Methods of making kinase inhibitors

Abstract

In one aspect, the disclosure provides methods of synthesizing TNIK and / or MAP4K4 kinase inhibitors to treat disease. In one aspect, the disclosure provides intermediates for use in the synthetic processes described herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This international patent application claims the benefit of international application No. PCT / CN2022 / 114447 filed on August 24, 2022, the entire text of which is incorporated herein by reference. Background Art

[0003] The biologically active enzyme known as Traf2- and Nck-interacting protein kinase is an enzyme commonly referred to as TNIK in humans and is encoded by the TNIK gene. As a serine / threonine kinase, TNIK is involved in various biological processes. New drug candidates that can target TNIK are needed. Summary of the invention

[0004] In one aspect, methods for preparing kinase inhibitors (e.g., TNIK inhibitors) and intermediates used in the methods are described herein. TNIK is a serine / threonine kinase that participates 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. In addition, TNIK can act as an activator of Wnt target gene expression, and regulates the actin cytoskeleton and activates 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 the extension and arbonization of neuronal dendrites during development. More generally, TNIK can play a role in cytoskeletal rearrangement and regulate cell proliferation. TNIK also causes weak Smad1 T322 phosphorylation, participating in TGF-b1 signaling transduction transduction.

[0005] TNIK is considered a germinal center kinase (GCK) and can be characterized by an N-terminal kinase domain and a C-terminal GCK domain that exerts a regulatory function.

[0006] TNIK activation of Wnt signaling can play an important role in carcinogenesis and embryonic development. Mutations in this gene are associated with an autosomal recessive form of cognitive impairment.

[0007] Additionally, TNIK has been implicated in cancer, including, for example, colorectal cancer, and has therefore been identified as an attractive drug candidate for targeting certain cancers.

[0008] The current data may implicate TNIK as 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 forms of cognitive impairment.

[0009] Additionally, therapeutic targets associated with EMT, such as TNIK as a target for inhibition, may be used in therapies to treat and / or prevent EMT-based disorders such as cancer metastasis and fibrosis.

[0010] Therefore, it would be advantageous to have a TNIK inhibitor that could inhibit the kinase activity of TNIK, which is a member of the Ste20 family of MAP kinase kinases (MAP4Ks).

[0011] In one aspect, provided herein is a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0012]

[0013] in:

[0014] R 1 Selected from:

[0015] N(R 5 )2, where each R 5 independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0016] Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -O-C1-6 alkyl-OC(O)(OC 1-10 Alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0017] An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C2-10 Alkynyl, C 3-12 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0018] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0019] R 4 Selected from:

[0020] hydrogen;

[0021] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0022] Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0023] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings,

[0024] The method comprises making a compound represented by formula (A) or a pharmaceutically acceptable salt thereof

[0025]

[0026] Among them, ring W, R 3 and R 4 defined above, and

[0027] R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-6 alkyl;

[0028] subjected to a hydrolysis step to produce a compound represented by formula (B) or a pharmaceutically acceptable salt thereof,

[0029]

[0030] Among them, ring W, R 3 and R 4 Defined above.

[0031] In one aspect, provided herein is a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0032]

[0033] in:

[0034] R 1 Selected from:

[0035] N(R 5 )2, where each R 5 independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0036] Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0037] An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0038] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0039] R 4 Selected from:

[0040] hydrogen;

[0041] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0042] Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic rings and 3 to 12 membered heterocyclic rings; and

[0043] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings,

[0044] The method comprises making a compound represented by formula (E) or a pharmaceutically acceptable salt thereof

[0045]

[0046] in,

[0047] Ring W is defined above,

[0048] En is 0 or 1,

[0049] R EN is a protecting group, and

[0050] RE1 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;

[0051] and a compound represented by formula (F) or a pharmaceutically acceptable salt thereof

[0052]

[0053] Where R 3 As defined above, and R F is a substituted or unsubstituted phenyl group,

[0054] reacting in the presence of a compound of formula (K) or a pharmaceutically acceptable salt thereof,

[0055] R 4 -NH2 (K),

[0056] Thus producing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof,

[0057]

[0058] Where R 3 , R 4 、Ring W、En、R EN and R E1 Defined above.

[0059] In one aspect, provided herein is a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0060]

[0061] in:

[0062] R 1 Selected from:

[0063] N(R 5 )2, where each R 5 independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0064] Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -O-C1-6 alkyl-OC(O)(OC 1-10 Alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0065] An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0066] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic rings and 3 to 12 membered heterocyclic rings; and

[0067] R 4 Selected from:

[0068] hydrogen;

[0069] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0070] Optionally substituted C 3-10 A carbon ring wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0071] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings,

[0072] The method comprises making a compound represented by formula (E) or a pharmaceutically acceptable salt thereof

[0073]

[0074] in,

[0075] Ring W is defined above,

[0076] En is 0,

[0077] R EN is a protecting group, and

[0078] RE1 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;

[0079] reacting with a compound represented by formula (F) or a pharmaceutically acceptable salt thereof,

[0080]

[0081] Where R 3 defined above, and

[0082] R F is a substituted or unsubstituted phenyl group,

[0083] Thereby producing a compound of formula (Ga) or a pharmaceutically acceptable salt thereof,

[0084]

[0085] Where R 3 、Ring W、En、R EN and R E1 As defined above, and wherein the method 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,

[0086] R 4 -R J (J)

[0087] Where R J is a leaving group, and R 4 As defined above, thereby producing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof,

[0088]

[0089] Where R 3 , R 4 , R EN , En and R E1 Defined above.

[0090] In one aspect, provided herein is a method for preparing a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof,

[0091]

[0092] in:

[0093] R 1is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0094] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0095] R 4 is an unsubstituted C1-C6 alkyl group;

[0096] The method comprises making a compound represented by formula (E-1) or a pharmaceutically acceptable salt thereof

[0097]

[0098] in,

[0099] R EN' is hydrogen or R EN , and where R EN is a protecting group;

[0100] 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;

[0101] reacting with a compound represented by formula (F) or a pharmaceutically acceptable salt thereof,

[0102]

[0103] Where R 3 defined above, and

[0104] R F is a substituted or unsubstituted phenyl group,

[0105] Thereby producing a compound of formula (G-1a) or a pharmaceutically acceptable salt thereof,

[0106]

[0107] Where R 3 , R EN ' and R E1 In the above definition,

[0108] And wherein the method further comprises 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,

[0109] R 4 -R J (J)

[0110] Where R J is the leaving group,

[0111] Thus, a compound represented by formula (G-1) or a pharmaceutically acceptable salt thereof is produced,

[0112]

[0113] Where R 3 , R 4 , R EN ' and R E1 Defined above.

[0114] In one aspect, provided herein is a compound represented by formula (A) or a pharmaceutically acceptable salt thereof,

[0115]

[0116] in

[0117] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0118] R 4 Selected from:

[0119] hydrogen;

[0120] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0121] Optionally substituted C 3-10 A carbon ring wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0122] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 210 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0123] R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-6 alkyl.

[0124] In certain embodiments, the present disclosure provides a method for synthesizing a compound represented by formula (I):

[0125]

[0126] or a pharmaceutically acceptable salt thereof, wherein:

[0127] R 1 Selected from:

[0128] -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the optional substituents on C1-C6 alkyl are independently selected at each occurrence from one or more halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0129] Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -O-C1-6 alkyl-OC(O)(OC 1-10 Alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0130] An optionally substituted 3 to 8 membered heterocycle; wherein the optional substituents on the 3 to 8 membered heterocycle are independently selected at each occurrence from one or more 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0131] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocyclic ring, wherein the optional substituents on each occurrence are independently selected from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0132] R 4 Selected from:

[0133] hydrogen;

[0134] Optionally substituted C1-C6 alkyl, wherein the optional substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0135] Optionally substituted C 3-10 Carbon ring, where C 3-10 The optional substituents on the carbocyclic ring are independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring; and

[0136] W is selected from optionally substituted 5- to 6-membered heteroaryl, wherein the substituents on the optionally substituted 5- to 8-membered heteroaryl are independently selected at each occurrence from 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 Carbocyclic ring, 3- to 12-membered heterocyclic ring.

[0137] In some aspects, 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 method described herein (e.g., a compound of formula (Ia) or formula (I) or a salt thereof) and a pharmaceutically acceptable excipient. In some aspects, the disease is cancer. In some cases, the cancer is selected from colorectal cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, chronic myeloid leukemia, cancer metastasis, fibrosis and mental disorder. In some cases, the pharmaceutical composition can be used in combination with chemotherapy or immune checkpoint inhibitor therapy for cancer as a tumor immunosuppression inhibitor. In some cases, the pharmaceutical composition can be used to treat fibrotic diseases or conditions, including but not limited to chronic renal fibrosis ("CKD"), cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, skin fibrosis, systemic sclerosis ("SSc") and graft-versus-host disease ("GVHD"). In some cases, 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 a disease associated with TNIK kinase.

[0138] In some aspects, the present disclosure provides a method of 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.

[0139] In some aspects, the present disclosure provides a method of inhibiting MAP4K4 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.

[0140] Other aspects and advantages of the present disclosure will become apparent to those skilled in the art from the following detailed description, in which only illustrative embodiments of the present disclosure are shown and described. As will be appreciated, the present disclosure is capable of other and different embodiments, and its several details can be modified in various obvious aspects, all without departing from the present disclosure. Therefore, the drawings and descriptions are to be regarded as illustrative in nature, rather than restrictive.

[0141] Incorporated by Reference

[0142] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If the publications and patents or patent applications incorporated by reference conflict with the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such conflicting material. DETAILED DESCRIPTION

[0143] Although 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 only as examples. Without departing from the present disclosure, those skilled in the art may conceive of many variations, changes and substitutions. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed.

[0144] A. Definition

[0145] Unless defined otherwise, 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.

[0146] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C 15 In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (i.e., C1-C 13 In certain embodiments, the alkyl group comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (i.e., C5-C 15In some embodiments, the 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), 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group can be optionally substituted by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0147] When used in conjunction with a chemical moiety such as alkyl, alkenyl or alkynyl, the term "C x-y " is intended to include groups containing from x to y carbons in the chain. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group which may 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.

[0148] "Alkoxy" refers to a group bonded by the oxygen atom of the formula -O-alkyl, wherein the alkyl is an alkyl chain as defined above. Unless otherwise specifically stated in the specification, the alkoxy may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted by halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH or -NO. In some embodiments, the alkoxy is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkoxy is optionally substituted by halogen.

[0149] "Alkenyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C 12In some embodiments, alkenyl includes two to eight carbon atoms (i.e., C2-C8 alkenyl). In some embodiments, alkenyl includes two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, alkenyl includes two to four carbon atoms (i.e., C2-C4 alkenyl). Alkenyl is connected to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, alkenyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0150] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C 12 Alkynyl). In certain embodiments, alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). Alkynyl is connected to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in the specification, alkynyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, alkynyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0151] The term "C x-y "Alkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group similar in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively. The term -C x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain having from x to y carbons in the alkenylene chain. For example, -C 2-6Alkenylene- may be selected from vinylene, propenylene, butenylene, pentenylene and hexenylene, any of which is optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. x-y Alkyne- refers to a substituted or unsubstituted alkynylene chain having from x to y carbons in the alkenylene chain. For example, -C 2-6 Alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene and hexynylene, any of which is optionally substituted. The alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0152] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group consisting only of carbon and hydrogen, which does not contain unsaturation, and preferably has one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. The connection point of the alkylene chain to the rest of the molecule and the group can be through any two carbons in the chain. In certain embodiments, the alkylene comprises one to ten carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, the alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (i.e., C3-C5 alkylene). The term -C x-y Alkylene- refers to a group having from x to y A substituted or unsubstituted alkylene chain having 1 carbon atom. For example, -C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene and hexylene, any of which is optionally substituted.

[0153] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group consisting only of carbon and hydrogen, contains at least one carbon-carbon double bond, and preferably has two to twelve carbon atoms. The alkenylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. The point of attachment of the alkenylene chain to the rest of the molecule and to the group can be through any two carbons in the chain. In certain embodiments, the alkenylene group contains two to ten carbon atoms (i.e., C2-C 10 In certain embodiments, the alkenylene group comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, the alkenylene group comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, the alkenylene group comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, the alkenylene group comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, the alkenylene group comprises two carbon atoms (i.e., C2 alkenylene). In other embodiments, the alkenylene group comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, the alkenylene group comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0154] "Alkynylidene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group consisting only of carbon and hydrogen, contains at least one carbon-carbon triple bond, and preferably has two to twelve carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the group can be through any two carbons in the chain. In certain embodiments, the alkynylene group comprises two to ten carbon atoms (i.e., C2-C 10 In certain embodiments, the alkynylene group comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, the alkynylene group comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, the alkynylene group comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, the alkynylene group comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, the alkynylene group comprises two carbon atoms (i.e., C2 alkynylene). In other embodiments, the alkynylene group comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, the alkynylene group comprises three to five carbon atoms (i.e., C3-C5 alkynylene).

[0155] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms, wherein the ring system contains at least one aromatic ring. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and five to eighteen carbon atoms, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hüückel theory. The ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. In some embodiments, aryl is a 6- to 10-membered aryl. In some embodiments, aryl is a 6-membered aryl (phenyl). Aryl includes but is not limited to the aryl of the hydrocarbon ring system derived from anthracene, naphthyl, phenanthrenes, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenanthrenes, phenanthrenes, pyrene and triphenylene. Unless otherwise specifically stated in the specification, aryl can be optionally substituted by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, aryl is optionally substituted by halogen.

[0156] "Heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof). The heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group is composed of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof), wherein the heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated in the specification, heteroalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroalkyl is optionally substituted by halogen.

[0157] "Arylalkyl" refers to a group of the formula -R c -aryl radical, wherein R c is an alkylene chain as defined above, for example methylene, ethylene, and the like.

