhance drug transport to site-specific tissues or increase drug retention within cells.

[0401] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent, hi some embodiments, the prodrug design increases the effective water solubility. 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,Vol.14 of the ACSSymposium Series;and Edward B.Roche,Bioreversible Carriers in See Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein for such disclosures. According to another embodiment, the present disclosure provides methods for producing the compounds defined above. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0402] Synthetic chemical transformations and methodologies useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989), T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 2d. Ed. (1991), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0403] D. Treatment method The compounds synthesized by the methods described herein can be used in the preparation of a medicament for the prevention or treatment of a disease or condition. Additionally, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition containing a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0404] In the embodiments provided herein, the present disclosure provides a method for synthesizing inhibitors of TNIK kinase.Therefore, TNIK kinase inhibitors can be used to inhibit downstream biological pathways that inhibit TNIK.In some embodiments, TNIK inhibitors can inhibit fibrillar collagen, thereby inhibiting the biological activity associated with the regulation of extracellular matrix and the regulation of extracellular matrix remodeling.TNIK inhibitors can inhibit the regulation of cell proliferation, differentiation, cell migration, proliferation and metabolism.

[0405] In certain embodiments, the present disclosure provides a method for synthesizing a compound that can be used to treat or prevent a disease, condition, or state in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound according to any one of the embodiments of the present disclosure, or a pharmaceutically acceptable salt thereof. The disease, condition, or state may be selected from the group consisting of colorectal cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, chronic myelogenous leukemia, cancer metastasis, fibrosis, and psychiatric disorders. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is chronic myelogenous leukemia. In some embodiments, the cancer is cancer metastasis. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is not a solid tumor. In certain embodiments, inhibiting TNIK inhibits embryonic development. Thus, TNIK inhibitors can inhibit the progression of pregnancy, thereby being used to terminate pregnancy. In some embodiments, inhibiting TNIK inhibits TGF-beta signaling. The TGF-beta signaling pathway is involved in various processes, and inhibiting the TGF-beta signaling pathway can inhibit these processes, some of which are described herein. This can include inhibiting embryonic development as described herein to inhibit the progression of pregnancy. This can include inhibiting cell proliferation, cell differentiation, which can be used to inhibit not only the progression of pregnancy, but also cancer.

[0406] In certain embodiments, the present disclosure provides a method for synthesizing a compound that can be used to treat or prevent a fibrotic disease or condition. In some embodiments, the fibrotic disease or condition is selected from pulmonary fibrosis, cystic fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, cerebral fibrosis, arterial fibrosis, arthrofibrosis, intestinal fibrosis, Dupitren's contracture fibrosis, keloid fibrosis, mediastinal fibrosis, bone marrow fibrosis, Peyronie's disease fibrosis, progressive diffuse fibrosis, retroperitoneal fibrosis, scleroderma fibrosis, adhesive capsulitis fibrosis, or a combination thereof. In some embodiments, the fibrotic disease is selected from liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc), and graft-versus-host disease (GVHD). In some embodiments, the fibrotic disease is renal fibrosis.

[0407] In certain embodiments, the present disclosure provides methods of synthesizing compounds that can be used to treat kidney diseases. In some embodiments, the kidney disease is chronic renal fibrosis (CKD). In some embodiments, the kidney disease is renal fibrosis. In some embodiments, the fibrotic disease is liver cirrhosis. In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrotic disease is renal fibrosis, and the disease is 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). In some embodiments, the fibrotic disease is systemic sclerosis (SSc). In some embodiments, the fibrotic disease is graft-versus-host disease (GVHD). In some embodiments, the fibrotic disease is hypertrophic scarring (HTS). [Example]

[0408] The following examples are offered to illustrate, but not to limit, the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0409] The following synthetic schemes are provided for illustrative purposes and are not limiting. The following examples show various methods for making the compounds described herein. It is understood that those skilled in the art may be able to make these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art can prepare the compounds in a similar manner to those described below by using appropriate starting materials and modifying the synthetic route as necessary. In general, the starting materials and reagents can be obtained from commercially available vendors, or synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0410] Certain abbreviations are used in the examples and throughout the application. Abbreviations include: DIEA = N,N-diisopropylethylamine, PE = petroleum ether, EA = ethyl acetate, 1 H-NMR = proton nuclear magnetic resonance spectroscopy; DMA = N,N-dimethylacetamide, DCM = dichloromethane, NIS = N-iodosuccinimide, TFA = trifluoroacetic acid, DMSO = dimethyl sulfoxide, THF = tetrahydrofuran, NBS = N-bromosuccinimide, AIBN = azodiisobutyronitrile, TLC = thin layer chromatography; DMF = N,N-dimethylformamide, SEM = (trimethylsilicon)ethoxymethyl HATU = 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-MeTHF = 2-methyltetrahydrofuran, MTBE = methyl tert-butyl ether; T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, MCH = methylcyclohexane, HPLC = high performance liquid chromatography.

[0411] Exemplary Synthetic Schemes Compounds and salts of formula (I), (Ia), or (IIB) can be synthesized according to one or more exemplary schemes herein and / or techniques known in the art. Materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are used for illustrative purposes and are not limited by the compounds listed in the examples or any particular substituents. Various steps are described and illustrated in the synthetic schemes below, although in some cases, the 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 numbers or R groups in the claims or other schemes or tables herein.

[0412] Example 1. Reference Procedure for Compound 112 (Stille Coupling)

[0413] [ka]

[0414] In some instances, the reference procedure of Example 1 presents challenges in quality control due to the number of steps and / or the use of Sn reagents.

[0415] Step 1-1: General procedure for the preparation of (4-(4-fluorophenyl)-1H-imidazole (Compound A3)

[0416] [ka]

[0417] To a solution of 4-bromo-1H-imidazole (compound A1) (60 g, 408.24 mmol, 1 equiv.) and (4-fluorophenyl)boronic acid (compound A2) (114.24 g, 816.48 mmol, 2 equiv.) in dioxane (500 mL) and HO (100 mL) was added KCO (169.26 g, 1.22 mol, 3 equiv.) and Pd(dppf)Cl (35.85 g, 48.99 mmol, 0.12 equiv.) at 30 °C. The mixture was stirred at 110 °C for 16 h. LCMS showed that compound A1 was consumed, with 57% of the desired mass detected. The mixture was combined with three other batches. The mixture was poured into HO (1000 mL). The mixture was extracted with EA (1000 mL × 2). The combined organic phase was poured into 1N HCl (1000 mL). The mixture was extracted with ethyl acetate (1000 mL x 2). The aqueous phase was basified with Na2CO3 to pH = 8. The mixture was extracted with ethyl acetate (1000 mL x 3). The combined organic phase was concentrated in vacuo to give the crude product. Compound A3 (102 g, crude) was obtained as a brown solid, which was 1 H-NMR. 1 Determined by H-NMR (400 MHz, DMSO-d), δ = 7.85–7.76 (m, 2H), 7.73 (d, J = 0.9 Hz, 1H), 7.57 (d, J = 0.7 Hz, 1H), 7.27–7.12 (m, 2H).

[0418] Step 1-2: General procedure for the preparation of 4-(4-fluorophenyl)-1-isopropyl-1H-imidazole (compound A5)

[0419] [ka]

[0420] To a solution of NaH (49.08 g, 1.23 mol, 60% purity, 2 equiv.) in DMA (1000 mL) was added compound A3 (99.5 g, 613.58 mmol, 1 equiv.) at 0° C. The mixture was stirred at 0° C. for 0.5 h. 2-Bromopropane (compound A4) (113.20 g, 920.37 mmol, 86.41 mL, 1.5 equiv.) was added to the mixture at 0° C. The mixture was stirred at 80° C. for 16 h. LCMS showed that 20% of compound A3 remained and 71% of the desired mass was detected. The mixture was poured into aqueous NH4Cl (2 L). The mixture was extracted with ethyl acetate (2000 mL × 2). The combined organic phases were concentrated in vacuo to give the crude product. Compound A5 (140 g, crude) was obtained as a brown oil, which was determined by LCMS and 1 Determined by H-NMR. LCMS: Retention time: 0.521 min, (M+H)=205.1. 1 H-NMR: (400 MHz, chloroform-d) δ = 7.76–7.71 (m, 2H), 7.57 (d, J = 1.2 Hz, 1H), 7.21 (d, J = 1.2 Hz, 1H), 7.11–7.05 (m, 2H), 4.36 (td, J = 6.7, 13.4 Hz, 1H), 1.53 (d, J = 6.7 Hz, 6H).

[0421] Step 1-3: General procedure for the preparation of 4-(4-fluorophenyl)-5-iodo-1-isopropyl-1H-imidazole (Compound A6)

[0422] [ka]

[0423] To a solution of compound A5 (136 g, 665.87 mmol, 1 equiv.) in DCM (1 L), NIS (449.42 g, 2.00 mol, 3.0 equiv.) and TFA (22.78 g, 199.76 mmol, 14.79 mL, 0.3 equiv.) were added and stirred at 25 °C for 16 h. TLC (PE:EA 3:1) showed that compound A5 (Rf = 0.1) was consumed and a new spot (Rf = 0.4) was detected. LCMS showed that compound A5 was consumed and the desired mass was detected. Saturated aqueous Na2SO3 (1 L) was added, and the organic layer was washed with brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE:EA 20:1 to 2:1). Compound A6 (75 g, 227.18 mmol, 34.12% yield) was obtained as a white solid, which was analyzed by LCMS and 1 Confirmed by H-NMR. LCMS: Retention time: 0.729 min, (M+H)=331.0. 1 H-NMR:(400MHz,DMSO-d6)δ=8.15(s,1H),7.95~7.84(m,2H),7.32~7.20(m,2H),4.41(spt,J=6.7Hz,1H),1.47(d,J=6.6Hz,6H).

[0424] Step 1-4: General procedure for the preparation of 4-(4-fluorophenyl)-1-isopropyl-5-(tributylstannyl)-1H-imidazole (Compound A7)

[0425] [ka]

[0426] To a solution of compound A6 (65 g, 196.89 mmol, 1 equiv.) in THF (2000 mL) under N2, n-BuLi (2.5 M, 102.38 mL, 1.3 equiv.) was added dropwise at -70 °C. After stirring at -70 °C for 15 min, tributyl(chloro)stannane (96.13 g, 295.33 mmol, 79.45 mL, 1.5 equiv.) was added dropwise at -70 °C, and the mixture was stirred at -40 to -50 °C for 0.5 h. LCMS showed that compound A6 was consumed and the desired mass was detected. This was poured into saturated aqueous KF solution (2 L), EA (2 L) was added, and the organic layer was washed with saturated aqueous NH4Cl (1 L) and brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO, PE:EA 50:1 to 1:1). Compound A7 (40 g, 72.27 mmol, 36.71% yield, 89.123% purity) was obtained as a yellow oil, which was confirmed by LCMS. LCMS: Retention time: 1.007 min, (M+H) = 494.9.