[0158] "Aralkenyl" refers to a group of the formula -R d -aryl radical, wherein Rd is an alkenylene chain as defined above. "Aralkynyl" refers to a radical of the formula -R e -aryl radical, wherein R e is an alkynylene chain as defined above.

[0159] "Carbocycle" refers to a saturated, unsaturated or aromatic ring system in which each ring atom of the ring system is carbon. Carbocycles may 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. Aromatic rings (e.g., phenyl) may be fused to saturated or unsaturated rings (e.g., cyclohexane, cyclopentane or cyclohexene). The definition of carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as long as valence permits. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl and naphthyl. In some embodiments, the carbocycle is an aryl group. In some embodiments, the carbocycle is a cycloalkyl group. In some embodiments, the carbocycle is a cycloalkenyl group. In some embodiments, the carbocycle contains a triple bond. Unless otherwise specifically stated in the specification, the carbocycle may be optionally substituted.

[0160] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including a fused or bridged ring system, and preferably has three to twelve carbon atoms. In certain embodiments, cycloalkyl comprises three to ten carbon atoms. In other embodiments, cycloalkyl comprises five to seven carbon atoms. Cycloalkyl can be connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1] heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1] heptyl, etc. Unless otherwise specifically stated in the specification, cycloalkyl is optionally, for example, substituted by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0161] "Heterocycloalkyl" refers to a cycloalkyl group as defined above wherein one or more ring carbons are replaced with one or more heteroatoms such as N, O, P and S. Heterocycloalkyl groups may be optionally substituted.

[0162] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, comprising a fused or bridged ring system, preferably having three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, the cycloalkenyl comprises a double bond. In certain embodiments, the cycloalkenyl comprises more than one double bond. In certain embodiments, the cycloalkenyl comprises three to ten carbon atoms. In other embodiments, the cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl can be connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

[0163] "Heterocycloalkenyl" refers to a cycloalkenyl group as defined above wherein one or more ring carbons are replaced with one or more heteroatoms such as N, O, P and S. Heterocycloalkenyl groups may be optionally substituted.

[0164] "Cycloalkylalkyl" refers to a group of the formula -R c -cycloalkyl radical, wherein R c is an alkylene chain as described above.

[0165] "Cycloalkylalkoxy" refers to a cycloalkyloxy group of the formula -OR c - a group bonded to the oxygen atom of a cycloalkyl group, wherein R c is an alkylene chain as described above.

[0166] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0167] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above, substituted with one or more halogen groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halogenated methane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalogenated and trihalogenated methane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen group, each halogen may be independently selected, for example, 1-chloro, 2-fluoroethane.

[0168] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluorine substituents, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0169] "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. Heterocycle includes, for example, 3 to 10-membered monocyclic rings, 6 to 12-membered bicyclic rings and 6 to 12-membered bridged rings. Each ring of the bicyclic heterocycle can be selected from saturated, unsaturated and aromatic rings. "Heterocyclylene" refers to a divalent heterocycle that connects the rest of the molecule to a group. Unless otherwise specifically stated in the specification, heterocycle is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycle is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen. In some embodiments, heterocycle is heteroaryl. In some embodiments, heterocycle is heterocycloalkyl. In some embodiments, the heterocycle is heterocycloalkenyl.In some embodiments, the heterocycle contains one or more triple bonds.

[0170] In some embodiments, the heterocycle contains one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocycle contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycle contains one to three nitrogen. In some embodiments, the heterocycle contains one or two nitrogen. In some embodiments, the heterocycle contains one nitrogen. In some embodiments, the heterocycle contains one nitrogen and one oxygen. Unless otherwise specifically stated in the specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused, spiro or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocyclic group can be optionally oxidized; The nitrogen atom can be optionally quaternized. Representative heterocycles include heteroaryl groups described below. Representative heterocycles also include, but are not limited to, having two to fifteen carbon atoms (C2-C 15 Heterocycloalkyl or C2-C 15 Heterocycloalkenyl), two to ten carbon atoms (C2-C 10 Heterocycloalkyl or C2-C 10C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl. Examples of such heterocyclic groups include, but are not limited to, aziridine, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithioxanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrrolid ... The term heterocycle also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. In some embodiments, the heterocycle has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in the heterocycle, the number of carbon atoms in the heterocycle is different from the total number of atoms (including heteroatoms) (i.e., the skeleton atoms of the heterocycle ring) constituting the heterocycle. In some embodiments, the heterocycle is 3 to 8 yuan. In some embodiments, the heterocycle is 3 to 7 members. In some embodiments, the heterocycle is 3 to 6 members. In some embodiments, the heterocycle is 4 to 6 members. In some embodiments, the heterocycle is 5 to 6 members.

[0171] "Heteroaryl" or "aromatic heterocycle" refers to a group derived from a heteroaromatic ring group, which contains one to thirteen carbon atoms, at least one heteroatom (wherein each heteroatom can be selected from N, O and S) and at least one aromatic ring. As used herein, the heteroaryl ring can be selected from a monocyclic or bicyclic and fused or bridged ring system ring, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. One or more heteroatoms in the heteroaryl group can be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl group can be connected to the rest of the molecule through any atom of the heteroaryl group (as long as the valence permits), such as a carbon or nitrogen atom of the heteroaryl group. Examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzothiazole and imidazopyridine. "X-membered heteroaryl" refers to the number of endocylic atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocyclic ring has 5 atoms in the ring, for example, triazole, oxazole, thiophene, etc. In some embodiments, heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, heteroaryl is a 6-membered heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, aza yl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophene benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine The term "heteroaryl" refers to a group consisting of 1-phenyl-1H-pyrrolyl, ... In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroaryl is optionally substituted by halogen.

[0172] The term "substituted" refers to a portion with a substituent that replaces one or more carbons of the structure or replaceable heteroatoms such as hydrogen on NH. It should be understood that "replacement" or "replaced by..." includes implicit conditions, i.e., such substitution is consistent with the allowed valence of the substituted atom and the substituent, and the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to a portion with a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino or thio group. As used herein, the term "substituted" is intended to include all allowed substituents of an organic compound. In a broad sense, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For appropriate organic compounds, allowed substituents may be one or more and may be the same or different. 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.

[0173] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-Ra , -R b -OC(O)-OR a ,

[0174] -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a ,

[0175] -R b -OC(O)-N(R a 2. -R b-N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); wherein each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl and heterocycle, wherein each R a The alkyl radicals may be optionally replaced (as long as the valence permits) by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=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 a2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); and wherein each R b independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, each R c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0176] As used in the specification and claims, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0177] 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, etc. 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, etc. 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, etc. 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, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium and magnesium salts.

[0178] As used herein, the expressions "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0179] The expression "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which 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.

[0180] As used herein, the expression "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means 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", that is, compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, etc. and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, 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) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0181] In certain embodiments, the terms "prevent" or "preventing" with respect to a disease or condition may refer to a compound that reduces the occurrence of the disease or condition in a treated sample relative to an untreated control sample, or delays the onset of or lessens the severity of one or more symptoms of the disease or condition relative to an untreated control sample.

[0182] As used herein, the terms "treat," "treating," or "treatment" can include alleviating, reducing, or ameliorating symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying cause of symptoms, inhibiting the disease or condition, e.g., prophylactically and / or therapeutically arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating conditions caused by the disease or condition, or halting symptoms of the disease or condition.

[0183] B. Synthetic Methods and Compounds

[0184] In one aspect, provided herein is a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0185]

[0186] in:

[0187] R 1 Selected from:

[0188] N(R 5 )2, where each R 5 independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0189] Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0190] An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0191] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0192] R 4 Selected from:

[0193] hydrogen;

[0194] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0195] Optionally substituted C 3-10 A carbon ring wherein the C 3-10The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0196] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings,

[0197] The method comprises making a compound represented by formula (A) or a pharmaceutically acceptable salt thereof

[0198]

[0199] Among them, ring W, R 3 and R 4 defined above, and

[0200] R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-6 alkyl;

[0201] subjected to a hydrolysis step to produce a compound represented by formula (B) or a pharmaceutically acceptable salt thereof,

[0202]

[0203] Among them, ring W, R 3 and R 4 Defined above.

[0204] In one aspect, provided herein is a method for preparing a compound represented by formula (B) or a pharmaceutically acceptable salt thereof,

[0205]

[0206] in:

[0207] R 3is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0208] R 4 Selected from:

[0209] hydrogen;

[0210] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0211] Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic rings and 3 to 12 membered heterocyclic rings; and

[0212] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 3-12Carbocyclic and 3- to 12-membered heterocyclic rings,

[0213] The method comprises making a compound represented by formula (A) or a pharmaceutically acceptable salt thereof

[0214]

[0215] Among them, ring W, R 3 and R 4 defined above, and

[0216] R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-6 alkyl;

[0217] It is subjected to a hydrolysis step, thereby producing a compound represented by formula (B) or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments of Formula (A), R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-3 In some embodiments, R A1 , R A2 and R A3 Each of R is independently selected from halogen. A1 , R A2 and R A3 Each of which is independently selected from -OC 1-6 In some embodiments, R A1 , R A2 and R A3 Each of is independently selected from F, Cl, Br, OMe and OEt. In some embodiments, is CBr3, CCl3, CF3, CF2Cl, CFCl2, CF2Br, CFBr2, C(OMe)3 or C(OEt)3. In some embodiments, It is CF3. In some embodiments, the hydrolysis step is carried out in a solvent (e.g., MeOH / water) selected from ether, alcohol, water, and mixtures thereof. 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, wherein the base is a base, a basic salt, or a mixture thereof. In some embodiments, the basic salt is a carbonate, a bicarbonate, or a phosphate (e.g., a phosphate, a hydrogen phosphate, and a dihydrogen phosphate). In some embodiments, the base is selected from NaOH, KOH, LiOH, Ca(OH)2, K2CO3, KHCO3, Na2CO3, NaHCO3, K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, NaH2PO4, or a combination thereof. In some embodiments, the base is NaOH.

[0219] 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,

[0220]

[0221] Where R 1 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 ether. In some embodiments, the condensation reaction is carried out in THF. In some embodiments, the condensation reaction is carried out at a temperature of 15-25° C. In some embodiments, the condensation reaction is carried out at a temperature of 0-40° C.

[0222] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia),

[0223]

[0224] in:

[0225] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected from oxo and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0226] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0227] R 4 is a substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by one or more halogens.

[0228] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia),

[0229]

[0230] in,

[0231] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0232] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0233] R 4 It is an unsubstituted C1-C6 alkyl group.

[0234] In one aspect, provided herein is a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0235]

[0236] in:

[0237] R 1 Selected from:

[0238] N(R 5 )2, where each R 5 independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0239] Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0240] An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0241] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0242] R 4 Selected from:

[0243] hydrogen;

[0244] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0245] Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic rings and 3 to 12 membered heterocyclic rings; and

[0246] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings,

[0247] The method comprises making a compound represented by formula (E) or a pharmaceutically acceptable salt thereof

[0248]

[0249] in,

[0250] Ring W is defined above,

[0251] En is 0 or 1,

[0252] R EN is a protecting group, and

[0253] RE1 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;

[0254] and a compound represented by formula (F) or a pharmaceutically acceptable salt thereof

[0255]

[0256] Where R 3 defined above, and

[0257] R F is a substituted or unsubstituted phenyl group,

[0258] reacting in the presence of a compound of formula (K) or a pharmaceutically acceptable salt thereof,

[0259] R 4 -NH2 (K),

[0260] Thus producing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof,

[0261]

[0262] Where R 3 , R 4 、Ring W、En、R EN and R E1 Defined above.

[0263] In one aspect, provided herein is a method for preparing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof,

[0264]

[0265] in:

[0266] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0267] R 4 Selected from:

[0268] hydrogen;

[0269] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0270] Optionally substituted C 3-10 A carbon ring wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic rings and 3 to 12 membered heterocyclic rings; and

[0271] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0272] En is 0 or 1;

[0273] R EN is a protecting group; and

[0274] 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;

[0275] The method comprises making a compound represented by formula (E) or a pharmaceutically acceptable salt thereof

[0276]

[0277] in,

[0278] Ring W, En, R EN and R E1 In the above definition,

[0279] and a compound represented by formula (F) or a pharmaceutically acceptable salt thereof

[0280]

[0281] Where R 3 defined above, and

[0282] R F is a substituted or unsubstituted phenyl group,

[0283] reacting in the presence of a compound of formula (K) or a pharmaceutically acceptable salt thereof,

[0284] R 4 -NH2 (K),

[0285] Thereby producing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments of formula (E), (E-1), (G), (Ga), (G-1), and (G-1a), RE1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. In some embodiments, RE1 is ethyl. In some embodiments, RE1 is phenyl, benzyl, or p-methoxybenzyl. In some embodiments, RE1 is substituted or unsubstituted phenyl. In some embodiments, R E1 is a substituted or unsubstituted heteroaryl. In some embodiments, RE1 is optionally substituted by one or more substituents selected from 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)2NHC l -C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC l -C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OCl -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. In some embodiments, RE1 is optionally substituted with one or more substituents selected from halogen, -NH2, CN, NO2, -OH, -C(=O)OH, -SH, SF5, C1-C6 alkyl, -OC1-C6 alkyl, C1-C6 haloalkyl and -OC1-C6 alkyl.

[0287] In some embodiments, En is 0. In some embodiments, En is 1.

[0288] In some embodiments, the compound of formula (E) has the structure of formula (E-1),

[0289]

[0290] Where R EN' is hydrogen or R EN In some embodiments, the compound of formula (E-1) has In some embodiments, the compound of formula (E-1) has In some embodiments, the compound of formula (E-1) has structure.

[0291] In some embodiments of Formulas (E), (G), (Ga), and (H), R EN is selected from (trimethylsilyl)ethoxymethyl (SEM), methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl (CBz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), p-toluenesulfonyl (Tos), 2,2,2-trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (2,4-dimethocybenzyl) (Dmb), p-methoxybenzyl (Pmb) and benzyl (Bn). In some embodiments, R EN For SEM.

[0292] In some embodiments of Formula (F), R F Optionally one or more R F1 is replaced, and each R F1 independently selected from halogen, -NH2, CN, NO2, -OH, -SH, SF5, C1-C6 alkyl, -OC1-C6 alkyl, C1-C6 haloalkyl, -OCl -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 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.

[0293] In some embodiments of Formula (F), R F Optionally one or more R F1 is replaced, and each R F1 Independently selected from F, Cl, Br, methyl and methoxy.

[0294] In some embodiments, the compound of formula (F) has the structure of formula (F-1):

[0295]

[0296] Where Fn is 0, 1, 2, 3, 4, or 5, and each R F1 independently selected from 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 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. In some embodiments, the compound of formula (F) is

[0297] In some embodiments, a compound represented by formula (E), formula (E-1) or a salt thereof and a 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.

[0298] In some embodiments, the compound represented by formula (G) has the structure of formula (G-1):

[0299]

[0300] Where R EN' is hydrogen or R EN .

[0301] In some embodiments, the compound represented by formula (G-1) has In some embodiments, the compound represented by formula (G-1) has In some embodiments, the compound represented by formula (G-1) has structure.

[0302] 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,

[0303]

[0304] In some embodiments, the compound represented by formula (H) has the structure of formula (H-1),

[0305]

[0306] In some embodiments, the compound represented by formula (H-1) has structure.

[0307] 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,

[0308]

[0309] In some embodiments, a deprotection reaction is also included. In some embodiments, the deprotection reaction includes replacing R with hydrogen. ENIn some embodiments, the deprotection reaction occurs after the condensation reaction. In some embodiments, the deprotection reaction occurs before the condensation reaction.

[0310] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia),

[0311]

[0312] in:

[0313] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected from oxo and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0314] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0315] R 4 is a substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by one or more halogens.

[0316] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia),

[0317]

[0318] in,

[0319] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0320] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0321] R 4 It is an unsubstituted C1-C6 alkyl group.

[0322] In one aspect, provided herein is a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0323]

[0324] in:

[0325] R 1 Selected from:

[0326] N(R 5 )2, where each R 5 independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0327] Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0328] An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0329] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic rings and 3 to 12 membered heterocyclic rings; and

[0330] R 4 Selected from:

[0331] hydrogen;

[0332] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0333] Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0334] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings,

[0335] The method comprises making a compound represented by formula (E) or a pharmaceutically acceptable salt thereof

[0336]

[0337] in,

[0338] Ring W is defined above,

[0339] En is 0,

[0340] R EN is a protecting group, and

[0341] 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;

[0342] reacting with a compound represented by formula (F) or a pharmaceutically acceptable salt thereof,

[0343]

[0344] Where R 3 defined above, and

[0345] R F is a substituted or unsubstituted phenyl group,

[0346] Thereby producing a compound of formula (Ga) or a pharmaceutically acceptable salt thereof,

[0347]

[0348] Where R 3 、Ring W、En、R EN and R E1 In the above definition,

[0349] And wherein the method further comprises reacting the compound of formula (Ga) or a pharmaceutically acceptable salt thereof with a compound of formula (J) or a pharmaceutically acceptable salt thereof,

[0350] R 4 -R J (J)

[0351] Where R J is a leaving group and R 4 In the above definition,

[0352] Thus producing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof,

[0353]

[0354] Where R 3 , R 4 , R EN , En and R E1 Defined above.

[0355] In some embodiments, the compound represented by formula (E) or its pharmaceutically acceptable salt and the compound represented by formula (F) or its pharmaceutically acceptable salt are reacted in the presence of NH3 gas or NH3 in a solvent, such as NH3.H2O, NH3 in MeOH, NH3 in EtOH and other NH3 solutions to produce a compound of formula (Ga) or its pharmaceutically acceptable salt. In some embodiments, NH3 is present in solvents such as alcohol and water.

[0356] In some embodiments, the compound of formula (E) has structure.

[0357] In some embodiments, the compound of formula (Ga) has structure.

[0358] In some embodiments, the compound of formula (G) has structure.

[0359] In some embodiments of Formula (J), R J is halogen (e.g., Br, Cl, I). J is an alkyl sulfonate (e.g., trifluoromethanesulfonate (triflate or TfO-)) or an aryl sulfonate (e.g., 4-methylbenzenesulfonate). In some embodiments, R J is Br. In some embodiments, R J In some embodiments, R J is 1. In some embodiments, R J In some embodiments, R J It is 4-methylbenzenesulfonate.

[0360] 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. 4 -R J is isopropyl trifluoromethanesulfonate. In some embodiments, R 4 -RJ It is isopropyl 4-methylbenzenesulfonate.

[0361] In some embodiments, R 4 -R J is 2-chloro-1,1,1-trifluoroethane. 4 -R J is 2-bromo-1,1,1-trifluoroethane. 4 -R J is 2-iodo-1,1,1-trifluoroethane. 4 -R J It is 2,2,2-trifluoroethyl p-toluenesulfonate.

[0362] 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.

[0363] 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,

[0364]

[0365] In some embodiments, the compound of formula (H) has structure.

[0366] 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,

[0367]

[0368] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia),

[0369]

[0370] in:

[0371] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected from oxo and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0372] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0373] R 4 is a substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by one or more halogens.

[0374] In some embodiments, the compound represented by Formula (I) has the structure of Formula (Ia),

[0375]

[0376] in,

[0377] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0378] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0379] R 4 It is an unsubstituted C1-C6 alkyl group.

[0380] In one aspect, provided herein is a method for preparing a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof,

[0381]

[0382] in:

[0383] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0384] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0385] R 4 is an unsubstituted C1-C6 alkyl group;

[0386] The method comprises making a compound represented by formula (E-1) or a pharmaceutically acceptable salt thereof

[0387]

[0388] in,

[0389] R EN' is hydrogen or R EN , and where R EN is a protecting group;

[0390] 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;

[0391] reacting with a compound represented by formula (F) or a pharmaceutically acceptable salt thereof,

[0392]

[0393] Where R 3 defined above, and

[0394] R F is a substituted or unsubstituted phenyl group,

[0395] Thereby producing a compound of formula (G-1a) or a pharmaceutically acceptable salt thereof,

[0396]

[0397] Where R 3 , R EN' and R E1 In the above definition,

[0398] And wherein the method further comprises 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,

[0399] R 4 -R J (J)

[0400] Where R J is the leaving group,

[0401] Thus, a compound represented by formula (G-1) or a pharmaceutically acceptable salt thereof is produced,

[0402]

[0403] Where R3 , R 4 , R EN' and R E1 Defined above.

[0404] In some embodiments, the compound represented by formula (E-1) or a pharmaceutically acceptable salt thereof and the compound represented by formula (F) or a pharmaceutically acceptable salt thereof are reacted in the presence of NH3 gas or NH3 in a solvent, such as NH3.H2O, NH3 in MeOH, NH3 in EtOH and other NH3 solutions to produce a compound of formula (G-1a) or a pharmaceutically acceptable salt thereof. In some embodiments, NH3 is present in a solvent such as alcohol and water.

[0405] 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,

[0406]

[0407] In some embodiments, 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,

[0408]

[0409] In some embodiments, R EN' In some embodiments, R EN' For R EN In some embodiments, R EN' is selected from (trimethylsilyl)ethoxymethyl (SEM), methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl (CBz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), p-toluenesulfonyl (Tos), 2,2,2-trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (Pmb) and benzyl (Bn). In some embodiments, R EN' For SEM.

[0410] In some embodiments, the method further comprises a deprotection reaction. In some embodiments, the deprotection reaction occurs after the condensation reaction, and wherein the deprotection reaction comprises replacing R with hydrogen. ENIn 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 has structure.

[0411] In one aspect, provided herein is a compound represented by formula (A) or a pharmaceutically acceptable salt thereof,

[0412]

[0413] in

[0414] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0415] R 4 Selected from:

[0416] hydrogen;

[0417] Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and

[0418] Optionally substituted C 3-10 A carbon ring wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0419] Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 210 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings;

[0420] R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-6 alkyl.

[0421] In some embodiments, the compound of formula (A) has structure.

[0422] In certain embodiments, the present disclosure provides a method for synthesizing a compound represented by formula (I):

[0423]

[0424] or a pharmaceutically acceptable salt thereof, wherein:

[0425] R 1 Selected from:

[0426] -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the optional substituents on C1-C6 alkyl are independently selected at each occurrence from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0427] Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10Haloalkyl, -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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0428] An optionally substituted 3 to 8 membered heterocycle; wherein the optional substituents on the 3 to 8 membered heterocycle are independently selected at each occurrence from one or more 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0429] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 carbocyclic ring, wherein the optional substituents on each occurrence are independently selected from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0430] R 4 Selected from:

[0431] hydrogen;

[0432] Optionally substituted C1-C6 alkyl, wherein the optional substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more 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 3-12Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0433] Optionally substituted C 3-10 Carbon ring, where C 3-10 The optional substituents on the carbocyclic ring are independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring; and

[0434] Ring W is selected from optionally substituted 5- to 8-membered (e.g., 5- or 6-membered) heteroaryl, wherein the substituents on the optionally substituted 5- to 8-membered heteroaryl are independently selected at each occurrence from one or more 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 Carbocyclic ring, 3- to 12-membered heterocyclic ring.

[0435] In certain embodiments, the present disclosure provides a method for synthesizing a compound represented by formula (I):

[0436]

[0437] or a pharmaceutically acceptable salt thereof, wherein:

[0438] R 1 Selected from:

[0439] -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0440] Substituted C1-C6 alkyl; and

[0441] optionally substituted 3- to 14-membered heterocycle (such as 5-6-membered heterocycloalkyl);

[0442] R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 Carbon ring;

[0443] R 4 Selected from:

[0444] hydrogen;

[0445] Optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl;

[0446] Optionally substituted C 3-10 carbocyclic or optionally substituted 3- to 12-membered heterocyclic ring; and

[0447] Ring W is selected from optionally substituted 5- to 6-membered heteroaryl.

[0448] In some embodiments of Formula (I), (Ia), (A), (B), (G), (G-1), (H), (H-1), (K), and (J), R 4 is an optionally substituted C1-C6 alkyl. 4 is an optionally substituted C 3-10 Carbon ring.

[0449] In some embodiments, for compounds or salts of Formula (X), (X*) or (I), when R 1 When R is methylpiperazine and W is pyridine, 4 is not methyl. In some cases, when R 1 for When W is pyridine, R 4 Not a methyl group.

[0450] In some embodiments, for compounds or salts of Formula (X), (X*) or (I), when W is furan, R 4 is not ethyl-1-one. In some cases, when W is furan and R 4 When it is cyclopentyl or cyclohexyl, R 1 is not ethyl-1-one. In some cases, when W is furan and R 4 When it is cyclopentyl or cyclohexyl, R 1 is not ethyl-1-one. In some cases, R 1 Not for

[0451] In some embodiments, for compounds or salts of formula (X), (X*), (A), (B), (E), (G), (Ga), (H) or (I), W is selected from an optionally substituted 5- to 6-membered heterocyclic ring. In some cases, the heterocyclic ring is a 5- to 6-membered heteroaryl. In some cases, the heterocyclic ring of W is an unsubstituted 5- to 6-membered heteroaryl. In some cases, the heterocyclic ring of W is an unsubstituted 5-membered heteroaryl. In some cases, the heterocyclic ring of W has at least 2 heteroatoms. In some cases, the heterocyclic ring of W has up to 2 heteroatoms. In some cases, the heterocyclic ring of W has only 2 heteroatoms. In some cases, the heterocyclic ring of W is unsubstituted. In some cases, the heterocyclic ring of W has 2 heteroatoms selected from nitrogen, sulfur and oxygen. In some cases, the heterocyclic ring of W has at least 2 different heteroatoms. In some cases, the heterocyclic ring of W has 2 nitrogen atoms. In some cases, the heterocyclic ring of W has 1 nitrogen atom and 1 oxygen atom.

[0452] 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. 1 is optionally substituted with 1 to 3 substituents. 1 is optionally substituted with 1 to 2 substituents. 1 Optionally substituted with 1 substituent. In some embodiments, R 1 Optionally substituted with 2 substituents. In some embodiments, R 1 Optionally substituted with 3 substituents. 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is an optionally substituted 3-12 membered ring. 1 is an optionally substituted 5- to 8-membered ring.

[0453] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Optionally substituted with an oxide.

[0454] 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, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, =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 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, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from 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 1 is an optionally substituted C1-C3 alkyl. 1 Optionally substituted with one or more substituents selected from oxo, halogen, -OC 1-10 Alkyl, -C 1-10 Haloalkyl and -OH.

[0455] 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 group, wherein the substituents on the C1-C6 heteroalkyl group are independently selected at each occurrence from 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 group, wherein the substituents on the C1-C6 heteroalkyl group are independently selected at each occurrence from one or more halogen, -OH, -CN, -NO2, -NH2, =S, -C 1-3 Haloalkyl, -C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic and 3- to 12-membered heterocyclic rings.

[0456] In some cases, when W is furan, R 1 is selected from substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more 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 Carbocyclic and 3- to 12-membered heterocyclic rings.

[0457] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from -N(R 5 )2, in some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from -N(R 5 )2, where R 5 is selected from optionally substituted C1-C6 alkyl groups, wherein the optional substituents on the C1-C6 alkyl groups are selected from hydroxyl groups.

[0458] 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 heterocyclic ring.

[0459] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 is a substituted C1-C6 alkyl. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R1 is selected from substituted C1-C6 alkyl, wherein the substituent is selected from hydroxy, oxo and -OC 1-10 alkyl.