[0427] Steps 1-6: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (Compound A9)

[0428] [ka]

[0429] To a suspension of NaH (42.81 g, 1.07 mol, 60% purity, 1.5 equiv.) in THF (1 L), ethyl 1H-imidazole-5-carboxylate (compound A8) (100 g, 713.57 mmol, 1 equiv.) was added portionwise at 0 °C and stirred at 20 °C for 0.5 h. SEM-Cl (178.45 g, 1.07 mol, 189.44 mL, 1.5 equiv.) was added dropwise at 0 °C and stirred at 25 °C for 16 h. TLC (PE:EA 1:1) showed that compound A8 (Rf = 0.1) was completely consumed, and a new spot (Rf = 0.3) was detected. This was poured into saturated aqueous NH4Cl (1 L) and extracted with ethyl acetate (1 L). The organic layer was washed with brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO, PE:EA 10:1 to 0:1) to give compound A9 (136 g, 502.96 mmol, 70.48% yield) as a yellow solid. 1 Confirmed by H-NMR. 1 H-NMR:(400MHz,CHLOROFORM-d)δ=7.74(d,J=1.3Hz,1H),7.65(d,J=1.1Hz,1H),5.32(s,2H),4.43~4.36 (m,2H),3.54~3.44(m,2H),1.44~1.38(m,3H),1.29~1.26(m,2H),0.96~0.89(m,3H),0.02~-0.02(m,9H)

[0430] Step 1-7: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (compound A10)

[0431] [ka]

[0432] To a solution of ethyl compound A9 (116 g, 429.00 mmol, 1 equiv.) in CHCl3 (1 L), NBS (83.99 g, 471.89 mmol, 1.1 equiv.) and AIBN (8.45 g, 51.48 mmol, 0.12 equiv.) were added and stirred at 65 °C for 4 h. TLC (PE:EA 3:1) showed that compound A9 (Rf = 0.1) was consumed and a new peak (Rf = 0.4) was detected. The reaction mixture was quenched with brine (1 L), and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE:EA 20:1 to 2:1). Compound A10 (80 g, 229.03 mmol, 53.39% yield) was obtained as a yellow solid. 1 H-NMR. 1 The product was confirmed by H-NMR (400 MHz, DMSO-d6) δ = 8.30-8.24 (m, 1H), 8.20 (s, 1H), 5.38 (s, 2H), 4.30-4.22 (m, 2H), 3.63-3.53 (m, 2H), 1.33-1.28 (m, 3H), 0.89 (t, J = 7.9 Hz, 2H), 0.02--0.03 (m, 9H).

[0433] Steps 1-8: General procedure for the preparation of ethyl 5'-(4-fluorophenyl)-3'-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (compound A11)

[0434] [ka]

[0435] To a solution of compound A7 (10 g, 20.27 mmol, 1 equiv.) and compound A10 (10.62 g, 30.41 mmol, 1.5 equiv.) in toluene (100 mL), [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphane (4.07 g, 6.08 mmol, 0.3 equiv.) was added at 25 °C, the mixture was filled with N2 three times, and stirred at 110 °C for 16 h. TLC (PE:EA 1:1) showed that compound A7 (Rf = 0.4) was consumed and a new spot (Rf = 0.3) was detected. LCMS showed that compound A7 was consumed and the desired mass was detected. The mixture was filtered and poured into water (300 ml). The pH of the mixture was adjusted to 3 with 1N HCl. The organic layer was washed with saturated aqueous NaHCO (300 ml) and brine (300 ml), filtered, dried over NaSO, and concentrated in vacuo. The crude product was purified by column chromatography (SiO, PE:EA 100:1 to 1:2). Compound A11 (20 g, 25.00 mmol, 41.11% yield, 59.089% purity) was obtained as a yellow oil, which was confirmed by LCMS. LCMS: Retention time: 0.927 min, (M+H) = 473.3.

[0436] Steps 1-9: 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 A12)

[0437] [ka]

[0438] To a solution of compound A11 (20 g, 42.32 mmol, 1 equiv.) in THF (60 mL), MeOH (60 mL), and HO (60 mL), LiOH·HO (17.76 g, 423.17 mmol, 10 equiv.) was added and stirred at 25 °C for 2 h. TLC (PE:EA 1:1) showed that compound A11 was consumed and a new spot (Rf = 0) was detected. The crude was concentrated in vacuo to remove THF and MeOH, 0.5 L of water was added, the pH of the mixture was adjusted to 6 with 1 N HCl, ethyl acetate (1 L) was added, and the organic layer was washed with brine (0.5 L), dried over NaSO, and concentrated in vacuo. The crude material was triturated with petroleum ether (70 ml) and MTBE (25 ml), the mixture was filtered, the cake was washed with petroleum ether (20 ml), dried in vacuo, and the cake was purified by reverse-phase HPLC (1% TFA condition). Compound A12 (11.5 g, 25.01 mmol, 59.10% yield, 96.686% purity) was obtained as an off-white solid, as determined by LCMS and HPLC. 1 Confirmed by H-NMR. LCMS: Retention time: 0.877 min, (M+H)=445.2. 1 H-NMR:(400MHz,DMSO-d6)δ=13.40~11.99(m,1H),8.34(s,1H),8.24(s,1H),7.4 1~7.36(m,2H),7.27~7.20(m,2H),5.12~4.96(m,2H),4.22~4.15(m,1H),3.33(br d,J=4.5Hz,2H),1.58~1.43(m,6H),0.68(br dd,J=5.0,8.8Hz,2H),0.03~-0.02(m,9H),

[0439] Step 1-10: 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 A14)

[0440] [ka]

[0441] To a solution of compound A12 (3.5 g, 7.87 mmol, 1 equiv.) and 4-(4-methylpiperazin-1-yl)aniline (compound A13) (1.81 g, 9.45 mmol, 1.2 equiv.) in DMF (35 mL), HATU (4.49 g, 11.81 mmol, 1.5 equiv.) and DIEA (3.05 g, 23.62 mmol, 4.11 mL, 3.0 equiv.) were added and stirred at 25 °C for 2 h. LCMS showed that compound A12 was consumed and the desired mass was detected. This was combined with two other batches for workup. The mixture was poured into water (300 mL), ethyl acetate (300 mL) was added, and the organic layer was washed with brine (200 mL × 3), dried over Na SO , and concentrated in vacuo. The crude product was used directly in the next step. Compound A14 (9 g, crude) was obtained as a yellow solid, which was confirmed by LCMS: Retention time: 0.801 min, (M+H)=618.4.

[0442] Step 1-11: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 112)

[0443] [ka]

[0444] To a solution of compound A14 (9 g, 14.57 mmol, 1 equiv.) in DCM (10 mL), TFA (90 mL) was added and stirred at 25 °C for 2 h. LCMS showed that compound A14 was consumed and the desired mass was detected. This was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Kromasil Eternity XT 250 × 80 mm × 10 μm, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 30% to 60%, 15 min) and lyophilized. Compound 112 (4.42 g, 8.45 mmol, 58.03% yield, 93.215% purity) was obtained, which was 1 Confirmed by H-NMR and LCMS. LCMS: Retention time: 0.611 min, (M+H)=488.3. 1 H-NMR:(400MHz,DMSO-d6)δ=13.64~12.60(m,1H),9.67(br s,1H),8.03(s,1H),7.93(s,1H),7.65(br d,J=8.9Hz,2H),7.43(dd,J=5.7,8.6Hz,2H),7.20~7.06(m,2H),6.89(d,J=9.0Hz,2H),4.26(td ,J=6.7,13.4Hz,1H),3.16~3.02(m,4H),2.47~2.41(m,4H),2.22(s,3H),1.39(d,J=6.7Hz,6H).

[0445] Example 2: Novel synthesis route 1 of compound 112

[0446] [ka]

[0447] Step 2-1: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (compound A9)

[0448] [ka]

[0449] To a suspension of NaH (42.81 g, 1.07 mol, 60% purity, 1.5 equiv.) in THF (1 L), ethyl 1H-imidazole-5-carboxylate (compound A8) (100 g, 713.57 mmol, 1 equiv.) was added portionwise at 0 °C and stirred at 20 °C for 0.5 h. SEM-Cl (178.45 g, 1.07 mol, 189.44 mL, 1.5 equiv.) was added dropwise at 0 °C and stirred at 25 °C for 16 h. TLC (PE:EA 1:1) showed that compound A8 (Rf = 0.1) was completely consumed, and a new spot (Rf = 0.3) was detected. This was poured into saturated aqueous NH4Cl (1 L) and extracted with ethyl acetate (1 L). The organic layer was washed with brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO, PE:EA 10:1 to 0:1) to give compound A9 (136 g, 502.96 mmol, 70.48% yield) as a yellow solid. 1 Confirmed by H-NMR. 1 H-NMR: (400MHz, chloroform-d)δ=7.74(d,J=1.3Hz,1H),7.65(d,J=1.1Hz,1H),5.32(s,2H),4.43~4.36(m ,2H),3.54~3.44(m,2H),1.44~1.38(m,3H),1.29~1.26(m,2H),0.96~0.89(m,3H),0.02~-0.02(m,9H)

[0450] Further examples of step 2-1: The ethyl ester group of compound A8 can be replaced with a methyl ester, n-PrOH ester, i-PrOH ester, t-BuOH ester, phenyl ester, benzyl ester, p-methoxybenzyl ester, and the like.

[0451] The protecting group SEM can be replaced by commercially available protecting groups such as methyloxycarbonyl, ethyloxycarbonyl, Cbz (benzyloxycarbonyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), Teoc (2-(trimethylsilyl)ethyloxycarbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Tos (para-toluenesulfonyl), Tfa (2,2,2-trifluoroacetyl), Trt (trityl), Dmb (2,4-dimethoxybenzyl), Pmb (p-methoxybenzyl), and Bn (benzyl).