[0460] 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 heterocyclic ring. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 is selected from an optionally substituted 5- to 6-membered heterocyclic ring. 1 In some embodiments, R 1 In some embodiments, R 1 is a fused bicyclic group. 1 is a bridged bicyclic group. In some embodiments, R 1 is an optionally substituted 5-membered heterocyclic ring. 1 is an optionally substituted heteroaryl. 1 is an optionally substituted heterocycloalkyl. 1 Contains 0-3 nitrogen and 0-1 oxygen atoms in the ring. In some embodiments, R 1 Contains 1-2 nitrogen and 0-1 oxygen atoms in the ring. In some embodiments, R 1 Contains 1-2 ring nitrogen atoms. In some embodiments, R 1 Contains 2 ring nitrogen atoms. In some embodiments, R 1 Contains 1 ring nitrogen atom.

[0461] 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 heterocyclic ring.

[0462] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 is an optionally substituted piperazine. 1 is an optionally substituted piperazine, wherein the piperazine is attached to the remainder of the compound (e.g., to a phenyl group) via the nitrogen. In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C), or (IIB), R 1 For one or more 1-6In some embodiments, for the 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 compounds or salts of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 is piperazine optionally substituted with one or more methyl groups. In some embodiments, for compounds or salts of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 For one or more 1-6 alkyl-substituted piperazine, wherein the alkyl is optionally substituted with hydroxy, halogen, oxo and -NH2. In some embodiments, for compounds or salts of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 is piperazine which is optionally substituted by an oxide.

[0463] 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 selected from oxo, -S(O2)NH2 and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo and -NH2. In some embodiments, for compounds or salts of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 The optional substituents on the optionally substituted piperazine are selected from 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 Optionally substituted with heteroalkyl. 1Optionally substituted by 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.

[0464] 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 heterocyclic ring. 1 is an optionally substituted 4- to 8-membered heterocyclic ring. 1 is an optionally substituted 4-membered heterocyclic ring. 1 is an optionally substituted 6-membered heterocycle. 1 When piperazine is piperazine, the piperazine is substituted. 1 is not unsubstituted piperazine. In some cases, R 1 is a substituted 3- to 10-membered heterocyclic ring.

[0465] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), for R 1 , the optional substituents of the heterocycle are independently selected at each occurrence from one or more substituents selected from 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 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C 1-10 Haloalkyl, -NH2, -CN, -OC 1-10 Alkyl and -NO2.

[0466] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1The optional substituents are independently selected at each occurrence from one or more substituents selected from -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, oxo and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more oxo and -OC 1-10 alkyl.

[0467] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 The optional substituents are independently selected at each occurrence from one or more substituents selected from -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, oxo and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more oxo and -OC 1-10 alkyl.

[0468] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), for R 1 , the heterocyclic ring has at least one nitrogen atom, phosphorus atom or oxygen atom. In some cases, for R 1 , the heterocyclic ring has at least one nitrogen atom. 1 , the heterocyclic ring has at least two nitrogen atoms. 1 , the heterocyclic ring has up to two nitrogen atoms. 1 , the heterocyclic ring has at most one nitrogen atom. 1 , the heterocyclic ring has two nitrogen atoms. In some cases, for R 1 , the heterocycle is a spiro heterocycle. In some cases, for R 1 , the heterocycle is a bridged heterocycle. In some cases, for R 1 , the heterocyclic ring is unsaturated. In some cases, for R 1 , the heterocyclic ring is saturated.

[0469] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from Any one of them is optionally substituted.

[0470] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from Any one of them is optionally substituted by one or more substituents selected from -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, oxo and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more oxo and -OC 1-10 In some embodiments, R 1 Optionally substituted with one or more substituents selected from -NH2, -N(H)C1-C6 alkyl, -N(C1-C6 alkyl)2, oxo, optionally substituted C 1-10 Heteroalkyl and optionally substituted C 1-10 alkyl.

[0471] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0472] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0473] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0474] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0475] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0476] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 is an optionally substituted 6- to 10-membered heterocycloalkyl. 1 The optional substituents of the optionally substituted 6- to 10-membered heterocycloalkyl are selected from C 1-6 In some embodiments, the 6- to 10-membered heterocycloalkyl is a spiro heterocycloalkyl. 1 is selected from optionally substituted piperazine, optionally substituted diazabicyclo[3.2.1]octane, optionally substituted diazabicyclo[3.1.1]heptane, optionally substituted diazaspiro[3.5]nonane and optionally substituted diazaspiro[3.3]heptane. In some cases, the optional C 1-6 alkyl.

[0477] 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. 3 is optionally substituted with 1 to 3 substituents. 3 is optionally substituted with 1 to 2 substituents. 3 Optionally substituted with 1 substituent. In some embodiments, R 3 Optionally substituted with 2 substituents. In some embodiments, R 3 Optionally substituted with 3 substituents.

[0478] 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 Selected from optionally substituted C 3-6 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 Selected from optionally substituted C 3-6 Cycloalkyl.

[0479] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), or (IIB), R 3 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 compounds or salts 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 by 1-3 halogens. In some embodiments, for compounds or salts 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 by 1-2 halogens. In some embodiments, for compounds or salts 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 by one halogen.

[0480] 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 of the phenyl group are selected from 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 of the phenyl group are selected from halogen and -C 1-3 Halogenated alkyl.

[0481] 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 4In 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 Substituted by one or more substituents selected from 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 In some embodiments, R 4 Substituted by one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -O-C1-6 alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 In some embodiments, R 4 Substituted by one or more substituents selected from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -OC 1-6 Alkyl, -C 1-6 Haloalkyl and -OC 1-6 In some embodiments, R 4 Substituted by one or more substituents selected from halogen, -OH, -NO2, -NH2, oxo, -C 1-6 Haloalkyl and -OC 1-6 In some embodiments, R 4 In some embodiments, R 4 is substituted with 1 halogen. 4 is substituted with 2 halogens. 4 Substituted with 3 halogens.

[0482] 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 For hydrogen.

[0483] 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 optionally substituted C1-C6 alkyl and 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 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 is an optionally substituted aryl group.

[0484] 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 group are selected from halogen.

[0485] 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 C3-C6 carbocyclic ring are selected from hydroxyl groups.

[0486] In some embodiments, for compounds or salts of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H), or (I), W is selected from 5- to 6-membered heteroaryl.

[0487] In some embodiments, for compounds or salts 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.

[0488] In some embodiments, for compounds or salts 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.

[0489] In some embodiments, for compounds or salts of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H) or (I), W is imidazole. In some embodiments, for compounds or salts of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H) or (I), W is pyridine.

[0490] In some embodiments, for compounds or salts of Formula (X), (X*), (A), (B), (E), (G), (Ga), (H) or (I), W is selected from optionally substituted 5- to 6-membered heteroaryl.

[0491] 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.

[0492] 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.

[0493] In some aspects, the compound or salt of Formula (I) is represented by Formula (Ia):

[0494]

[0495] or a pharmaceutically acceptable salt thereof.

[0496] In some aspects, the compound or salt of formula (I) is represented by formula (IIB):

[0497]

[0498] or a pharmaceutically acceptable salt thereof.

[0499] 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.

[0500] 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), 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 wherein the C6 carbocyclic ring is substituted by one or more substituents selected from halogen and -C 1-10 Halogenated alkyl.

[0501] 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 Selected from

[0502] 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 carbocyclic ring substituted by one or more substituents selected from halogen.

[0503] 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, wherein the phenyl is optionally substituted by one or more halogens.

[0504] 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 Selected from

[0505] 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 for

[0506] 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 hydrogen, C1-C6 alkyl optionally substituted by one or more substituents selected from halogen, and C1-C6 alkyl optionally substituted by one or more substituents selected from hydroxyl and amine. 5-6 Carbon ring.

[0507] 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 It is an unsubstituted C1-C6 alkyl group.

[0508] 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 group, wherein the C1-C6 alkyl group is substituted by one or more halogens.

[0509] 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 Selected from

[0510] 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 Selected from C1-C6 alkyl optionally substituted by one or more substituents selected from fluorine and C6 cycloalkyl substituted by hydroxy.

[0511] 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 Selected from

[0512] 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 Selected from In certain embodiments, R 4 for

[0513] 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 Selected from

[0514] 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 Selected from

[0515] In some cases, R 4 Select from unsubstituted C 1-10 alkyl, unsubstituted 3- to 6-membered heterocyclic ring and optionally substituted C3-C6 carbocyclic ring.

[0516] 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 Select C at each occurrence 1-10 Alkyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, wherein the C 1-10 Alkyl, C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0517] 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 Select from unsubstituted C 1-10 alkyl, an unsubstituted 3 to 6 membered heterocycle and an optionally substituted C3-C6 carbocycle, wherein the optional substituents are independently selected from one or more halogen-C 1-10 Halogenated alkyl.

[0518] 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 Select C at each occurrence 1-10 alkyl, an unsubstituted 4-membered heterocycle and an optionally substituted C3-C5 carbocycle, wherein the optional substituents are independently selected from one or more halogen-C 1-10 In some cases, R 4 Selected from C 1-10 In some cases, R 4 is selected from a 4-membered heterocyclic ring. 4 is a 4-membered heterocyclic ring. 4 It is a saturated 4-membered heterocyclic ring.

[0519] 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 Selected from In some cases, R 4 Selected from In some cases, R 4 Selected from

[0520] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from:

[0521] -N(R 5 )2, where R 5 is selected from optionally substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more halogen, -OH, -CN, -NO2, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 alkyl,

[0522] Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more of halogen, -OH, -NH2, oxo, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, -OC 1-6 Alkyl-OC(O)(OC 1-10 alkyl);

[0523] An optionally substituted 6- to 8-membered heterocyclic ring; wherein the optional substituents on the 6- to 8-membered heterocyclic ring are independently selected at each occurrence from one or more oxo, -S(O2)NH2, -NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C 1-10 Haloalkyl, -NH2, -CN and -NO2.

[0524] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0525] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0526]

[0527] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from:

[0528] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from:

[0529] Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more of halogen, -OH, oxo, -C 1-10 Haloalkyl and -OC 1-10 alkyl;

[0530] An optionally substituted 6- to 8-membered saturated heterocyclic ring; wherein the optional substituents are independently selected at each occurrence from one or more -S(O2)NH2 and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C 1-10 Haloalkyl and -NH2.

[0531] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0532] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 is selected from an optionally substituted 6- to 8-membered saturated heterocyclic ring; wherein the optional substituents are independently selected at each occurrence from one or more -S(O2)NH2 and an optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C 1-10 Haloalkyl and -NH2.

[0533] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0534] 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, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more halogen, -OH, oxo, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0535] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0536] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R1 Selected from:

[0537] Substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more of -OH, oxo and -OC 1-10 alkyl;

[0538] An optionally substituted 6- to 8-membered saturated heterocyclic ring; wherein the optional substituents are independently selected at each occurrence from one or more optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, oxo, -C 1-10 Haloalkyl and -NH2.

[0539] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from:

[0540] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, and -NH2. 1 For one or more C 1-3 Alkyl-substituted piperazine, wherein the C 1-3 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halo, oxo and -NH2.

[0541] In some embodiments, for a compound or salt of Formula (X), (X*), (I), (Ia), (C) or (IIB), R 1 Selected from

[0542] In some embodiments, for a compound or salt of Formula (X), (X*), (C) or (I), the compound is not In some cases, the compound is not

[0543] In some embodiments, for the compound or salt of formula (I),

[0544] R 1 Selected from -N(R 5 )2, where R 5 is selected from optionally substituted C1-C6 alkyl, wherein the optional substituent on the C1-C6 alkyl is selected from hydroxyl;

[0545] Substituted C1-C6 alkyl, wherein the substituent is selected from hydroxy, oxo and -OC 1-10 Alkyl; and

[0546] An optionally substituted 5- to 6-membered heterocyclic ring, wherein the optional substituent is selected from oxo, -S(O2)NH2 and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on alkyl are independently selected at each occurrence from one or more of hydroxy, halogen, oxo and -NH2;

[0547] R 3 is an optionally substituted phenyl group, wherein R 3 The optional substituents of the phenyl group are selected from halogen and -C 1-10 Haloalkyl;

[0548] R 4 is selected from optionally substituted C1-C6 alkyl and optionally substituted C 3-6 Carbon ring, where R 4 The optional substituents of the C1-C6 alkyl group are selected from halogen, and wherein R 4 The optional substituents of the C3-C6 carbocyclic ring are selected from hydroxyl groups; and

[0549] W is selected from imidazole, furan and pyridine.

[0550] In some embodiments, for the compound or salt of formula (I),

[0551] R 1 Selected from -N(R 5 )2, where R 5 is selected from optionally substituted C1-C6 alkyl, wherein the optional substituent on the C1-C6 alkyl is selected from hydroxyl;

[0552] Substituted C1-C6 alkyl, wherein the substituent is selected from hydroxy, oxo and -OC 1-10 Alkyl; and

[0553] An optionally substituted 5- to 6-membered heterocyclic ring, wherein the optional substituent is selected from oxo, -S(O2)NH2 and optionally substituted C 1-10 Alkyl, wherein the C 1-10The optional substituents on alkyl are independently selected at each occurrence from one or more of hydroxy, halogen, oxo and -NH2;

[0554] R 3 is an optionally substituted phenyl group, wherein R 3 The optional substituents of the phenyl group are selected from halogen and -C 1-10 Haloalkyl;

[0555] R 4 is selected from optionally substituted C1-C6 alkyl and optionally substituted C 3-6 Carbon ring, where R 4 The optional substituents of the C1-C6 alkyl group are selected from halogen, and wherein R 4 The optional substituents of the C3-C6 carbocyclic ring are selected from hydroxyl groups; and

[0556] W is selected from imidazole.

[0557] In some embodiments, for a compound or salt of Formula (X), (X*), (Ia), (IIB) or (I), R 1 Selected from R 3 for And R 4 Selected from

[0558] In one aspect, provided herein is a method for synthesizing a compound represented by formula (Ia):

[0559]

[0560] or a pharmaceutically acceptable salt thereof, wherein:

[0561] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0562] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0563] R 4 It is an unsubstituted C1-C6 alkyl group.