[0452] Step 2-2: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (compound A10)

[0453] [ka]

[0454] To a solution of ethyl compound A9 (116 g, 429.00 mmol, 1 equiv.) in CHCl3 (1 L), NBS (83.99 g, 471.89 mmol, 1.1 equiv.) and AIBN (8.45 g, 51.48 mmol, 0.12 equiv.) were added and stirred at 65 °C for 4 h. TLC (PE:EA 3:1) showed that compound A9 (Rf = 0.1) was consumed and a new peak (Rf = 0.4) was detected. The reaction mixture was quenched with brine (1 L), and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE:EA 20:1 to 2:1). Compound A10 (80 g, 229.03 mmol, 53.39% yield) was obtained as a yellow solid. 1 This was confirmed by H-NMR. 1H-NMR:(400MHz,DMSO-d6)δ=8.30~8.24(m,1H),8.20(s,1H),5.38(s,2H),4.30~4.22(m ,2H),3.63~3.53(m,2H),1.33~1.28(m,3H),0.89(t,J=7.9Hz,2H),0.02~-0.03(m,9H).

[0455] Step 2-3: General procedure for the preparation of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound B1)

[0456] [ka]

[0457] To a solution of compound A10 (28 g, 80.16 mmol, 1 equiv) in THF (300 mL) was added i-PrMgCl (2 M, 120.24 mL, 3 equiv) at -40 °C. The mixture was stirred at -40 °C for 10 min. To the mixture was added DMF (35.16 g, 480.97 mmol, 37.01 mL, 6 equiv) at -70 °C. The mixture was stirred at 20 °C for 1 h. HPLC showed that compound A10 was consumed. LCMS showed that the desired mass was detected. The mixture was poured into 1 N 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 give a residue. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 3:1). Compound B1 (15 g, 50.27 mmol, 62.71% yield) was obtained as a yellow oil, which was analyzed by LCMS and 1 Checked by H-NMR. LCMS: Retention time: 0.955 min, (M+H)=299.2. 1 H-NMR:(400MHz,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)

[0458] In some cases, the strong base i-PrMgCl for the bromine-metal exchange reaction can be replaced with commercially available strong bases such as LDA, n-BuLi, t-BuLi, LiHMDS, KHMDS, i-PrMgBr, MeMgCl, MeMgBr, EtMgCl, EtMgBr, etc.

[0459] DMF can be replaced with other formylating reagents, such as N,N-diethylformamide.

[0460] Step 2-4: General procedure for the preparation of ethyl 5'-(4-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (Compound B3)

[0461] [ka]

[0462] To a mixture of compound B1 (12.5 g, 41.89 mmol, 1 equiv.) in THF (200 mL), NH3·HO (22.73 g, 162.11 mmol, 24.97 mL, 25% purity, 3.87 equiv.) was added. The mixture was stirred at 20 °C for 4 h. To the mixture, compound B2 (14.54 g, 50.27 mmol, 1.2 equiv.) and DIEA (16.24 g, 125.67 mmol, 21.89 mL, 3 equiv.) were added at 20 °C. The mixture was stirred at 20 °C for 2 h. TLC (PE:EA = 0:1) showed that compound B1 was consumed and a new spot (Rf = 0.3) was detected. The residue was poured into water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (200 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EA = 1:1 to 0:1). Compound B3 (10 g, 22.51 mmol, 53.74% yield, 96.914% purity) was obtained as a yellow solid, which was checked by LCMS. LCMS: Retention time: 0.799 min, (M+H) = 431.2.

[0463] Step 2-5: General procedure for the preparation of ethyl 5'-(4-fluorophenyl)-3'-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (compound A11)

[0464] [ka]

[0465] To a mixture of compound B3 (10 g, 23.23 mmol, 1 equiv.) in DMF (60 mL), K2CO3 (9.63 g, 69.68 mmol, 3 equiv.) and 2-bromopropane (8.57 g, 69.68 mmol, 6.54 mL, 3 equiv.) were added. The mixture was stirred at 60 °C for 6 h. LCMS showed that compound B3 was consumed and the desired mass was detected. The residue was poured into ice water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA = 1:1 to 1:5). Compound A11 (7.6 g, crude) was obtained as a yellow solid, which was identified by LCMS and HPLC. 1 Checked by H-NMR. LCMS: Retention time: 0.826 min, (M+H)=473.3. 1 H-NMR:(400MHz,DMSO-d6)δ=8.30(s,1H),8.16~8.09(m,1H),7.27(br dd,J=5.6,8.8Hz,2H),7.17~7.06(m,2H),5.03~4.83(m,2H),4.29(br d,J=6.4Hz,2H),4.06(br s,1H),3.28~3.18(m,2H),1.39(br s,6H),1.32(t,J=7.2Hz,3H),0.61~0.50(m,2H),-0.07~-0.14(m,9H)

[0466] Step 2-6: 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 A12)

[0467] [ka]

[0468] To a mixture of compound A11 (7.6 g, 16.08 mmol, 1 equiv.) in THF (80 mL) and HO (16 mL), LiOH (2.70 g, 112.56 mmol, 7 equiv.) was added. The mixture was stirred at 20 °C for 3 h. LCMS showed that the reactants were consumed and the desired mass was detected. The residue was acidified with 1N aqueous HCl, and the resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude compound was used in the next step without further purification. Compound A12 (6.1 g, crude) was obtained as a yellow solid, which was obtained by LCMS and HPLC. 1 Checked by H-NMR. LCMS: Retention time: 0.763 min, (M+H)=445.3. 1 H-NMR:(400MHz,DMSO-d6)δ=8.98~8.76(m,1H),8.27(s,1H),7.42~7.16(m,4H),5.00(br s,2H),4.16(td,J=6.8,13.2Hz,1H),3.21(br s,2H),1.43(br d,J=6.8Hz,6H),0.53(br d,J=3.2Hz,2H),-0.04~-0.15(m,9H) 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 A14)

[0469] [ka] To a mixture of compound A12 (6.5 g, 14.62 mmol, 1 eq.) and compound A13 (4.19 g, 21.93 mmol, 1.5 eq.) in DMF (50 mL) was added HATU (8.34 g, 21.93 mmol, 1.5 eq.) and DIEA (5.67 g, 43.86 mmol, 7.64 mL, 3 eq.). The mixture was stirred at 20 °C for 3 h. LCMS showed that compound A12 was consumed and the desired mass was detected. The residue was poured into water (500 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude compound was used in the next step without further purification. Compound A14 (9 g, crude) was obtained as a brown oil, which was checked by LCMS. LCMS: Retention time: 0.753 min, (M+H)=618.4.

[0470] Step 2-8: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 112)

[0471] [ka]

[0472] To a solution of compound A14 (9 g, 14.57 mmol, 1 equiv.) in DCM (10 mL), TFA (90 mL) was added and stirred at 25 °C for 2 h. LCMS showed that compound A14 was consumed and the desired mass was detected. This was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Kromasil Eternity XT 250 × 80 mm × 10 μm, mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN], B%: 30% to 60%, 15 min) and lyophilized. Compound 112 (4.42 g, 8.45 mmol, 58.03% yield, 93.215% purity) was obtained, which was 1 Confirmed by H-NMR and LCMS. LCMS: Retention time: 0.611 min, (M+H)=488.3.1 H-NMR:(400MHz,DMSO-d6)δ=13.64~12.60(m,1H),9.67(br s,1H),8.03(s,1H),7.93(s,1H),7.65(br d,J=8.9Hz,2H),7.43(dd,J=5.7,8.6Hz,2H),7.20~7.06(m,2H),6.89(d,J=9.0Hz,2H),4.26(td ,J=6.7,13.4Hz,1H),3.16~3.02(m,4H),2.47~2.41(m,4H),2.22(s,3H),1.39(d,J=6.7Hz,6H).

[0473] Example 3: Novel synthesis route 2 of compound 112

[0474] The imidazole ring of Compound A8 was protected with an SEM group and then brominated at the C-2 position to give Compound A10. Bromine-magnesium exchange with a Grignard reagent, followed by reaction with DMF, introduced a 2-formyl group. The imidazole ring was constructed in one step by isonitrile chemistry with Compound B2 to give Compound A11. Hydrolysis of the ester group and condensation with Compound A13 gave Compound A14. The final compound was obtained after deprotection of the SEM group.

[0475] [ka]

[0476] Step 3-1: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (Compound A9)

[0477] [ka]

[0478] To a suspension of NaH (42.81 g, 1.07 mol, 60% purity, 1.5 equiv.) in THF (1 L), ethyl 1H-imidazole-5-carboxylate (compound A8) (100 g, 713.57 mmol, 1 equiv.) was added portionwise at 0 °C and stirred at 20 °C for 0.5 h. SEM-Cl (178.45 g, 1.07 mol, 189.44 mL, 1.5 equiv.) was added dropwise at 0 °C and stirred at 25 °C for 16 h. TLC (PE:EA 1:1) showed that compound A8 (Rf = 0.1) was completely consumed, and a new spot (Rf = 0.3) was detected. This was poured into saturated aqueous NH4Cl (1 L) and extracted with ethyl acetate (1 L). The organic layer was washed with brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO, PE:EA 10:1 to 0:1) to give compound A9 (136 g, 502.96 mmol, 70.48% yield) as a yellow solid. 1 This was confirmed by H-NMR. 1 H-NMR: (400MHz, chloroform-d)δ=7.74(d,J=1.3Hz,1H),7.65(d,J=1.1Hz,1H),5.32(s,2H),4.43~4.36(m ,2H),3.54~3.44(m,2H),1.44~1.38(m,3H),1.29~1.26(m,2H),0.96~0.89(m,3H),0.02~-0.02(m,9H)

[0479] In some cases, the ethyl ester group of compound A8 can be replaced with a methyl ester, n-PrOH ester, i-PrOH ester, t-BuOH ester, phenyl ester, benzyl ester, p-methoxybenzyl ester, and the like.

[0480] The protecting group SEM can be replaced by commercially available protecting groups such as methyloxycarbonyl, ethyloxycarbonyl, Cbz (benzyloxycarbonyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), Teoc (2-(trimethylsilyl)ethyloxycarbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Tos (para-toluenesulfonyl), Tfa (2,2,2-trifluoroacetyl), Trt (trityl), Dmb (2,4-dimethoxybenzyl), Pmb (p-methoxybenzyl), and Bn (benzyl).

[0481] Step 3-2: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (compound A10)

[0482] [ka]

[0483] To a solution of ethyl compound A9 (116 g, 429.00 mmol, 1 equiv.) in CHCl3 (1 L), NBS (83.99 g, 471.89 mmol, 1.1 equiv.) and AIBN (8.45 g, 51.48 mmol, 0.12 equiv.) were added and stirred at 65 °C for 4 h. TLC (PE:EA 3:1) showed that compound A9 (Rf = 0.1) was consumed and a new peak (Rf = 0.4) was detected. The reaction mixture was quenched with brine (1 L), and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE:EA 20:1 to 2:1). Compound A10 (80 g, 229.03 mmol, 53.39% yield) was obtained as a yellow solid. 1 This was confirmed by H-NMR. 1H-NMR:(400MHz,DMSO-d6)δ=8.30~8.24(m,1H),8.20(s,1H),5.38(s,2H),4.30~4.22(m ,2H),3.63~3.53(m,2H),1.33~1.28(m,3H),0.89(t,J=7.9Hz,2H),0.02~-0.03(m,9H).

[0484] Step 3-3: General procedure for the preparation of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound B1)

[0485] [ka]

[0486] To a solution of compound A10 (28 g, 80.16 mmol, 1 equiv) in THF (300 mL) was added i-PrMgCl (2 M, 120.24 mL, 3 equiv) at -40 °C. The mixture was stirred at -40 °C for 10 min. To the mixture was added DMF (35.16 g, 480.97 mmol, 37.01 mL, 6 equiv) at -70 °C. The mixture was stirred at 20 °C for 1 h. HPLC showed that compound A10 was consumed. LCMS showed that the desired mass was detected. The mixture was poured into 1 N 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 give a residue. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 3:1). Compound B1 (15 g, 50.27 mmol, 62.71% yield) was obtained as a yellow oil, which was analyzed by LCMS and 1 Checked by H-NMR. LCMS: Retention time: 0.955 min, (M+H)=299.2. 1 H-NMR:(400MHz,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).

[0487] In some cases, the strong base i-PrMgCl for the bromine-metal exchange reaction can be replaced with commercially available strong bases such as LDA, n-BuLi, t-BuLi, LiHMDS, KHMDS, i-PrMgBr, MeMgCl, MeMgBr, EtMgCl, EtMgBr, etc.

[0488] In some cases, DMF can be replaced with other formylating reagents, such as N,N-diethylformamide.

[0489] Step 3-4: General procedure for the preparation of ethyl 5'-(4-fluorophenyl)-3'-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylate (compound A11)

[0490] [ka]

[0491] To a mixture of compound B1 (5 g, 16.76 mmol, 1 equiv.) in THF (20 mL) was added i-PrNH2 (3.96 g, 67.02 mmol, 5.76 mL, 4 equiv.). The mixture was stirred at 20 °C for 4 h. To the mixture, compound B2 (5.82 g, 20.11 mmol, 1.2 equiv.) and DIEA (6.50 g, 50.27 mmol, 8.76 mL, 3 equiv.) were added at 20 °C. The mixture was stirred at 20 °C for 1 h. LCMS showed that 81.7% of compound A11 was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® Silica Flash Column, eluent: 0-100% ethyl acetate / petroleum ether gradient at 120 mL / min). Compound A11 (6.17 g, 13.05 mmol, 77.91% yield, 100% purity) was obtained as a yellow oil.

[0492] Step 3-5: 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 A12)

[0493] [ka]

[0494] To a mixture of compound A11 (7.6 g, 16.08 mmol, 1 equiv.) in THF (80 mL) and HO (16 mL), LiOH (2.70 g, 112.56 mmol, 7 equiv.) was added. The mixture was stirred at 20 °C for 3 h. LCMS showed that the reactants were consumed and the desired mass was detected. The residue was acidified with 1 M aqueous HCl, and the resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude compound was used in the next step without further purification. Compound A12 (6.1 g, crude) was obtained as a yellow solid, which was obtained by LCMS and HPLC. 1 Checked by H-NMR. LCMS: Retention time: 0.763 min, (M+H)=445.3. 1 H-NMR:(400MHz,DMSO-d6)δ=8.98~8.76(m,1H),8.27(s,1H),7.42~7.16(m,4H),5.00(br s,2H),4.16(td,J=6.8,13.2Hz,1H),3.21(br s,2H),1.43(br d,J=6.8Hz,6H),0.53(br d,J=3.2Hz,2H),-0.04~-0.15(m,9H)

[0495] Step 3-6: 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 A14)

[0496] [ka]

[0497] To a mixture of compound A12 (6.5 g, 14.62 mmol, 1 eq.) and compound A13 (4.19 g, 21.93 mmol, 1.5 eq.) in DMF (50 mL) was added HATU (8.34 g, 21.93 mmol, 1.5 eq.) and DIEA (5.67 g, 43.86 mmol, 7.64 mL, 3 eq.). The mixture was stirred at 20 °C for 3 h. LCMS showed that compound A12 was consumed and the desired mass was detected. The residue was poured into water (500 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude compound was used in the next step without further purification. Compound A14 (9 g, crude) was obtained as a brown oil, which was checked by LCMS. LCMS: Retention time: 0.753 min, (M+H)=618.4.

[0498] Step 3-7: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 112)

[0499] [ka]

[0500] To a mixture of compound A14 (9 g, 14.57 mmol, 1 equiv.) in CHCl (2 mL) was added TFA (30.80 g, 270.12 mmol, 20.00 mL, 18.54 equiv.). The mixture was stirred at 20 °C for 5 h. LCMS indicated that compound A14 was consumed and the desired mass was detected. The mixture was basified with aqueous NaHCO (pH 8), and the resulting mixture was extracted with ethyl acetate (200 mL × 4). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC (0.1% NH H O). Compound 112 (3.04 g, 6.20 mmol, 42.58% yield, 99.492% purity) was obtained as an off-white solid, which was identified by LCMS and HPLC. 1 Checked by H-NMR. LCMS: Retention time: 0.683 min, (M+H)=488.2. 1 H-NMR:(400MHz,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=9.2Hz,2H),7.44~7.34(m,2H),7.1 4(t,J=8.8Hz,2H),6.90(d,J=9.0Hz,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=6.4Hz,6H).

[0501] Example 4: New synthetic route 3 to compound 112.

[0502] The synthesis of compound B1 from compound A8 was the same as in new route 1. The imidazole ring was constructed in one step by deprotection of compound B1, followed by isonitrile chemistry with compound B2. Hydrolysis of the ester group and condensation with compound A13 gave the target compound, compound 112.

[0503] [ka]

[0504] Step 4-1: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (compound A9)

[0505] [ka]

[0506] To a suspension of NaH (42.81 g, 1.07 mol, 60% purity, 1.5 equiv.) in THF (1 L), 1H-imidazole-5-ethyl carboxylate (compound A8) (100 g, 713.57 mmol, 1 equiv.) was added portionwise at 0 °C and stirred at 20 °C for 0.5 h. SEM-Cl (178.45 g, 1.07 mol, 189.44 mL, 1.5 equiv.) was added dropwise at 0 °C and stirred at 25 °C for 16 h. TLC (PE:EA 1:1) showed that compound A8 (Rf = 0.1) was completely consumed, and a new spot (Rf = 0.3) was detected. This was poured into saturated aqueous NH4Cl (1 L) and extracted with ethyl acetate (1 L). The organic layer was washed with brine (1 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO, PE:EA 10:1 to 0:1) to give compound A9 (136 g, 502.96 mmol, 70.48% yield) as a yellow solid. 1 This was confirmed by H-NMR. 1 H-NMR:(400MHz,CHLOROFORM-d)δ=7.74(d,J=1.3Hz,1H),7.65(d,J=1.1Hz,1H),5.32(s,2H),4.43~4.36 (m,2H),3.54~3.44(m,2H),1.44~1.38(m,3H),1.29~1.26(m,2H),0.96~0.89(m,3H),0.02~-0.02(m,9H).

[0507] In some cases, the ethyl ester group of compound A8 can be replaced with a methyl ester, n-PrOH ester, i-PrOH ester, t-BuOH ester, benzyl ester, benzylmethyl ester, 4-methylbenzylmethyl ester, and the like.

[0508] The protecting group SEM can be replaced by commercially available protecting groups such as methyloxycarbonyl, ethyloxycarbonyl, Cbz (benzyloxycarbonyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), Teoc (2-(trimethylsilyl)ethyloxycarbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Tos (para-toluenesulfonyl), Tfa (2,2,2-trifluoroacetyl), Trt (trityl), Dmb (2,4-dimethoxybenzyl), Pmb (p-methoxybenzyl), and Bn (benzyl).

[0509] Step 4-2: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (compound A10)

[0510] [ka]

[0511] To a solution of compound A9 (116 g, 429.00 mmol, 1 equiv.) in CHCl3 (1 L), NBS (83.99 g, 471.89 mmol, 1.1 equiv.) and AIBN (8.45 g, 51.48 mmol, 0.12 equiv.) were added and stirred at 65 °C for 4 h. TLC (PE:EA 3:1) showed that compound A9 (Rf = 0.1) was consumed and a new peak (Rf = 0.4) was detected. The reaction mixture was quenched with brine (1 L), and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE:EA 20:1 to 2:1). Compound A10 (80 g, 229.03 mmol, 53.39% yield) was obtained as a yellow solid. 1 This was confirmed by H-NMR. 1H-NMR:(400MHz,DMSO-d6)δ=8.30~8.24(m,1H),8.20(s,1H),5.38(s,2H),4.30~4.22(m ,2H),3.63~3.53(m,2H),1.33~1.28(m,3H),0.89(t,J=7.9Hz,2H),0.02~-0.03(m,9H).

[0512] Step 4-3: General procedure for the preparation of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound B1)

[0513] [ka]

[0514] To a solution of compound A10 (28 g, 80.16 mmol, 1 equiv) in THF (300 mL) was added i-PrMgCl (2 M, 120.24 mL, 3 equiv) at -40 °C. The mixture was stirred at -40 °C for 10 min. To the mixture was added DMF (35.16 g, 480.97 mmol, 37.01 mL, 6 equiv) at -70 °C. The mixture was stirred at 20 °C for 1 h. HPLC showed that compound A10 was consumed. LCMS showed that the desired mass was detected. The mixture was poured into 1 N 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 give a residue. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 3:1). Compound B1 (15 g, 50.27 mmol, 62.71% yield) was obtained as a yellow oil, which was analyzed by LCMS and 1 Checked by H-NMR. LCMS: Retention time: 0.955 min, (M+H)=299.2. 1 H-NMR:(400MHz,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).

[0515] In some cases, the strong base i-PrMgCl for the bromine-metal exchange reaction can be replaced with commercially available strong bases such as LDA, n-BuLi, t-BuLi, LiHMDS, KHMDS, i-PrMgBr, MeMgCl, MeMgBr, EtMgCl, EtMgBr, etc. DMF can be replaced with other formylating reagents such as N,N-diethylformamide.