[0564] In some embodiments of Formula (I), (A), (B), (Ia), (K), (G), (H), (Ga), (J), (G-1), (H-1), and (K), R 4 Selected from

[0565] In some embodiments of Formula (I), (A), (B), (Ia), (F), (G), (H), (Ga), (G), (H), (G-1a), (G-1), and (H-1), R 3 Selected from

[0566] In some embodiments of Formula (I), (Ia), and (C), R 1 For one or more C 1-3 Alkyl-substituted piperazine, wherein the C 1-3 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halo, oxo and -NH2.

[0567] In some embodiments of Formula (I), (Ia), and (C), R 1 Selected from

[0568] In some embodiments of Formula (I), (Ia) and (C),

[0569] R 1 Selected from

[0570] R 3 Selected from and

[0571] R 4 Selected from

[0572] In some embodiments, provided herein is a method of synthesizing a compound, wherein the compound is

[0573] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0574] In one aspect, provided herein is a method for synthesizing a compound represented by formula (Ia):

[0575]

[0576] or a pharmaceutically acceptable salt thereof, wherein:

[0577] R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected from oxo and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2;

[0578] R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and

[0579] R 4 is a substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by one or more halogens.

[0580] In some embodiments of Formula (I), (A), (B), (Ia), (K), (G), (H), (Ga), (J), (G-1), (H-1), and (K), R 4 Replaced by two or three fluorines.

[0581] In some embodiments of Formula (I), (A), (B), (Ia), (K), (G), (H), (Ga), (J), (G-1), (H-1), and (K), R 4 Selected from

[0582] In some embodiments of Formula (I), (A), (B), (Ia), (F), (G), (H), (Ga), (G), (H), (G-1a), (G-1), and (H-1), R3 Selected from

[0583] In some embodiments of Formula (I), (Ia), and (C), R 1 For one or more C 1-3 Alkyl-substituted piperazine, wherein the C 1-3 The alkyl group is optionally substituted with one or more halogens.

[0584] In some embodiments of Formula (I), (Ia), and (C), R 1 Selected from In some embodiments, R 1 Selected from

[0585] In some embodiments, R 1 Selected from

[0586] R 3 Selected from and

[0587] R 4 Selected from

[0588] In some embodiments, provided herein is a method of synthesizing a compound, wherein the compound is selected from:

[0589] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0590] In certain embodiments, the present disclosure provides a method for synthesizing a compound represented by formula (X):

[0591]

[0592] or a pharmaceutically acceptable salt thereof, wherein:

[0593] Z is selected from an optionally substituted 3- to 12-membered heterocyclic ring and an optionally substituted C3-C 12 carbocyclic ring, wherein the substituents on each occurrence are independently 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0594] Wherein the C1-C 10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0595] Wherein C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are each optionally substituted at each occurrence by one or more substituents independently selected from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C1-10 alkyl ring, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C1- 10 Alkyl halides, -NH2, -CN and -NO 2；

[0596] R 10 is selected from optionally substituted C1-C6 alkyl, wherein the optional substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0597] W is selected from optionally substituted 5- to 8-membered (e.g., 5- or 6-membered) heterocyclic rings and optionally substituted C3-C8 carbocyclic rings, wherein the substituents on each are independently selected at each occurrence from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring, wherein the C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 Alkyl; and

[0598] Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein the substituents on each occurrence are independently selected from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring, wherein the C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0599] In some aspects, the compound of formula (X) is represented by formula (X*).

[0600] In some embodiments, for the compound or salt of Formula (X), Z is selected from an optionally substituted 3- to 12-membered heterocycle and an optionally substituted C3-C 12 carbocyclic ring, wherein the substituents on each occurrence are independently selected from one or more halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C1-10 Haloalkyl, -OC 1-10 In some cases, for Z, the heterocyclic ring includes at least one nitrogen atom. In some cases, Z is selected from optionally substituted phenyl and optionally substituted pyridine. In some cases, the optional substituents of the optionally substituted phenyl of Z are selected from one or more selected from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 In some cases, the optional substituents of the optionally substituted phenyl of Z are selected from one or more selected from halogen and C 1-10 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 1 or 2 nitrogen atoms. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 2 nitrogen atoms. In some cases, the heterocycle is a 6-membered heterocycle. In some cases, Z is selected from In some cases, the optional substituent of the optionally substituted phenyl of Z is halogen. In some cases, Z is selected from In some cases, Z is substituted phenyl. In some cases, Z is phenyl substituted with halogen.

[0601] In some aspects, the present disclosure provides a method for synthesizing a compound represented by formula (X*):

[0602]

[0603] R 1 Selected from:

[0604] -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the optional substituents on C1-C6 alkyl are independently selected at each occurrence from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0605] Optionally substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more of halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C1-10 Haloalkyl, -OC 1-10 Alkyl, -O-C1-6 alkyl-OC(O)(OC 1-10 Alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0606] An optionally substituted 3 to 8 membered heterocycle; wherein the optional substituents on the 3 to 8 membered heterocycle are independently selected at each occurrence from one or more 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0607] W is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein the substituents on each occurrence are independently selected from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring, wherein the C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 Alkyl; and

[0608] Y is selected from an optionally substituted 5- to 8-membered heterocyclic ring and an optionally substituted C3-C8 carbocyclic ring, wherein the substituents on each occurrence are independently selected from one or more halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12Carbocyclic ring, 3 to 12 membered heterocyclic ring, wherein the C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0609] In some aspects, the compound of Formula (X) or Formula (X*) is represented by Formula (I).

[0610] In some aspects, the present disclosure provides a method for synthesizing a compound represented by formula (X*):

[0611]

[0612] R 1 Selected from:

[0613] -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the optional substituents on C1-C6 alkyl are independently selected at each occurrence from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0614] Optionally substituted C1-C6 alkyl, wherein the substituents on the C1-C6 alkyl are independently selected at each occurrence from one or more halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -C1- 10 Haloalkyl, -OC 1-10 Alkyl, -O-C1-6 alkyl-OC(O)(OC 1-10 Alkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic ring, 3 to 12 membered heterocyclic ring;

[0615] An optionally substituted 3 to 14 membered heterocycle; wherein the optional substituents on the 3 to 8 membered heterocycle are independently selected at each occurrence from one or more halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Heteroalkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The optional substituents on the alkyl group are independently selected at each occurrence from one or more of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2;

[0616] W is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein the substituents on each occurrence are independently selected from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring, wherein the C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 Alkyl; and

[0617] Y is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle, wherein the substituents on each occurrence are independently selected from one or more 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 Carbocyclic ring, 3 to 12 membered heterocyclic ring, wherein the C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, C 1-10 Alkyl, -C 1-10 Haloalkyl and -OC 1-10 alkyl.

[0618] In some aspects, the present disclosure provides a method for synthesizing a compound represented by formula (X*):

[0619]

[0620] R1 Selected from:

[0621] -N(R 5 )2, where R 5 is selected from hydrogen and optionally substituted C1-C6 alkyl;

[0622] Optionally substituted C1-C6 alkyl;

[0623] an optionally substituted 3- to 14-membered heterocyclic ring or an optionally substituted 3- to 14-membered carbocyclic ring;

[0624] W is selected from an optionally substituted 5- to 8-membered heterocycle and an optionally substituted C3-C8 carbocycle;

[0625] and Y is selected from an optionally substituted 5- to 8-membered heterocyclic ring and an optionally substituted C3-C8 carbocyclic ring.

[0626] In some embodiments, R is an optionally substituted 3- to 14-membered heterocyclic ring.

[0627] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0628]

[0629]

[0630] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0631]

[0632] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0633] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0634]

[0635] In some embodiments, provided herein is a method for synthesizing a compound or a salt thereof, wherein the compound is

[0636] In some embodiments, provided herein is a method of synthesizing a compound or a salt thereof, wherein the compound is selected from Table 1.

[0637] Table 1 Exemplary compounds

[0638]

[0639]

[0640]

[0641]

[0642] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficient acidity, sufficient basicity, or both functional groups can react with any of a number of inorganic bases and inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as those with quaternary nitrogen, can form salts with appropriate counterions, for example halides, such as bromides, chlorides, or fluorides, particularly bromides.

[0643] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z- or E-form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise indicated, the compounds described herein are also intended to include all Z-, E- and tautomeric forms.

[0644] "Tautomers" refers to molecules in which a proton can be transferred from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. Where tautomerization may occur, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0645]

[0646] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example, 2 H. 3 H. 11 C. 13 C and / or 14In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0647] 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, a compound having the present structure may differ except for the replacement of a hydrogen with a deuterium or tritium or the replacement of an isotopically enriched atom with a 13 C or 14 All of the above are within the scope of the present disclosure, except for the replacement of carbon with carbon.

[0648] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labeled with an isotope, such as, for example, deuterium ( 2 H), deuterium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Use 2 H. 11 C. 13 C. 14 C. 15 C. 12 N. 13 N. 15 N. 16 N. 16 O. 17 O. 14 F. 15 F. 16 F. 17 F. 18 F. 33 S. 34 S. 35 S. 36 S. 35 Cl, 37 Cl, 79 Br, 81 Br and 125 Isotopic substitutions of I are all included. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. In some embodiments, where isotopic variations are indicated, the remaining atoms of the compound may optionally contain unnatural portions of atomic isotopes.

[0649] In certain embodiments, some or all of the compounds disclosed herein 1 The H atoms are replaced by2 H atom. Methods for the synthesis of deuterium containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0650] Deuterium substituted compounds are synthesized using various 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.

[0651] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0652] 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 a percentage of deuterium that is higher than the natural abundance of deuterium.

[0653] In some embodiments of the compounds disclosed herein, in the following group R 1 , R 3 , R 4 , R 5 , RA1 , R.A. A2 , R.A. A3 , R EN , R EN' , R F , R F1 , R E1 , R J , W, Z, Y, and R 10 one or more of 1 H is replaced by one or more deuteriums.

[0654] 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 The abundance of deuterium in each of is independently at least 1 mol%, at least 10 mol%, at least 20 mol%, at least 30 mol%, at least 40 mol%, at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol%, or 100 mol%.

[0655] In some embodiments of the compounds disclosed herein, one or more of Ring W 1 H is replaced by one or more deuteriums.

[0656] The compounds of the present disclosure also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0657] In some cases, the compounds described herein can exist as diastereomers, enantiomers, or other stereoisomeric forms. In the absence of a specified absolute stereochemistry, the compounds presented herein include all diastereomers, enantiomers, and dimer forms and their appropriate mixtures. The separation of stereoisomers can be performed by chromatography or by forming diastereomers and separating by recrystallization or chromatography or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0658] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Moreover, 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 as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0659] In certain embodiments, the compound or the salt of the compound can be a prodrug, for example, wherein the hydroxyl group in the parent compound is presented as an ester or carbonate, or the carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted into pharmaceutical agents of the present disclosure under physiological conditions. One method of preparing a prodrug is to include one or more selected parts that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a specific target cell in a host animal such as a 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.

[0660] Prodrug forms of the compounds described herein are included within the scope of the claims, wherein the prodrug is metabolized in vivo to produce a compound as described herein. In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0661] Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug cannot. Prodrugs can help enhance the cell permeability of the compound relative to the parent drug. Prodrugs may also have improved solubility than the parent drug in pharmaceutical compositions. Prodrugs may be designed as reversible drug derivatives, used as modifiers to enhance the delivery of drugs to site-specific tissues or to increase the residence time of drugs within cells.

[0662] In some embodiments, the design of the prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269: G210-218 (1995); McLoed et al., Gastroenterol, 106: 405-413 (1994); Hochhaus et al., Biomed. Chrom., 6: 283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACSSymposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein for such disclosure). According to another embodiment, the present disclosure provides a method for producing the above-mentioned compounds. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0663] Synthetic chemistry transformations and methods that can be used to synthesize 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 PGM Wuts, Protective Groups in Organic Synthesis, 2nd 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).

[0664] D. Treatment methods

[0665] The compounds synthesized by the methods described herein can be used to prepare a medicament for preventing or treating a disease or condition. In addition, a method of treating any disease or condition described herein in a subject in need of such treatment involves administering to the subject a pharmaceutical composition containing at least one compound described herein or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof in a therapeutically effective amount.

[0666] In one aspect provided herein, the disclosure provides methods for synthesizing inhibitors of TNIK kinase. Thus, TNIK kinase inhibitors can be used to inhibit downstream biological pathways to inhibit TNIK. In some aspects, TNIK inhibitors can inhibit fibrillar collagen, and thereby can inhibit biological activities associated with the regulation of the extracellular matrix and the regulation of remodeling the extracellular matrix. TNIK inhibitors can inhibit the regulation of cell growth, differentiation, cell migration, proliferation, and metabolism.

[0667] In certain embodiments, the present disclosure provides a method for synthesizing a compound that can be used to treat or prevent a disease, state, or condition in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of any one of the embodiments of the present disclosure, or a pharmaceutically acceptable salt thereof. The disease, state, or condition can be selected from colorectal cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, multiple myeloma, chronic myeloid leukemia, cancer metastasis, fibrosis, and mental disorders. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is chronic myeloid leukemia. In some embodiments, the cancer is cancer metastasis. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is not a solid tumor. In certain embodiments, inhibiting TNIK will inhibit embryonic development. Therefore, TNIK inhibitors can inhibit pregnancy progression and thus be used to terminate pregnancy. In some embodiments, inhibition of TNIK will inhibit TGF beta signaling. The TGF beta signaling pathway is involved in various processes, and therefore, inhibition of the TGF beta signaling pathway can inhibit these processes, some of which are described herein. This can include inhibiting the development of the embryo as described herein to inhibit the progression of pregnancy. This can include inhibiting cell growth, cell differentiation, which can be used to inhibit the progression of pregnancy and inhibit cancer.