[0516] Step 4-4: General procedure for the preparation of ethyl 2-formyl-1H-imidazole-4-carboxylate (compound C1)

[0517] [ka]

[0518] To a mixture of compound B1 (40 g, 134.04 mmol, 1 equiv.) in 2-MeTHF (80 mL) was added 36.5% aqueous HCl (90 mL, 9.1 equiv.). The mixture was stirred at 10 °C for 6-8 h. The reaction mixture was adjusted to pH 7-8 with 15% aqueous NaOH (333 mL) and saturated aqueous NaHCO3 (270 mL). The aqueous layer was separated and extracted five times with EA (200 mL). All organic phases were combined, concentrated to dryness below 40 °C, and EtOH (40 mL) was added. HO (400 mL) was added dropwise to a suspension of compound C1 in EtOH at 15-25 °C, stirred at -5-5 °C for 16 h, and then filtered and washed with HO. The wet cake was dried at 45-55 °C for 20 h. The assay yield was 85%. The structure was checked by LCMS. LCMS: (M+H)=169.2.

[0519] Step 4-5: General procedure for the preparation of ethyl 5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxylate (compound C2)

[0520] [ka]

[0521] Compound C1 (100 g, 0.59 mol, 1 equiv.) and THF (1 L) were added to R1, and i-PrNH2 (140.7 g, 2.38 mol, 4 equiv.) was added. The mixture was stirred at 15-25°C for 1 h. Compound B2 (172.1 g, 0.59 mol, 1.0 equiv.) was added at 15-25°C. The mixture was stirred at 15-25°C for 2-11 h. 500 mL of MTBE and 1 L of process water were added to the reaction mixture. The pH of the mixture was then adjusted to 1-2 with 35% aqueous HCl and separated. The organic phase was washed twice with 500 mL of 3.5% aqueous HCl. The aqueous phases were combined, and the pH was adjusted to 7-8 with 30% aqueous NaOH. The wet cake was filtered and dried at 45-55°C for 12-24 h. The assay yield was 89%. The structure was checked by LCMS: (M+H)=343.2.

[0522] In some cases, the 4-MePh group of compound B2 may be replaced with other commercially available or easily prepared substituted phenyl groups, and the substitution may be H, F, Cl, Br, methyl, methoxy, etc.

[0523] The reaction solvent may be selected from commercially available solvents such as THF, 2-MeTHF, toluene, 1,4-dioxane, 1,2-DCE, DCM, DMF, DMAc, NMP, DMSO, acetone, acetonitrile, EtOH, MeOH, i-PrOH, t-BuOH, etc., or combinations thereof.

[0524] An organic base such as TEA, DIEA, etc. can also be added to accelerate the reaction.

[0525] The reaction temperature can be from -20°C to about 110°C.

[0526] The crystallization solvent can be selected from the following solvents: EA, IPAc, MTBE, THF, Me-THF, ethyl ether, n-heptane, n-hexane, methylcyclohexane, petroleum ether, MeOH, EtOH, i-PrOH, acetone, acetonitrile, etc., and combinations thereof.

[0527] Steps 4-6: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxylic acid (compound C3)

[0528] [ka]

[0529] Compound C2 (100 g, 0.29 mol, 1 equiv.) and 1,4-dioxane (500 mL) were charged to a reactor, and 13.48% aqueous NaOH (346.7 g, 1.17 mol, 4 equiv.) was added. The mixture was stirred at 75-85 °C for 16 h. After cooling to 20-50 °C, 700 mL of process water was added to the reaction mixture. Then, 36-39% aqueous HCl (115 g, 1.17 mol, 4.0 equiv.) was charged at 20-50 °C. The reactor was adjusted to 0-10 °C and stirred at 0-10 °C for 2-4 h. The wet cake was then filtered and washed with 150 mL of process water. The wet cake was dried at 50-55 °C for 24 h. The assay yield was 90%. The structure was confirmed by LCMS. LCMS: (M+H) = 315.2.

[0530] The base NaOH for the hydrolysis reaction can be replaced with KOH, LiOH, Ca(OH)2, K2CO3, KHCO3, Na2CO3, NaHCO3, K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, NaH2PO4, etc.

[0531] The reaction solvent may be selected from 1,4-dioxane, MeOH, EtOH, i-PrOH, n-PrOH, THF, water, and combinations thereof.

[0532] The reaction temperature can be set to -20 to 110°C.

[0533] Steps 4-7: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 112)

[0534] [ka]

[0535] To a suspension of compound C3 (79 g, 76.4% assay, 0.192 mol, 1.0 equiv.) in THF (790 mL) was added EtN (77.6 g, 0.77 mol, 4.0 equiv.). The mixture was stirred at 15-25 °C for 30-60 min and then cooled to -5-5 °C. Compound A13 (47.7 g, 0.25 mol, 1.3 equiv.) was added, followed by the dropwise addition of 50% T3P in EA solution (183 g, 0.29 mol, 1.5 equiv.) at -5-5 °C. The mixture was stirred at -5-5 °C until complete conversion. EA (560 mL) and 560 mL of 5% aqueous Na2SO4 were added, followed by stirring and separation. The aqueous phase was extracted with 240 mL of EA and 400 mL of THF. The organic phases were combined and then washed with 7% NaHCO3 (560 mL) and water (560 mL). The resulting organic phase was decolorized through CUNO (12 g of activated cake) and then switched to EtOH (560 mL), followed by dropwise addition of water (800 mL) at 15-25 °C. The mixture was stirred at 15-25 °C for 2-4 h, then filtered and washed with water (400 mL). The wet cake was dissolved in 400 mL of THF at 45-55 °C, followed by dropwise addition of water (800 mL) at 20-30 °C. The mixture was stirred at 20-30 °C for 4-10 h, then filtered and washed with water (400 mL). The cake was dried under vacuum at 45-60 °C for 16-24 h to give 36.9 g of target compound 112 with 99.85% purity and 78.8% assay yield. The structures were analyzed by LCMS and 1Checked by H-NMR. LCMS: Retention time: 0.683 min, (M+H)=488.2. 1 H-NMR:(400MHz,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=9.2Hz,2H),7.44~7.34(m,2H),7.1 4(t,J=8.8Hz,2H),6.90(d,J=9.0Hz,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=6.4Hz,6H).

[0536] The condensation reagent T3P can be replaced with commercially available condensation reagents such as HATU, EDCI, PyBOP, HBTU, DPPA, CDI, and the like.

[0537] The T3P / EA solution can be replaced with other T3P solutions, such as T3P, T3P / THF solution, T3P / 2-MeTHF solution, T3P / IPAc solution.

[0538] Example 5: Novel synthetic route 4 for compound 112

[0539] The isonitrile chemical reaction between D1 and B2 and i-PrNH2 gave D2. Hydrolysis of the CF3 group to a carboxylic acid group, followed by condensation with A13, gave the target compound.

[0540] [ka]

[0541] Step 5-1: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-4-(trifluoromethyl)-1H,3'H-2,4'-biimidazole (compound D2)

[0542] [ka]

[0543] Compound D1 was prepared according to the procedure reported in WO2009084614A1.

[0544] To a mixture of compound D1 (10.0 g, 60.94 mmol, 1 equiv.) in THF (70.0 mL) was added i-PrNH2 (14.41 g, 243.78 mmol, 4.0 equiv.). The mixture was stirred at 20 °C for 1-2 h. To the mixture was added compound B2 (18.51 g, 67.05 mmol, 1.05 equiv.). The mixture was stirred at 20 °C for 2-6 h until complete conversion. EA (50 mL) and water (50 mL) were added. The pH of the mixture was adjusted to 5-6 with 36% aqueous HCl (11.5 g) and then separated. The organic phase was adjusted to pH 9-10 with 10% aqueous Na2CO3 (40 g) and then separated. The organic phase was washed with 5% aqueous Na2CO3 (20 g) and then separated. The organic phase was switched to EA solution (30 mL), and then n-heptane (30 mL) was added. The suspension was concentrated under vacuum to approximately 30 mL below 45°C, and then n-heptane (50 mL) was added dropwise at 15-25°C. The mixture was cooled to 0-10°C over 2.0 hours, stirred at 0-10°C for 4-6 hours, and then filtered and washed with n-heptane (20 mL). The wet cake was dried under vacuum at 40-50°C for 10-18 hours. The assay yield is 91%. The structure was checked by LCMS. LCMS: (M+H) = 339.2.

[0545] As a further example, the reaction conditions can be adjusted as follows:

[0546] The CF3 group of compound D1 is CR A1 R A2 R A3 and R A1 , R A2 , and R A3 may be the same or different groups and are selected from F, Cl, Br, OMe, OEt, such as CBr3, CCl3, CF2Cl, CFCl2, CF2Br, CFBr2, C(OMe)3, C(OEt)3, etc.

[0547] The 4-MePh group of compound B2 can be substituted with other commercially available or easily prepared substituted phenyl groups, the substitutions can be H, F, Cl, Br, methyl, methyloxy, and the like.

[0548] The reaction solvent may be selected from commercially available solvents such as THF, 2-MeTHF, toluene, 1,4-dioxane, 1,2-DCE, DCM, DMF, DMAc, NMP, DMSO, acetone, acetonitrile, EtOH, MeOH, i-PrOH, t-BuOH, and the like, and combinations thereof.

[0549] An organic base such as TEA, DIEA, etc. can also be added to accelerate the reaction.

[0550] The reaction temperature can be set to -20°C to -110°C.

[0551] The crystallization solvent can be the following solvents: EA, IPAc, MTBE, THF, Me-THF, ethyl ether, n-heptane, n-hexane, methylcyclohexane, petroleum ether, MeOH, EtOH, i-PrOH, acetone, acetonitrile, etc., and combinations thereof.

[0552] Step 5-2: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-1H,3'H-[2,4'-biimidazole]-4-carboxylic acid (compound C3)

[0553] [ka]

[0554] To a mixture of compound D2 (10.0 g, 29.56 mmol, 1 equiv.) in MeOH (50 mL), a solution of NaOH (7.09 g, 177.36 mmol, 6.0 equiv.) dissolved in water (50 mL) was added, and the mixture was stirred at 60-70 °C for 16 h until compound D2 was completely consumed. The mixture was adjusted to pH 4.7-5.5 by adding aqueous HCl and filtered. The cake was washed with water (20 g), then slurried in water (100 g) at 35-45 °C for 6-8 h and stirred at 15-25 °C for 4-6 h. The wet cake was filtered and dried under vacuum at 40-50 °C for 12-18 h. The assay yield is 90%. The structure was confirmed by LCMS. LCMS: (M+H)=315.3.