[0668] In certain embodiments, the disclosure provides a method for synthesizing a compound that can be used to treat or prevent a fibrotic disease or condition. In some embodiments, a fibrotic disease or condition is selected from pulmonary fibrosis, cystic fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, brain fibrosis, arterial fibrosis, arthrofibrosis, intestinal fibrosis, Duchenne contracture fibrosis, keloid fibrosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma sclerosis fibrosis, adhesive capsulitis fibrosis or a combination thereof. In some embodiments, a fibrotic disease is selected from cirrhosis of the liver, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc) and graft versus host disease (GVHD). In some embodiments, a fibrotic disease is renal fibrosis.

[0669] In certain embodiments, the present disclosure provides a method for synthesizing a compound that can be used to treat kidney disease. In some embodiments, kidney disease is chronic renal fibrosis (CKD). In some embodiments, kidney disease is renal fibrosis. In some embodiments, fibrotic disease is liver cirrhosis. In some embodiments, fibrotic disease is pulmonary fibrosis. In some embodiments, fibrotic disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, fibrotic disease is renal fibrosis, wherein the disease is chronic or acute. In some embodiments, renal fibrosis causes glomerular sclerosis or tubulointerstitial fibrosis. In some embodiments, fibrotic disease is renal interstitial fibrosis. In some embodiments, fibrotic disease is acute interstitial nephritis (AIN). In some embodiments, fibrotic disease is systemic sclerosis (SSc). In some embodiments, fibrotic disease is graft versus host disease (GVHD). In some embodiments, fibrotic disease is hypertrophic scar (HTS).

[0670] Example

[0671] The following examples are provided to illustrate but not to limit the claimed invention.The following examples further illustrate the invention but, of course, should not be construed as limiting its scope in any way.

[0672] The following synthetic schemes are provided for the purpose of illustration and not limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art will be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art will be able to prepare in a manner similar to that described below by using appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0673] In the examples and throughout the application, certain abbreviations are used. They include:

[0674] DIEA = N,N-diisopropylethylamine;

[0675] PE = petroleum ether;

[0676] EA = ethyl acetate;

[0677] 1 H-NMR = proton nuclear magnetic resonance spectroscopy;

[0678] DMA = N,N-dimethylacetamide;

[0679] DCM = dichloromethane;

[0680] NIS = N-iodosuccinimide;

[0681] TFA = trifluoroacetic acid;

[0682] DMSO = dimethyl sulfoxide;

[0683] THF = tetrahydrofuran;

[0684] NBS = N-bromosuccinimide;

[0685] AIBN = azobisisobutyronitrile;

[0686] TLC = thin layer chromatography;

[0687] DMF = N,N-dimethylformamide;

[0688] SEM = (trimethylsilyl)ethoxymethyl

[0689] HATU = 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0690] 2-MeTHF = 2-methyltetrahydrofuran;

[0691] MTBE = methyl tert-butyl ether;

[0692] T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide;

[0693] MCH = methylcyclohexane;

[0694] HPLC=high performance liquid chromatography.

[0695] Illustrative synthetic schemes

[0696] Compounds and salts of formula (I), (Ia) or (IIB) can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. The materials used herein are commercially available or prepared by synthetic methods known in the art. These schemes are not limited to the compounds listed in the examples or any particular substituents, which are for illustrative purposes only. Although various steps are described and depicted in the following synthetic schemes, in some cases, these steps may be performed in an order different from the order shown below. The numbering or R groups in each scheme do not necessarily correspond to the numbering or R groups of the claims or other schemes or tables herein.

[0697] Example 1. Reference procedure for compound 112 (Stille coupling)

[0698]

[0699] In some cases, the reference procedure of Example 1 was challenging in terms of quality control due to the number of steps and / or the use of Sn reagents.

[0700] Step 1-1: General procedure for preparing (4-(4-fluorophenyl)-1H-imidazole (Compound A3)

[0701]

[0702] To a solution of 4-bromo-1H-imidazole (Compound A1) (60 g, 408.24 mmol, 1 eq.) and (4-fluorophenyl) boronic acid (Compound A2) (114.24 g, 816.48 mmol, 2 eq.) in dioxane (500 mL) and H2O (100 mL) was added K2CO3 (169.26 g, 1.22 mol, 3 eq.) and Pd(dppf)Cl2 (35.85 g, 48.99 mmol, 0.12 eq.) at 30°C. The mixture was stirred at 110°C for 16 hours. LCMS showed that Compound A1 was consumed and 57% of the expected mass was detected. The mixture was combined with 3 other batches. The mixture was poured into H2O (1000 mL). The mixture was extracted with EA (1000 mL×2). The combined organic phases were poured into 1N HCl (1000 mL). The mixture was extracted with ethyl acetate (1000 mL x 2). The aqueous phase was basified to pH = 8 with Na2CO3. The mixture was extracted with ethyl acetate (1000 mL x 3). The organic phases were combined and concentrated in vacuo to give a crude product. Compound A3 (102 g, crude) was obtained as a brown solid, which was 1 H-NMR. 1 H-NMR: (400 MHz, DMSO-d6), 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) determination.

[0703] Step 1-2: General procedure for the preparation of 4-(4-fluorophenyl)-1-isopropyl-1H-imidazole (Compound A5)

[0704]

[0705] Compound A3 (99.5 g, 613.58 mmol, 1 eq.) was added to a solution of NaH (49.08 g, 1.23 mol, 60% purity, 2 eq.) in DMA (1000 mL) at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hours. 2-Bromopropane (Compound A4) (113.20 g, 920.37 mmol, 86.41 mL, 1.5 eq.) was added to the mixture at 0 ° C. The mixture was stirred at 80 ° C for 16 hours. LCMS showed that 20% of Compound A3 remained and 71% of the expected mass was detected. The mixture was poured into NH4Cl aqueous solution (2L). The mixture was extracted with ethyl acetate (2000 mL × 2). The organic phases were combined and concentrated in vacuo to give a crude product. Compound A5 (140 g, crude product) was obtained as a brown oil, which was determined by LCMS and 1 H-NMR determination.

[0706] 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).

[0707] Step 1-3: General procedure for the preparation of 4-(4-fluorophenyl)-5-iodo-1-isopropyl-1H-imidazole (Compound A6)

[0708]

[0709] To a solution of compound A5 (136 g, 665.87 mmol, 1 eq.) in DCM (1 L) was added NIS (449.42 g, 2.00 mol, 3.0 eq.) and TFA (22.78 g, 199.76 mmol, 14.79 mL, 0.3 eq.) which was stirred at 25 °C for 16 hours. 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 expected mass was detected. Saturated aqueous Na2SO3 solution (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 20:1-2:1). Compound A6 (75 g, 227.18 mmol, yield 34.12%) was obtained as a white solid, which was analyzed by LCMS and 1H-NMR confirmation. 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).

[0710] Step 1-4: General procedure for the preparation of 4-(4-fluorophenyl)-1-isopropyl-5-(tributylstannyl)-1H-imidazole (Compound A7)

[0711]

[0712] To a solution of compound A6 (65 g, 196.89 mmol, 1 eq.) in THF (2000 mL) was added n-BuLi (2.5 M, 102.38 mL, 1.3 eq.) dropwise at -70°C under N2, and after stirring at -70°C for 15 minutes, tributyl(chloro)stannane (96.13 g, 295.33 mmol, 79.45 mL, 1.5 eq.) was added dropwise at -70°C, and the mixture was stirred at -40°C to -50°C for 0.5 hours. LCMS showed that compound A6 was consumed and the expected mass was detected. It was poured into saturated aqueous KF solution (2 L), EA (2 L) was added, and the organic layer was washed with saturated aqueous NH4Cl solution (1 L) and brine (1 L), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE:EA 50:1 to 1:1). Compound A7 (40 g, 72.27 mmol, yield 36.71%, purity 89.123%) was obtained as a yellow oil, which was confirmed by LCMS. LCMS: retention time: 1.007 min, (M+H)=494.9.

[0713] Step 1-6: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (Compound A9)

[0714]

[0715] To a suspension of NaH (42.81 g, 1.07 mol, purity 60%, 1.5 eq.) in THF (1 L) was added 1H-imidazole-5-carboxylic acid ethyl ester (Compound A8) (100 g, 713.57 mmol, 1 eq.) in portions at 0°C, which was stirred at 20°C for 0.5 hours, SEM-C1 (178.45 g, 1.07 mol, 189.44 mL, 1.5 eq.) was added dropwise at 0°C, which was stirred at 25°C for 16 hours. TLC (PE: EA 1: 1) showed that Compound A8 (Rf = 0.1) was completely consumed, and a new spot (Rf = 0.3) was detected. It was poured into a saturated aqueous solution of NH4Cl (1 L) and extracted with ethyl acetate (1 L), 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 10:1-0:1). Compound A9 (136 g, 502.96 mmol, yield 70.48%) was obtained as a yellow solid. 1 H-NMR confirmed. 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)

[0716] Step 1-7: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound A10)

[0717]

[0718] To a solution of ethyl compound A9 (116 g, 429.00 mmol, 1 eq.) in CHCl3 (1 L) were added NBS (83.99 g, 471.89 mmol, 1.1 eq.) and AIBN (8.45 g, 51.48 mmol, 0.12 eq.), which was stirred at 65°C for 4 hours. 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:EA20:1-2:1). Compound A10 (80 g, 229.03 mmol, yield 53.39%) was obtained as a yellow solid, which was obtained by1 H-NMR. 1 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) confirmed.

[0719] Step 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)

[0720]

[0721] To a solution of compound A7 (10 g, 20.27 mmol, 1 eq.) and compound A10 (10.62 g, 30.41 mmol, 1.5 eq.) in toluene (100 mL) was added [2-(2-aminophenyl)phenyl]-chloro-palladium; bis(1-adamantyl)-butyl-phosphine (4.07 g, 6.08 mmol, 0.3 eq.) at 25°C, filled with N2 three times, and stirred at 110°C for 16 hours. 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 expected mass was detected. It 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 NaHCO3 aqueous solution (300 ml) and brine (300 ml), filtered, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE: EA 100: 1-1: 2). Compound A11 (20 g, 25.00 mmol, yield 41.11%, purity 59.089%) was obtained as a yellow oil, which was confirmed by LCMS. LCMS: retention time: 0.927 min, (M+H) = 473.3.

[0722] Step 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)

[0723]

[0724] To a solution of compound A11 (20 g, 42.32 mmol, 1 eq.) in THF (60 mL), MeOH (60 mL) and H2O (60 mL) was added LiOH.H2O (17.76 g, 423.17 mmol, 10 eq.), which was stirred at 25°C for 2 hours. TLC (PE:EA 1:1) showed that compound A11 was consumed and a new spot was detected (Rf = 0). The crude product 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 1N HCl, ethyl acetate (1 L) was added, the organic layer was washed with brine (0.5 L), dried over Na2SO4 and concentrated in vacuo. The crude product was triturated with petroleum ether (70 ml) and MTBE (25 ml), the mixture was filtered, the filter cake was washed with petroleum ether (20 ml) and dried in vacuo, and the filter cake was purified by reverse phase HPLC (1% TFA condition). Compound A12 (11.5 g, 25.01 mmol, yield 59.10%, purity 96.686%) was obtained as an off-white solid, which was analyzed by LCMS and 1 H-NMR confirmation. 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 l-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),

[0725] 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)

[0726]

[0727] To a solution of compound A12 (3.5 g, 7.87 mmol, 1 eq.) and 4-(4-methylpiperazine-1-yl)aniline (compound A13) (1.81 g, 9.45 mmol, 1.2 eq.) in DMF (35 mL) was added HATU (4.49 g, 11.81 mmol, 1.5 eq.) and DIEA (3.05 g, 23.62 mmol, 4.11 mL, 3.0 eq.), which was stirred at 25 ° C for 2 hours. LCMS showed that compound A12 was consumed and the desired mass was detected. It was combined with two other batches for post-treatment, the mixture was poured into water (300 ml), ethyl acetate (300 ml) was added, the organic layer was washed with brine (200 ml×3), dried over Na2SO4 and concentrated in vacuo. The crude product was used directly in the next step. Compound A14 (9 g, crude product) was obtained as a yellow solid, which was confirmed by LCMS. LCMS: retention time: 0.801 min, (M+H)=618.4.

[0728] 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)

[0729]

[0730] To a solution of compound A14 (9 g, 14.57 mmol, 1 equivalent) in DCM (10 mL) was added TFA (90 mL), which was stirred at 25 ° C for 2 hours. LCMS showed that compound A14 was consumed and the expected mass was detected. It was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Kromasil Eternity XT 250×80 mm×10 um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 30%-60%, 15 min) and lyophilized (lyophylizated). Compound 112 (4.42 g, 8.45 mmol, yield 58.03%, purity 93.215%) was obtained, which was obtained by 1 H-NMR and LCMS confirmed. LCMS: retention time: 0.611 min, (M+H)=488.3. 1H-NMR: (400MHz, DMSO-d6) δ = 13.64-12.60 (m, 1H), 9.67 (brs, 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).

[0731] Example 2: New Synthesis Route 1 of Compound 112

[0732]

[0733] Step 2-1: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (Compound A9)

[0734]

[0735] To a suspension of NaH (42.81 g, 1.07 mol, purity 60%, 1.5 eq.) in THF (1 L) was added 1H-imidazole-5-carboxylic acid ethyl ester (Compound A8) (100 g, 713.57 mmol, 1 eq.) portionwise at 0°C, which was stirred at 20°C for 0.5 hours, SEM-Cl (178.45 g, 1.07 mol, 189.44 mL, 1.5 eq.) was added dropwise at 0°C, which was stirred at 25°C for 16 hours. TLC (PE: EA 1: 1) showed that Compound A8 (Rf = 0.1) was completely consumed, and a new spot (Rf = 0.3) was detected. It was poured into a saturated aqueous solution of NH4Cl (1 L) and extracted with ethyl acetate (1 L), 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 10:1-0:1). Compound A9 (136 g, 502.96 mmol, yield 70.48%) was obtained as a yellow solid. 1 H-NMR confirmed. 1H-NMR: (400 MHz, chloroform-d) δ = 7.74 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 1.1 Hz, 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)

[0736] Other examples of step 2-1: the ethyl ester group of compound A8 can be replaced with methyl ester, n-PrOH ester, i-PrOH ester, t-BuOH ester, phenyl ester, benzyl ester, p-methoxybenzyl ester, and the like.

[0737] The protecting group SEM can be replaced by a commercially available protecting group, for example, methoxycarbonyl, ethoxycarbonyl, Cbz (benzyloxycarbonyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), Alloc (allyloxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Tos (p-toluenesulfonyl), Tfa (2,2,2-trifluoroacetyl), Trt (trityl), Dmb (2,4-dimethoxybenzyl), Pmb (p-methoxybenzyl), Bn (benzyl).

[0738] Step 2-2: General procedure for preparing ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound A10)

[0739]

[0740] To a solution of ethyl compound A9 (116 g, 429.00 mmol, 1 eq.) in CHCl3 (1 L) were added NBS (83.99 g, 471.89 mmol, 1.1 eq.) and AIBN (8.45 g, 51.48 mmol, 0.12 eq.), which was stirred at 65°C for 4 hours. 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: EA20: 1-2: 1). Compound A10 (80 g, 229.03 mmol, yield 53.39%) was obtained as a yellow solid, which was obtained by 1 H-NMR confirmed. 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).

[0741] Step 2-3: General procedure for the preparation of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound B1)

[0742]

[0743] To a solution of compound A10 (28 g, 80.16 mmol, 1 eq.) in THF (300 mL) was added i-PrMgCl (2 M, 120.24 mL, 3 eq.) at -40 °C. The mixture was stirred at -40 °C for 10 minutes. DMF (35.16 g, 480.97 mmol, 37.01 mL, 6 eq.) was added to the mixture at -70 °C. The mixture was stirred at 20 °C for 1 hour. HPLC showed that compound A10 was consumed. LCMS showed that the expected mass was detected. The mixture was poured into 1N HCl (500 mL). The mixture was extracted with EA (300 mL×2). The organic layers were combined, 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=10:1-3:1). Compound B1 (15 g, 50.27 mmol, yield 62.71%) was obtained as a yellow oil and analyzed by LCMS and 1 H-NMR examination. 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)

[0744] In some cases, the strong base i-PrMgCl used in the bromine-metal exchange reaction can be replaced with a commercially available strong base, such as LDA, n-BuLi, t-BuLi, LiHMDS, KHMDS, i-PrMgBr, MeMgCl, MeMgBr, EtMgCl, EtMgBr, etc.

[0745] DMF can be replaced by other formylating agents, such as N,N-diethylformamide.

[0746] 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)

[0747]

[0748] To a mixture of compound B1 (12.5 g, 41.89 mmol, 1 eq.) in THF (200 mL) was added NH3·H2O (22.73 g, 162.11 mmol, 24.97 mL, 25% purity, 3.87 eq.). The mixture was stirred at 20°C for 4 hours. Compound B2 (14.54 g, 50.27 mmol, 1.2 eq.) and DIEA (16.24 g, 125.67 mmol, 21.89 mL, 3 eq.) were added to the mixture at 20°C. The mixture was stirred at 20°C for 2 hours. TLC (PE:EA=0:1) showed that compound B1 was consumed and a new spot was detected (Rf=0.3). The residue was poured into water (150 mL) and extracted with ethyl acetate (150 mL×3). The organic phases were combined, washed with brine (200 mL×1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE:EA=1:1-0:1). Compound B3 (10 g, 22.51 mmol, yield 53.74%, purity 96.914%) was obtained as a yellow solid and checked by LCMS. LCMS: retention time: 0.799 min, (M+H)=431.2.

[0749] 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)

[0750]

[0751] To a mixture of compound B3 (10 g, 23.23 mmol, 1 eq.) in DMF (60 mL) was added K2CO3 (9.63 g, 69.68 mmol, 3 eq.) and 2-bromopropane (8.57 g, 69.68 mmol, 6.54 mL, 3 eq.). The mixture was stirred at 60 ° C for 6 hours. LCMS showed that compound B3 was consumed and the expected mass was detected. The residue was poured into ice water (500 mL) and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with brine (200 mL×1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA=1:1-1:5). Compound A11 (7.6 g, crude product) was obtained as a yellow solid, which was analyzed by LCMS and 1 H-NMR examination. 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)

[0752] 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)

[0753]

[0754] To a mixture of compound A11 (7.6 g, 16.08 mmol, 1 eq.) in THF (80 mL) and H2O (16 mL) was added LiOH (2.70 g, 112.56 mmol, 7 eq.). The mixture was stirred at 20 ° C for 3 hours. LCMS showed that the reactant was consumed and the desired mass was detected. The residue was acidified with 1N HCl aqueous solution, and the resulting mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude compound was used in the next step without further purification. Compound A12 (6.1 g, crude product) was obtained as a yellow solid, which was purified by LCMS and1 H-NMR examination. 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)

[0755] : 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)

[0756]

[0757] 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 hours. LCMS showed that compound A12 was consumed and the expected mass was detected. The residue was poured into water (500 mL) and extracted with ethyl acetate (150 mL×3). The organic phases were combined, 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 product) was obtained as a brown oil and checked with LCMS. LCMS: retention time: 0.753 min, (M+H)=618.4.

[0758] 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)

[0759]

[0760] To a solution of compound A14 (9 g, 14.57 mmol, 1 equivalent) in DCM (10 mL) was added TFA (90 mL), which was stirred at 25 ° C for 2 hours. LCMS showed that compound A14 was consumed and the expected mass was detected. It was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Kromasil Eternity XT 250×80 mm×10 um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 30%-60%, 15 min) and lyophilized. Compound 112 (4.42 g, 8.45 mmol, yield 58.03%, purity 93.215%) was obtained, which was obtained by 1 H-NMR and LCMS confirmed. 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).

[0761] Example 3: New Synthesis Route 2 of Compound 112

[0762] The imidazole ring of compound A8 is protected with a SEM group and then brominated at the C-2 position to obtain compound A10. Bromine-magnesium is exchanged with a Grignard reagent and then reacted with DMF to introduce a 2-formyl group. The isonitrile chemistry with compound B2 builds the imidazole ring in one step to obtain compound A11. Hydrolysis of the ester group and condensation reaction with compound A13 give compound A14. The final compound is obtained after deprotection of the SEM group.

[0763]

[0764] Step 3-1: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (Compound A9)

[0765]

[0766] To a suspension of NaH (42.81 g, 1.07 mol, purity 60%, 1.5 eq.) in THF (1 L) was added 1H-imidazole-5-carboxylic acid ethyl ester (Compound A8) (100 g, 713.57 mmol, 1 eq.) portionwise at 0°C, which was stirred at 20°C for 0.5 hours, SEM-Cl (178.45 g, 1.07 mol, 189.44 mL, 1.5 eq.) was added dropwise at 0°C, which was stirred at 25°C for 16 hours. TLC (PE: EA 1: 1) showed that Compound A8 (Rf = 0.1) was completely consumed, and a new spot (Rf = 0.3) was detected. It was poured into a saturated aqueous solution of NH4Cl (1 L) and extracted with ethyl acetate (1 L), 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 10:1-0:1). Compound A9 (136 g, 502.96 mmol, yield 70.48%) was obtained as a yellow solid. 1 H-NMR confirmed. 1 H-NMR: (400 MHz, chloroform-d) δ = 7.74 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 1.1 Hz, 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)

[0767] In some cases, the ethyl ester group of Compound A8 can be replaced with a methyl ester, an n-PrOH ester, an i-PrOH ester, a t-BuOH ester, a phenyl ester, a benzyl ester, a p-methoxybenzyl ester, or the like.

[0768] The protecting group SEM can be replaced by a commercially available protecting group, for example, methoxycarbonyl, ethoxycarbonyl, Cbz (benzyloxycarbonyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), Alloc (allyloxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Tos (p-toluenesulfonyl), Tfa (2,2,2-trifluoroacetyl), Trt (trityl), Dmb (2,4-dimethoxybenzyl), Pmb (p-methoxybenzyl), Bn (benzyl).

[0769] Step 3-2: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound A10)

[0770]

[0771] To a solution of ethyl compound A9 (116 g, 429.00 mmol, 1 eq.) in CHCl3 (1 L) were added NBS (83.99 g, 471.89 mmol, 1.1 eq.) and AIBN (8.45 g, 51.48 mmol, 0.12 eq.), which was stirred at 65°C for 4 hours. 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: EA20: 1-2: 1). Compound A10 (80 g, 229.03 mmol, yield 53.39%) was obtained as a yellow solid, which was obtained by 1 H-NMR confirmed. 1 H-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).

[0772] Step 3-3: General procedure for preparing ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound B1)

[0773]

[0774] To a solution of compound A10 (28 g, 80.16 mmol, 1 eq.) in THF (300 mL) was added i-PrMgCl (2 M, 120.24 mL, 3 eq.) at -40°C. The mixture was stirred at -40°C for 10 minutes. DMF (35.16 g, 480.97 mmol, 37.01 mL, 6 eq.) was added to the mixture at -70°C. The mixture was stirred at 20°C for 1 hour. HPLC showed that compound A10 was consumed. LCMS showed that the expected mass was detected. The mixture was poured into 1N HCl (500 mL). The mixture was extracted with EA (300 mL×2). The organic layers were combined, 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=10:1-3:1). Compound B1 (15 g, 50.27 mmol, yield 62.71%) was obtained as a yellow oil and analyzed by LCMS and 1H-NMR examination. 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).

[0775] In some cases, the strong base i-PrMgCl used in the bromine-metal exchange reaction can be replaced with a commercially available strong base, such as LDA, n-BuLi, t-BuLi, LiHMDS, KHMDS, i-PrMgBr, MeMgCl, MeMgBr, EtMgCl, EtMgBr, etc.

[0776] In some cases, DMF can be replaced by other formylating agents, for example, N,N-diethylformamide and the like.

[0777] 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)

[0778]

[0779] To a mixture of compound B1 (5 g, 16.76 mmol, 1 eq.) in THF (20 mL) was added i-PrNH2 (3.96 g, 67.02 mmol, 5.76 mL, 4 eq.). The mixture was stirred at 20 ° C for 4 hours. Compound B2 (5.82 g, 20.11 mmol, 1.2 eq.) and DIEA (6.50 g, 50.27 mmol, 8.76 mL, 3 eq.) were added to the mixture at 20 ° C. The mixture was stirred for 1 hour at 20 ° C. 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 ( 80g The product was purified by silica gel flash column, elution with a gradient of 0-100% ethyl acetate / petroleum ether at 120 mL / min to obtain compound A11 (6.17 g, 13.05 mmol, yield 77.91%, purity 100%) as a yellow oil.

[0780] Step 3-5: General procedure for preparing 5′-(4-fluorophenyl)-3′-isopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,3′H-[2,4′-biimidazole]-4-carboxylic acid (Compound A12)

[0781]

[0782] To a mixture of compound A11 (7.6 g, 16.08 mmol, 1 eq.) in THF (80 mL) and H2O (16 mL) was added LiOH (2.70 g, 112.56 mmol, 7 eq.). The mixture was stirred at 20 ° C for 3 hours. LCMS showed that the reactants were consumed and the desired mass was detected. The residue was acidified with 1 M HCl aqueous solution, and the resulting mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude compound was used in the next step without further purification. Compound A12 (6.1 g, crude product) was obtained as a yellow solid, which was purified by LCMS and 1 H-NMR examination. 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), 3.2l (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)

[0783] 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)

[0784]

[0785] 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 hours. LCMS showed that compound A12 was consumed and the expected mass was detected. The residue was poured into water (500 mL) and extracted with ethyl acetate (150 mL×3). The organic phases were combined, 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 product) was obtained as a brown oil and checked with LCMS. LCMS: retention time: 0.753 min, (M+H)=618.4.

[0786] 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)

[0787]

[0788] To a mixture of compound A14 (9 g, 14.57 mmol, 1 eq.) in CH2Cl2 (2 mL) was added TFA (30.80 g, 270.12 mmol, 20.00 mL, 18.54 eq.). The mixture was stirred at 20 ° C for 5 hours. LCMS showed that compound A14 was consumed and the desired mass was detected. The mixture was alkalized to pH = 8 with an aqueous NaHCO3 solution, and the resulting mixture was extracted with ethyl acetate (200 mL×4). The organic phases were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (0.1% NH3·H2O). Compound 112 (3.04 g, 6.20 mmol, yield 42.58%, purity 99.492%) was obtained as an off-white solid, which was analyzed by LCMS and 1 H-NMR examination. LCMS: retention time: 0.683 min, (M+H)=488.2. 1H-NMR: (400 MHz, DMSO-d6) δ = 13.14-12.98 (m, 1H), 9.72 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.67 (d, J = 9.2Hz, 2H), 7.44-7.34 (m, 2H), 7.14 (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).

[0789] Example 4: New synthetic route 3 of compound 112.

[0790] The synthesis from compound A8 to compound B1 is the same as in new route 1. Compound B1 is deprotected and then reacted with compound B2 in one step to form the imidazole ring. Hydrolysis of the ester group and condensation reaction with compound A13 give the target compound compound 112.

[0791]

[0792] Step 4-1: General procedure for the preparation of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (Compound A9)

[0793]

[0794] To a suspension of NaH (42.81 g, 1.07 mol, purity 60%, 1.5 eq.) in THF (1 L) was added 1H-imidazole-5-carboxylic acid ethyl ester (Compound A8) (100 g, 713.57 mmol, 1 eq.) in portions at 0°C, which was stirred at 20°C for 0.5 hours, SEM-Cl (178.45 g, 1.07 mol, 189.44 mL, 1.5 eq.) was added dropwise at 0°C, which was stirred at 25°C for 16 hours. TLC (PE: EA 1: 1) showed that Compound A8 (Rf = 0.1) was completely consumed, and a new spot (Rf = 0.3) was detected. It was poured into a saturated aqueous solution of NH4Cl (1 L) and extracted with ethyl acetate (1 L), 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 10:1-0:1). Compound A9 (136 g, 502.96 mmol, yield 70.48%) was obtained as a yellow solid. 1 H-NMR confirmed. 1H-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).