[0555] In some cases, the base NaOH for the hydrolysis reaction can be replaced with KOH, LiOH, Ca(OH)2, K2CO3, KHCO3, Na2CO3, NaHCO3, K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, NaH2PO4, etc.

[0556] The reaction solvent may be selected from 1,4-dioxane, MeOH, EtOH, i-PrOH, n-PrOH, THF, water, and combinations thereof.

[0557] The reaction temperature can be set to -20 to 110°C.

[0558] Step 5-3: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 112)

[0559] [ka]

[0560] To a suspension of compound C3 (79 g, 1.0 equiv., 76.4% assay, 0.192 mol) in THF (790 mL) was added EtN (77.6 g, 0.77 mol, 4.0 equiv.). The mixture was stirred at 15-25 °C for 30-60 min and then cooled to -5-5 °C. Compound A13 (47.7 g, 0.25 mol, 1.3 equiv.) was added, followed by the dropwise addition of 50% T3P in EA solution (183 g, 0.29 mol, 1.5 equiv.) at -5-5 °C. The mixture was stirred at -5-5 °C until complete conversion. EA (560 mL) and 560 mL of 5% aqueous Na2SO4 were added, followed by stirring and separation. The aqueous phase was extracted with 240 mL of EA and 400 mL of THF. The organic phases were combined and then washed with 7% NaHCO3 (560 mL) and water (560 mL). The resulting organic phase was decolorized through CUNO (12 g of activated cake) and then switched to EtOH (560 mL), followed by dropwise addition of water (800 mL) at 15-25 °C. The mixture was stirred at 15-25 °C for 2-4 h, then filtered and washed with water (400 mL). The wet cake was dissolved in 400 mL of THF at 45-55 °C, followed by dropwise addition of water (800 mL) at 20-30 °C. The mixture was stirred at 20-30 °C for 4-10 h, then filtered and washed with water (400 mL). The cake was dried under vacuum at 45-60 °C for 16-24 h to give 36.9 g of target compound 112 with a purity of 99.85% and an assay yield of 78.8%. The structures were analyzed by LCMS and 1 Checked by H-NMR. LCMS: Retention time: 0.683 min, (M+H)=488.2. 1 H-NMR:(400MHz,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=9.2Hz,2H),7.44~7.34(m,2H),7.1 4(t,J=8.8Hz,2H),6.90(d,J=9.0Hz,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=6.4Hz,6H).

[0561] In some cases, the condensation reagent T3P can be replaced by commercially available condensation reagents such as HATU, EDCI, PyBOP, HBTU, DPPA, CDI, and the like.

[0562] The T3P / EA solution can be replaced with other T3P solutions, such as T3P, T3P / THF solution, T3P / 2-MeTHF solution, T3P / IPAc solution.

[0563] Example 6: New Route 4 of compound 112 can also be used to synthesize compound 120.

[0564] [ka]

[0565] The isonitrile chemistry between D1, B2, and 2,2,2-trifluoroethylamine gave E1. Hydrolysis of the CF3 group to a carboxylic acid group, followed by condensation with A13, gave the target compound, 120.

[0566] Step 6-1: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-neopentyl-4-(trifluoromethyl)-1H,3'H-2,4'-biimidazole (Compound E1)

[0567] [ka] Compound D1 was prepared according to the procedure reported in WO2009084614A1.

[0568] To a solution of compound D1 (100 g, 0.61 mol, 1.0 equiv.) in THF (1 L) was added 2,2,2-trifluoroethanamine (362 g, 3.7 mol, 6.0 equiv.). The mixture was stirred at 15-25 °C for 3-4 h, then DIEA (315 g, 2.4 mol, 4.0 equiv.) and compound B2 (194 g, 0.67 mol, 1.1 equiv.) were added. The reaction was stirred at 30-35 °C for 40-50 h, then 2,2,2-trifluoroethanamine (122 g, 1.22 mol, 2.0 equiv.) was added. The resulting mixture was stirred at 30-35 °C until the reaction was complete, as determined by HPLC. MTBE (500 g) and water (700 g) were then added at 20-25 °C. The pH of the reaction mixture was adjusted to 5-7 with 35% aqueous HCl (170 g), then stirred and separated. The resulting aqueous phase was extracted again with MTBE (500 g). The resulting organic layers were combined, washed with water (500 g), concentrated, and switched to toluene (100 mL) by distillation. The resulting mixture was heated and stirred at 40-45 °C for 1 h, then slowly cooled to 10-15 °C. MCH (365 g) was slowly added, followed by slow cooling to 0-5 °C. MCH (365 g) was slowly added at 0-5 °C, followed by stirring for 6-14 h. The mixture was filtered. The cake was washed with MCH (150 mL). The cake was dried under vacuum at 45-55 °C to give solid A. The assay yield was 85%. The structure was checked by LCMS. LCMS: (M+H) = 367.2.

[0569] Step 6-2: General procedure for the preparation of 5'-(4-fluorophenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxylic acid (compound E2)

[0570] [ka]

[0571] To a mixture of compound E1 (100 g, 0.27 mol, 1.0 equiv.) in MeOH (600 mL) was added 9.56% aqueous NaOH (697 g, 1.67 mol, 6.1 equiv.). The mixture was heated and stirred at 50-55 °C until complete conversion was achieved, as determined by HPLC. Water (500 mL) was added, and the mixture was adjusted to pH 4-5 using 35% aqueous HCl. The mixture was stirred at 15-25 °C for 2-4 h and filtered. The filter cake was washed twice with water (200 mL) and then dried under vacuum at 40-50 °C for 12-18 h to give solid compound E2. The assay yield was 90%. The structure was checked by LCMS. LCMS: (M+H) = 355.2.

[0572] Step 6-3: General procedure for the preparation of 5'-(4-fluorophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-3'-(2,2,2-trifluoroethyl)-1H,3'H-[2,4'-biimidazole]-4-carboxamide (compound 120)

[0573] [ka]

[0574] A suspension of compound E2 (100 g, 0.28 mol, 1.0 equiv.) in THF (850 mL) was double-distilled to reduce the water content. To a suspension of compound E2 in THF (1 L), EtN (114 g, 1.13 mol, 4.0 equiv.) and compound A13 (80.9 g, 0.42 mol, 1.5 equiv.) were added. The mixture was stirred at 15-25 °C for 30-60 min and then cooled to -5-5 °C. Compound A13 (72.8 g, 0.38 mol, 1.35 equiv.) was added, followed by the dropwise addition of 50% T3P EA solution (121 g, 0.38 mol, 1.35 equiv.) at -5-5 °C. The mixture was stirred at -5-5 °C until complete conversion. EA (630 mL), 5% aqueous NaSO (354 g), and water (320 g) were added, then stirred and separated. The aqueous phase was extracted with EA (250 mL) and THF (450 mL). The organic phases were combined and then washed with 7% NaHCO (700 g * 2) and water (475 g * 2). The washed aqueous phases were combined and extracted with EA (70 g * 2). The organic phases were combined and decolorized by passing through CUNO (15 g of activated cake). THF (450 g) was washed with CUNO (0.15 g of activated cake) and combined with the EA / THF solution of compound 120. The EA / THF solution of compound 120 was concentrated and switched to EtOH (700 mL), followed by dropwise addition of water (1050 mL) at 15-25 °C. The mixture was stirred at 15-25°C for 2-4 hours, then filtered and washed with water (200 g). The cake was dried at 30-60°C for 10-18 hours under vacuum at 20-50% RH. The assay yield was 75%. The structure was checked by LCMS. LCMS: (M+H) = 528.2.

[0575] As mentioned above, the procedures in Examples 2-6 have short synthetic routes, relatively high yields, and can be easily scaled up. Furthermore, the Sn reagent required for the Stille coupling to form the biimidazole core is not required in the procedures in Examples 2-6. Furthermore, it is easy to perform quality control on the procedures of Examples 2-6.

[0576] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are within the spirit and purpose of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A method for producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, comprising: 【Chemical 1】 During the ceremony, R １ but below: N (R ５ ) ２ and each R ５ represents hydrogen and optionally substituted C １ -C ６ alkyl, wherein C １ -C ６ Alkyl is a halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ N(R ５ ) ２ , Substitution C １ -C ６ alkyl, wherein the C １ -C ６ Alkyl is halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, —O—C １－６ Alkyl-O—C(O)(O—C １－１０ alkyl), C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ substituted C optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; １ -C ６ alkyl, and An optionally substituted 3- to 8-membered heterocyclic ring, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -S(O ２ ) NH ２ , -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ The alkyl is hydroxy, halogen, oxo, -C １－１０ Haloalkyl, —NH ２ , -CN, and -NO ２ an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from R ３ is optionally substituted C １ -C ６ alkyl, optionally substituted 3- to 10-membered heterocycle, and optionally substituted C ３－１０ carbocycle, wherein each of said alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １－６ Alkyl, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R ４ but below: hydrogen, Optionally substituted C １ -C ６ alkyl, wherein the C １ -C ６ Alkyl is halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, ═S, —O—C １－１０ Alkyl, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. １ -C ６ alkyl, and Optionally substituted C ３－１０ A carbocyclic ring, ３－１０ The carbocyclic ring is a halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １－１０ Alkyl, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. ３－１０ selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -S(O ２ ) NH ２ , -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (A), or a pharmaceutically acceptable salt thereof, with 【Chemistry 2】 In the formula, rings W, R ３ , and R ４ is defined above, R Ａ１ , R Ａ２ , and R Ａ３ are each a halogen and —O—C １－６ independently selected from alkyl, subjecting the compound to a hydrolysis step to produce a compound represented by formula (B) or a pharmaceutically acceptable salt thereof; 【Chemistry 3】 In the formula, rings W, R ３ , and R ４ is defined above, method.

2. R Ａ１ , R Ａ２ , and R Ａ３ each of which is selected from halogen and —O—C １－３ 10. The method of claim 1, wherein the alkyl is independently selected from alkyl.

3. R Ａ１ , R Ａ２ , and R Ａ３ 10. The method of claim 1, wherein each of is independently selected from halogen.

4. R Ａ１ , R Ａ２ , and R Ａ３ Each of the groups is —O—C １－６ 10. The method of claim 1, wherein the alkyl is independently selected from alkyl.

5. R Ａ１ , R Ａ２ , and R Ａ３ 2. The method of claim 1 , wherein each of is independently selected from F, Cl, Br, OMe, and OEt. 【Request 6】 【Chemical 4】 But CBr ３ , CCl ３ , C.F. ３ , C.F. ２ Cl, CFCl ２ , C.F. ２ Br, CFBr ２ , C(OMe) ３ , or C(OEt) ３ The method of claim 1, wherein 【Request 7】 【Chemical 5】 is CF ３ The method of claim 1, wherein

8. 8. The method of any one of claims 1 to 7, wherein the hydrolysis step is carried out in a solvent selected from ethers, alcohols, water, and mixtures thereof (e.g., MeOH / water).

9. 9. The method of claim 8, wherein the hydrolysis step is carried out in a solvent selected from 1,4-dioxane, MeOH, EtOH, i-PrOH, n-PrOH, THF, water, or a mixture thereof.

10. 9. The method of claim 8, wherein the hydrolysis step is carried out in a mixture of methanol and water.

11. The method according to any one of claims 1 to 10, wherein the hydrolysis step is carried out under alkaline conditions.

12. 12. The method of any one of claims 1 to 11, wherein the hydrolysis step is carried out in the presence of a base, wherein the base is an alkali, an alkali salt, or a mixture thereof.

13. 13. The method of claim 12, wherein the alkali salt is a carbonate, bicarbonate, or phosphate (e.g., phosphate, hydrogen phosphate, and dihydrogen phosphate).

14. The base is NaOH, KOH, LiOH, Ca(OH) ２ , K. ２ CO ３ , KHCO ３ , Na ２ CO ３ , NaHCO ３ , K. ３ P.O. ４ , K. ２ HPO ４ , K.H. ２ P.O. ４ , Na ３ P.O. ４ , Na ２ HPO ４ , NaH ２ P.O. ４ 13. The method of claim 12, wherein the compound is selected from the group consisting of:

15. 13. The method of claim 12, wherein the base is NaOH.

16. further comprising subjecting the compound represented by formula (B) or a pharmaceutically acceptable salt thereof to a condensation reaction with a compound of formula (C) or a pharmaceutically acceptable salt thereof; 【Chemistry 6】 In the formula, R １ The method according to any one of claims 1 to 15, wherein is as defined above in formula (I).

17. 17. The method of claim 16, wherein the condensation step is carried out in the presence of a base (e.g., DIEA), a coupling agent (HATU), or both.

18. The condensation step is carried out using a condensation reagent (e.g., T ３ 17. The method of claim 16, wherein the method is carried out in the presence of: P, HATU, EDCI, PyBOP, HBTU, DPPA, CDI).

19. The compound represented by formula (I) has the structure of formula (Ia): 【Chemistry 7】 During the ceremony, R １ is piperazine, and said piperazine is oxo and C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ Alkyl includes hydroxy, halogen, oxo, and -NH ２ optionally substituted with one or more substituents independently selected at each occurrence from R ３ is phenyl, said phenyl being optionally substituted with one or more halogens; R ４ is a substitution C １ -C ６ alkyl, １ -C ６ The method of any one of claims 1 to 18, wherein the alkyl is substituted with one or more halogens.

20. The compound represented by formula (I) has the structure of formula (Ia): 【Chemistry 8】 During the ceremony, R １ is piperazine, and the piperazine is oxo, —S(O ２ ) NH ２ , and C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ Alkyl includes hydroxy, halogen, oxo, and -NH ２ optionally substituted with one or more substituents independently selected at each occurrence from R ３ is phenyl, said phenyl being optionally substituted with one or more halogens; R ４ is unsubstituted C １ -C ６ The method of any one of claims 1 to 18, wherein the alkyl is alkyl.

21. A method for producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 9】 During the ceremony, R １ but below: N (R ５ ) ２ and each R ５ represents hydrogen and optionally substituted C １ -C ６ alkyl, wherein C １ -C ６ Alkyl is a halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ N(R ５ ) ２ , Substitution C １ -C ６ alkyl, wherein the C １ -C ６ Alkyl is halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, —O—C １－６ Alkyl-O—C(O)(O—C １－１０ alkyl), C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ substituted C optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; １ -C ６ alkyl, and An optionally substituted 3- to 8-membered heterocyclic ring, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -S(O ２ ) NH ２ , -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ The alkyl is hydroxy, halogen, oxo, -C １－１０ Haloalkyl, —NH ２ , -CN, and -NO ２ an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from R ３ is optionally substituted C １ -C ６ alkyl, optionally substituted 3- to 10-membered heterocycle, and optionally substituted C ３－１０ carbocycle, wherein each of said alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １－６ Alkyl, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R ４ but below: hydrogen, Optionally substituted C １ -C ６ alkyl, wherein the C １ -C ６ Alkyl is halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, ═S, —O—C １－１０ Alkyl, —C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. １ -C ６ alkyl, and Optionally substituted C ３－１０ A carbocyclic ring, ３－１０ The carbocyclic ring is a halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １－１０ Alkyl, —C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. ３－１０ selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -S(O ２ ) NH ２ , -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises combining a compound represented by formula (E), or a pharmaceutically acceptable salt thereof, 【Chemistry 10】 During the ceremony, Ring W is defined above, En is 0 or 1, R ＥＮ is a protecting group, R Ｅ１ is C １ -C ６ Alkyl (e.g., ethyl), C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; a compound represented by formula (F), or a pharmaceutically acceptable salt thereof, 【Chemistry 11】 In the formula, R ３ is defined above, R Ｆ is a substituted or unsubstituted phenyl; reacting in the presence of a compound of formula (K) or a pharmaceutically acceptable salt thereof, R ４ -NH ２ (K)、 thereby producing a compound represented by formula (G), or a pharmaceutically acceptable salt thereof: 【Chemistry 12】 In the formula, R ３ , R ４ , Ring W, En, R ＥＮ , and R Ｅ１ is defined above, method.

22. R Ｅ１ 22. The method of claim 21, wherein is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl.

23. R Ｅ１ 22. The method of claim 21 , wherein is ethyl.

24. R Ｅ１ 22. The method of claim 21, wherein is phenyl, benzyl, or p-methoxybenzyl.

25. The method according to any one of claims 21 to 24, wherein En is 0.

26. The method according to any one of claims 21 to 24, wherein En is 1.

27. The compound of formula (E) has a structure of formula (E-1): 【Chemistry 13】 In the formula, R ＥＮ’ is hydrogen or R ＥＮ The method according to any one of claims 21 to 24, wherein

28. The compound of formula (E-1) 【Chemistry 14】 28. The method of claim 27 having the structure:

29. R ＥＮ is selected from (trimethylsilicon)ethoxymethyl (SEM), methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl (CBz), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), para-toluenesulfonyl (Tos), 2,2,2-trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (Pmb), and benzyl (Bn).

30. R ＥＮ The method of claim 29, wherein is SEM.

31. R Ｆ is one or more R Ｆ１ and each R Ｆ１ is halogen, -NH ２ , C.N., N.O. ２ , -OH, -SH, SF ５ , C １ -C ６ Alkyl, —OC １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —OC １ -C ６ Alkyl, —S(═O)C １ -C ６ Alkyl, —S(═O) ２ C １ -C ６ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ -C ６ Alkyl, —S(═O) ２ N (C １ -C ６ alkyl) ２ , -NH ２ , -NHC １ -C ６ Alkyl, —N(C １ -C ６ alkyl) ２ , -NHC(=O)OC １ -C ６ Alkyl, —C(═O)C １ -C ６ Alkyl, —C(═O)OH, —C(═O)OC １ -C ６ Alkyl, —C(═O)NH ２ , -C(=O)N(C １ -C ６ alkyl) ２ , -C(=O)NHC １ -C ６ Alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, and C １ -C ６ 31. The method of any one of claims 21 to 30, wherein the alkyl is independently selected from the group consisting of: heteroalkyl;

32. R Ｆ is one or more R Ｆ１ and each R Ｆ１ 32. The method of claim 31 , wherein is independently selected from F, Cl, Br, methyl, and methyloxy.

33. The compound of formula (F) has the structure of the formula: 【Chemistry 15】 33. The method of claim 31 or 32, wherein Fn is 0, 1, 2, 3, 4, or 5.

34. The compound of formula (F) 【Chemistry 16】 32. The method of claim 31 , wherein:

35. The compound represented by formula (G) has a structure of formula (G-1): 【Chemistry 17】 In the formula, R ＥＮ’ is hydrogen or R ＥＮ The method according to any one of claims 21 to 34, wherein

36. The compound represented by formula (G-1) 【Chemistry 18】 36. The method of claim 35, having the structure:

37. and further comprising subjecting the compound represented by formula (G) or a pharmaceutically acceptable salt thereof to a hydrolysis reaction, thereby producing a compound of formula (H) or a pharmaceutically acceptable salt thereof; 【Chemistry 19】 In the formula, R ３ , R ４ , rings W, En, and R ＥＮ A method according to any one of claims 21 to 36, wherein is defined above.

38. The compound represented by formula (H) has a structure of formula (H-1) 【Chemistry 20】 38. The method of claim 37, comprising:

39. The compound represented by formula (H-1) 【Chemical 21】 39. The method of claim 38 having the structure:

40. further comprising subjecting the compound represented by formula (H) or a pharmaceutically acceptable salt thereof to a condensation reaction with a compound of formula (C) or a pharmaceutically acceptable salt thereof; 【Chemical 22】 In the formula, R １ The method according to any one of claims 21 to 39, wherein is as defined above in formula (Ia).

41. The method of any one of claims 21 to 23 or 26 to 40, wherein the method further comprises a deprotection reaction.

42. The deprotection reaction is carried out by ＥＮ 42. The method of claim 41 , comprising replacing with hydrogen.

43. 43. The method of claim 41 or 42, wherein the deprotection reaction occurs after the condensation reaction.

44. The compound represented by formula (I) has the structure of formula (Ia): 【Chemical 23】 During the ceremony, R １ is piperazine, and said piperazine is oxo and C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ Alkyl includes hydroxy, halogen, oxo, and -NH ２ optionally substituted with one or more substituents independently selected at each occurrence from R ３ is phenyl, said phenyl being optionally substituted with one or more halogens; R ４ is a substitution C １ -C ６ alkyl, １ -C ６ The method of any one of claims 21 to 43, wherein the alkyl is substituted with one or more halogens.

45. The compound represented by formula (I) has the structure of formula (Ia): 【Chemistry 24】 During the ceremony, R １ is piperazine, and the piperazine is oxo, —S(O ２ ) NH ２ , and C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ Alkyl includes hydroxy, halogen, oxo, and -NH ２ optionally substituted with one or more substituents independently selected at each occurrence from R ３ is phenyl, said phenyl being optionally substituted with one or more halogens; R ４ is unsubstituted C １ -C ６ The method of any one of claims 21 to 43, wherein the alkyl is alkyl.

46. A method for producing a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 25】 During the ceremony, R １ but below: N (R ５ ) ２ and each R ５ represents hydrogen and optionally substituted C １ -C ６ alkyl, wherein C １ -C ６ Alkyl is a halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ N(R ５ ) ２ , Substitution C １ -C ６ alkyl, wherein the C １ -C ６ Alkyl is halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, —O—C １－６ Alkyl-O—C(O)(O—C １－１０ alkyl), C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ substituted C optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; １ -C ６ alkyl, and An optionally substituted 3- to 8-membered heterocyclic ring, wherein the 3- to 8-membered heterocyclic ring is selected from the group consisting of halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -S(O ２ ) NH ２ , -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Carbocycles, 3- to 12-membered heterocycles, and optionally substituted C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ The alkyl is hydroxy, halogen, oxo, -C １－１０ Haloalkyl, —NH ２ , -CN, and -NO ２ an optionally substituted 3- to 8-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from R ３ is optionally substituted C １ -C ６ alkyl, optionally substituted 3- to 10-membered heterocycle, and optionally substituted C ３－１０ carbocycle, wherein each of said alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １－６ Alkyl, —C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R ４ but below: hydrogen, Optionally substituted C １ -C ６ alkyl, wherein the C １ -C ６ Alkyl is halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, ═S, —O—C １－１０ Alkyl, —C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. １ -C ６ alkyl, and Optionally substituted C ３－１０ A carbocyclic ring, ３－１０ The carbocyclic ring is a halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １－１０ Alkyl, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. ３－１０ selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -S(O ２ ) NH ２ , -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; The method comprises reacting a compound represented by formula (E), or a pharmaceutically acceptable salt thereof, with ​ During the ceremony, The ring W is defined above, En is 0, R ＥＮ is a protecting group, R Ｅ１ is C １ -C ６ Alkyl (e.g., ethyl), C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; reacting a compound represented by formula (F), or a pharmaceutically acceptable salt thereof, 【Chemical 27】 In the formula, R ３ is defined above, R Ｆ is a substituted or unsubstituted phenyl; thereby producing a compound of formula (Ga), or a pharmaceutically acceptable salt thereof; 【Chemical Formula 28】 In the formula, R ３ , Ring W, En, R ＥＮ , and R Ｅ１ is defined above, the method comprising reacting the compound of formula (Ga) or a pharmaceutically acceptable salt thereof with a compound of formula (J) or a pharmaceutically acceptable salt thereof; R ４ -R Ｊ (J) In the formula, R Ｊ is a leaving group, thereby producing a compound represented by formula (G), or a pharmaceutically acceptable salt thereof; 【Chemical 29】 In the formula, R ３ , R ４ , R ＥＮ , and R Ｅ１ is defined above, method.

47. The compound of formula (E) 【Chemistry 30】 47. The method of claim 46, having the structure:

48. The compound of formula (Ga) 【Chemical 31】 48. The method of claim 46 or 47, having the structure:

49. The compound of formula (G) 【Chemical 32】 47. The method of claim 46, having the structure:

50. R Ｊ The method of any one of claims 46 to 49, wherein is a halogen (e.g., Br, Cl, I).

51. R Ｊ is an alkyl sulfonate (e.g., trifluoromethanesulfonate (triflate or TfO － 50. The method of any one of claims 46 to 49, wherein the aryl group is a methyl group, a methyl group, or an aryl sulfonate (e.g., 4-methylbenzenesulfonate).

52. The method of any one of claims 46 to 51, wherein the method further comprises a deprotection reaction.

53. 53. The method of claim 52, wherein the deprotection reaction occurs prior to the reaction of the compound represented by formula (E) with the compound represented by formula (F).

54. 54. The method of claim 53, wherein the compound represented by formula (E) is deprotected.

55. and further comprising subjecting the compound represented by formula (G) or a pharmaceutically acceptable salt thereof to a hydrolysis reaction, thereby producing a compound of formula (H) or a pharmaceutically acceptable salt thereof; 【Chemical 33】 In the formula, R ３ , R ４ , En, and R ＥＮ A method according to any one of claims 46 to 54, wherein is defined above.

56. wherein said compound of formula (H) 【Chemical 34】 56. The method of claim 55, having the structure:

57. further comprising subjecting the compound represented by formula (H) or a pharmaceutically acceptable salt thereof to a condensation reaction with a compound of formula (C) or a pharmaceutically acceptable salt thereof; 【Chemistry 35】 In the formula, R １ 57. The method of claim 55 or 56, wherein is defined above in formula (Ia).

58. The compound represented by formula (I) has the structure of formula (Ia): 【Chemical Formula 36】 During the ceremony, R １ is piperazine, and said piperazine is oxo and C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ Alkyl includes hydroxy, halogen, oxo, and -NH ２ optionally substituted with one or more substituents independently selected at each occurrence from R ３ is phenyl, said phenyl being optionally substituted with one or more halogens; R ４ is a substitution C １ -C ６ alkyl, １ -C ６ 58. The method of any one of claims 46 to 57, wherein the alkyl is substituted with one or more halogens.

59. The compound represented by formula (I) has the structure of formula (Ia): 【Chemical 37】 During the ceremony, R １ is piperazine, and the piperazine is oxo, —S(O ２ ) NH ２ , and C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ Alkyl includes hydroxy, halogen, oxo, and -NH ２ optionally substituted with one or more substituents independently selected at each occurrence from R ３ is phenyl, said phenyl being optionally substituted with one or more halogens; R ４ is unsubstituted C １ -C ６ 58. The method of any one of claims 46 to 57, wherein the alkyl is alkyl.

60. A method for producing a compound represented by formula (Ia), or a pharmaceutically acceptable salt thereof, comprising: 【Chemical Formula 38】 During the ceremony, R １ is piperazine, and the piperazine is oxo, —S(O ２ ) NH ２ , and C １－１０ and optionally substituted with one or more substituents independently selected at each occurrence from alkyl, １－１０ Alkyl includes hydroxy, halogen, oxo, and -NH ２ optionally substituted with one or more substituents independently selected at each occurrence from R ３ is phenyl, said phenyl being optionally substituted with one or more halogens; R ４ is unsubstituted C １ -C ６ is alkyl, The method comprises reacting a compound represented by formula (E-1), or a pharmaceutically acceptable salt thereof, 【Chemical Formula 39】 During the ceremony, R ＥＮ’ is hydrogen or R ＥＮ and R ＥＮ is a protecting group, R Ｅ１ is C １ -C ６ Alkyl (e.g., ethyl), C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; reacting a compound represented by formula (F), or a pharmaceutically acceptable salt thereof, 【Chemistry 40】 In the formula, R ３ is defined above, R Ｆ is a substituted or unsubstituted phenyl; thereby producing a compound of formula (G-1a) or a pharmaceutically acceptable salt thereof, 【Chemistry 41】 In the formula, R ３ , R ＥＮ’ , and R Ｅ１ is defined above, the method comprising reacting the compound of formula (G-1a) or a pharmaceutically acceptable salt thereof with a compound of formula (J) or a pharmaceutically acceptable salt thereof; R ４ -R Ｊ (J) In the formula, R Ｊ is a leaving group, thereby producing a compound represented by formula (G-1) or a pharmaceutically acceptable salt thereof, 【Chemistry 42】 In the formula, R ３ , R ４ , R ＥＮ’ , and R Ｅ１ is defined above, method.

61. The method further comprises subjecting the compound represented by formula (G-1) or a pharmaceutically acceptable salt thereof to a hydrolysis reaction, thereby producing a compound of formula (H-1) or a pharmaceutically acceptable salt thereof; 【Chemistry 43】 In the formula, R ３ , R ４ , and R ＥＮ’ 61. The method of claim 60, wherein is defined above.

62. The method further comprises subjecting the compound represented by formula (H-1) or a pharmaceutically acceptable salt thereof to a condensation reaction with a compound of formula (C) or a pharmaceutically acceptable salt thereof, 【Chemical 44】 In the formula, R １ 62. The method of claim 61 , wherein:

63. R ＥＮ’ The method of any one of claims 60 to 62, wherein is hydrogen.

64. R ＥＮ’ But, R ＥＮ The method according to any one of claims 60 to 62, wherein

65. R ＥＮ’ is selected from (trimethylsilicon)ethoxymethyl (SEM), methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl (CBz), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), para-toluenesulfonyl (Tos), 2,2,2-trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (Pmb), and benzyl (Bn).

66. R ＥＮ’ The method of claim 64, wherein is SEM.

67. The method of any one of claims 60 to 65, wherein the method further comprises a deprotection reaction.

68. The deprotection reaction occurs after the condensation reaction, and the deprotection reaction is ＥＮ 68. The method of claim 67, comprising replacing with hydrogen.

69. 68. The method of claim 67, wherein the deprotection reaction occurs before the reaction of the compound represented by formula (E-1) with the compound represented by formula (F).

70. 70. The method of claim 69, wherein the compound represented by formula (E-1) is deprotected.

71. The compound of formula (C), or a pharmaceutically acceptable salt thereof, 【Chemistry 45】 63. The method of any one of claims 16, 40, 57, or 62, having the structure:

72. A compound represented by formula (A), or a pharmaceutically acceptable salt thereof: 【Chemistry 46】 During the ceremony, R ３ is optionally substituted C １ -C ６ alkyl, optionally substituted 3- to 10-membered heterocycle, and optionally substituted C ３－１０ carbocycle, wherein each of said alkyl, heterocycle, and carbocycle is selected from halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １－６ Alkyl, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R ４ but below: hydrogen, Optionally substituted C １ -C ６ alkyl, wherein the C １ -C ６ Alkyl is halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, ═S, —O—C １－１０ Alkyl, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. １ -C ６ alkyl, and Optionally substituted C ３－１０ A carbocyclic ring, ３－１０ The carbocyclic ring is a halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, = S, C １－１０ Alkyl, -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ Optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle. ３－１０ selected from carbocycles, Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, —OH, —CN, —NO ２ , -NH ２ , oxo, =S, -S(O ２ ) NH ２ , -C １－１０ Haloalkyl, —O—C １－１０ Alkyl, C ２－１０ Alkenyl, C ２－１０ Alkynyl, C ３－１２ optionally substituted with one or more substituents independently selected at each occurrence from carbocycle, and 3- to 12-membered heterocycle; R Ａ１ , R Ａ２ , and R Ａ３ Each of the groups is selected from halogen and —O—C １－６ A compound represented by formula (A), or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from alkyl;

73. The compound is 【Chemistry 47】 73. The compound of claim 72 having the structure:

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