[0795] 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, benzyl methyl ester, 4-methylbenzyl methyl ester, and the like.

[0796] The protecting group SEM can be replaced by a commercially available protecting group, for example, methoxycarbonyl, ethoxycarbonyl, Cbz (benzyloxycarbonyl), Boc (tert-butoxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), Alloc (allyloxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Tos (p-toluenesulfonyl), Tfa (2,2,2-trifluoroacetyl), Trt (trityl), Dmb (2,4-dimethoxybenzyl), Pmb (p-methoxybenzyl), Bn (benzyl).

[0797] Step 4-2: General procedure for the preparation of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound A10)

[0798]

[0799] To a solution of compound A9 (116 g, 429.00 mmol, 1 eq.) in CHCl3 (1 L) were added NBS (83.99 g, 471.89 mmol, 1.1 eq.) and AIBN (8.45 g, 51.48 mmol, 0.12 eq.), which was stirred at 65°C for 4 hours. 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 20:1-2:1). Compound A10 (80 g, 229.03 mmol, yield 53.39%) was obtained as a yellow solid, which was obtained by 1 H-NMR confirmed. 1H-NMR: (400MHz, DMSO-d6) δ=8.30-8.24(m, lH), 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).

[0800] Step 4-3: General procedure for preparing ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (Compound B1)

[0801]

[0802] To a solution of compound A10 (28 g, 80.16 mmol, 1 eq.) in THF (300 mL) was added i-PrMgCl (2 M, 120.24 mL, 3 eq.) at -40 °C. The mixture was stirred at -40 °C for 10 minutes. DMF (35.16 g, 480.97 mmol, 37.01 mL, 6 eq.) was added to the mixture at -70 °C. The mixture was stirred at 20 °C for 1 hour. HPLC showed that compound A10 was consumed. LCMS showed that the expected mass was detected. The mixture was poured into 1N HCl (500 mL). The mixture was extracted with EA (300 mL×2). The organic layers were combined, 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=10:1-3:1). Compound B1 (15 g, 50.27 mmol, yield 62.71%) was obtained as a yellow oil and analyzed by LCMS and 1 H-NMR examination. 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).

[0803] In some cases, the strong base i-PrMgCl used in the bromine-metal exchange reaction can be replaced with a commercially available strong base, such as LDA, n-BuLi, t-BuLi, LiHMDS, KHMDS, i-PrMgBr, MeMgCl, MeMgBr, EtMgCl, EtMgBr, etc.

[0804] DMF can be replaced by other formylating agents, for example, N,N-diethylformamide and the like.

[0805] Step 4-4: General procedure for preparing ethyl 2-formyl-1H-imidazole-4-carboxylate (Compound C1)

[0806]

[0807] To a mixture of compound B1 (40 g, 134.04 mmol, 1 eq.) in 2-MeTHF (80 mL) was added 36.5% aqueous HCl solution (90 mL, 9.1 eq.). The mixture was stirred at 10°C for 6-8 hours. The pH of the reaction mixture was adjusted to 7-8 with 15% aqueous NaOH solution (333 mL) and saturated aqueous NaHCO3 solution (270 mL). The aqueous layer was separated and extracted five times with EA (200 mL). All organic phases were combined and concentrated, dried at less than 40°C, and EtOH (40 mL) was added. H2O (400 mL) was added dropwise to the EtOH suspension of compound C1 at 15-25°C, and stirred at -5-5°C for 16 hours, then filtered and washed with H2O. The wet cake was dried at 45-55°C for 20 hours. The yield (assay yield) converted according to the analytical results was 85%. The structure was checked by LCMS. LCMS: (M+H)=169.2.

[0808] 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)

[0809]

[0810] Compound C1 (100 g, 0.59 mol, 1 eq.) and THF (1 L) were added to R1, i-PrNH2 (140.7 g, 2.38 mol, 4 eq.) was added, and the mixture was stirred at 15-25° C. for 1 hour. Compound B2 (172.1 g, 0.59 mol, 1.0 eq.) was added at 15-25° C. The mixture was stirred at 15-25° C. for 2-11 hours. 500 mL MTBE and 1 L process water were added to the reaction mixture. The pH of the mixture was then adjusted to 1-2 with a 35% HCl aqueous solution and separated. The organic phase was washed twice with 500 mL 3.5% HCl aqueous solution. The aqueous phases were combined and the pH was adjusted to 7-8 with a 30% NaOH aqueous solution. The wet cake was filtered and dried at 45-55° C. for 12-24 hours. The yield converted according to the analytical results was 89%. The structure was checked with LCMS. LCMS: (M+H)=343.2.

[0811] In some cases, the 4-MePh group of compound B2 can be replaced with other commercially available or easily prepared substituted phenyl groups, and the substitution can be H, F, Cl, Br, methyl, methoxy, etc.

[0812] The reaction solvent can 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 a combination thereof.

[0813] An organic base such as TEA, DIEA, etc. may also be added to accelerate the reaction.

[0814] The reaction temperature may be -20°C to 110°C.

[0815] The crystallization solvent can be selected from the following solvents: EA, IPAc, MTBE, THF, Me-THF, diethyl ether, n-heptane, n-hexane, methylcyclohexane, petroleum ether, MeOH, EtOH, i-PrOH, acetone, acetonitrile, etc. and combinations thereof.

[0816] Step 4-6: General procedure for the preparation of 5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxylic acid (Compound C3)

[0817]

[0818] Compound C2 (100 g, 0.29 mol, 1 eq.) and 1,4-dioxane (500 mL) were added to the reactor, 13.48% NaOH aqueous solution (346.7 g, 1.17 mol, 4 eq.) was added and the mixture was stirred at 75-85°C for 16 hours. Cooled to 20-50°C, and 700 mL of process water was added to the reaction mixture. Then 36-39% HCl aqueous solution (115 g, 1.17 mol, 4.0 eq.) was added at 20-50°C. The reactor was adjusted to 0-10°C and stirred at 0-10°C for 2-4 hours. Then filtered and the wet cake was washed with 150 mL of process water. The wet cake was dried at 50-55°C for 24 hours. The yield converted according to the analytical results was 90%. The structure was checked by LCMS. LCMS: (M+H)=315.2.

[0819] The base NaOH used in the hydrolysis reaction can be replaced by KOH, LiOH, Ca(OH)2, K2CO3, KHCO3, Na2CO3, NaHCO3, K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, NaH2PO4, etc.

[0820] The reaction solvent may be selected from 1,4-dioxane, MeOH, EtOH, i-PrOH, n-PrOH, THF, water, and combinations thereof.

[0821] The reaction temperature may be -20 to 110°C.

[0822] Step 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)

[0823]

[0824] To a suspension of compound C3 (79 g, analytical purity 76.4%, 0.192 mol, 1.0 eq.) in THF (790 mL) was added Et3N (77.6 g, 0.77 mol, 4.0 eq.). The mixture was stirred at 15-25°C for 30-60 minutes and then cooled to -5-5°C. Compound A13 (47.7 g, 0.25 mol, 1.3 eq.) was added and then 50% T3P EA solution (183 g, 0.29 mol, 1.5 eq.) was added dropwise at -5-5°C. The mixture was stirred at -5-5°C until the reaction mixture was completely converted. EA (560 mL) and 560 mL of 5% Na2SO4 aqueous solution were added and then stirred and separated. The aqueous phase was extracted with 240 mL EA and 400 mL THF. The organic phases were combined and then washed with 7% NaHCO3 (560 mL) and water (560 mL). The obtained organic phase was decolorized by CUNO (12 g active cake), then switched to EtOH (560 mL), and then water (800 mL) was added dropwise at 15-25° C. The mixture was stirred at 15-25° C. for 2-4 hours, then filtered and washed with water (400 mL). The wet cake was dissolved with 400 mL THF at 45-55° C., and then water (800 mL) was added dropwise at 20-30° C. The mixture was stirred at 20-30° C. for 4-10 hours, then filtered and washed with water (400 mL). The filter cake was vacuum dried at 45-60° C. for 16-24 hours to obtain 36.9 g of the target compound 112 with a purity of 99.85%, and the yield converted according to the analytical results was 78.8%. The results were analyzed by LCMS and 1 H-NMR structure check. LCMS: retention time: 0.683 min, (M+H)=488.2. 1H-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).

[0825] The condensation reagent T3P can be replaced with a commercially available condensation reagent, such as HATU, EDCI, PyBOP, HBTU, DPPA, CDI, and the like.

[0826] The T3P / EA solution can be replaced with other T3P solutions, such as T3P, T3P / THF solution, T3P / 2-MeTHF solution, T3P / IPAc solution.

[0827] Example 5: New Synthesis Route 4 of Compound 112

[0828] The isonitrile chemical reaction between compound D1 and compound B2 and i-PrNH2 gives compound D2. The CF3 group is hydrolyzed to a carboxylic acid group, which then condenses with compound A13 to give the target compound.

[0829]

[0830] Step 5-1: General procedure for the preparation of 5′-(4-fluorophenyl)-3′-isopropyl-4-(trifluoromethyl)-1H,3′H-2,4′-biimidazole (Compound D2)

[0831]

[0832] Compound D1 was prepared according to the procedure reported in WO2009084614A1.

[0833] i-PrNH2 (14.41 g, 243.78 mmol, 4.0 equiv) was added to a mixture of compound D1 (10.0 g, 60.94 mmol, 1 equiv) in THF (70.0 mL). The mixture was stirred at 20 ° C for 1-2 hours. Compound B2 (18.51 g, 67.05 mmol, 1.05 equiv) was added to the mixture. The mixture was stirred at 20 ° C for 2-6 hours until the reaction mixture was completely converted. EA (50 mL) and water (50 mL) were added. The pH of the mixture was adjusted to 5-6 with 36% HCl aqueous solution (11.5 g) and then separated. The pH of the organic phase was adjusted to 9-10 with 10% Na2CO3 aqueous solution (40 g) and then separated. The organic phase was washed with 5% Na2CO3 aqueous solution (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 to 30 mL in vacuo at less than 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 and stirred at 0-10°C for 4-6 hours, then filtered and washed with n-heptane (20 mL). The wet cake was dried in vacuo at 40-50°C for 10-18 hours. The yield calculated according to the analytical results was 91%. The structure was checked by LCMS. LCMS: (M+H)=339.2.

[0834] As yet another example, the reaction conditions may be adjusted as follows:

[0835] The CF3 group of compound D1 can be composed of CR A1 R A2 R A3 Replace, and R A1 , R A2 and R A3 They can be the same or different groups selected from F, Cl, Br, OMe, OEt, for example, CBr3, CCl3, CF2Cl, CFCl2, CF2Br, CFBr2, C(OMe)3, C(OEt)3, etc.

[0836] The 4-MePh group of compound B2 can be replaced with other substituted phenyl groups which are commercially available or easily prepared, and the substitution can be H, F, Cl, Br, methyl, methoxy, etc.

[0837] The reaction solvent can 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. and combinations thereof.

[0838] An organic base such as TEA, DIEA, etc. may also be added to accelerate the reaction.

[0839] The reaction temperature may be -20°C to 110°C.

[0840] The crystallization solvent can be the following solvents: EA, IPAc, MTBE, THF, Me-THF, diethyl ether, n-heptane, n-hexane, methylcyclohexane, petroleum ether, MeOH, EtOH, i-PrOH, acetone, acetonitrile, etc. and combinations thereof.

[0841] Step 5-2: General procedure for preparing 5′-(4-fluorophenyl)-3′-isopropyl-1H,3′H-[2,4′-biimidazole]-4-carboxylic acid (Compound C3)

[0842]

[0843] To a mixture of compound D2 (10.0 g, 29.56 mmol, 1 eq.) in MeOH (50 mL) was added a solution of NaOH (7.09 g, 177.36 mmol, 6.0 eq.) dissolved in water (50 mL), and the mixture was stirred at 60-70 ° C for 16 hours until compound D2 was completely consumed. The pH of the mixture was adjusted to 4.7-5.5 by adding HCl aqueous solution and filtered. The filter cake was washed with water (20 g), then slurried with water (100 g) at 35-45 ° C for 6-8 hours, and stirred at 15-25 ° C for 4-6 hours. The wet filter cake was filtered and dried in vacuo at 40-50 ° C for 12-18 hours. The yield converted according to the analytical results was 90%. The structure was checked by LCMS.

[0844] LCMS: (M+H)=315.3.

[0845] In some cases, the base NaOH used in the hydrolysis reaction can be replaced with KOH, LiOH, Ca(OH)2, K2CO3, KHCO3, Na2CO3, NaHCO3, K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, NaH2PO4, etc.

[0846] The reaction solvent may be selected from 1,4-oxane, MeOH, EtOH, i-PrOH, n-PrOH, THF, water, and combinations thereof.

[0847] The reaction temperature may be -20 to 110°C.

[0848] Step 5-3: General procedure for preparing 5′-(4-fluorophenyl)-3′-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H,3′H-[2,4′-biimidazole]-4-carboxamide (Compound 112)

[0849]

[0850] To a suspension of compound C3 (79 g, 1.0 eq., analytical purity 76.4%, 0.192 mol) in THF (790 mL) was added Et3N (77.6 g, 0.77 mol, 4.0 eq.). The mixture was stirred at 15-25°C for 30-60 minutes and then cooled to -5-5°C. Compound A13 (47.7 g, 0.25 mol, 1.3 eq.) was added and then 50% T3P EA solution (183 g, 0.29 mol, 1.5 eq.) was added dropwise at -5-5°C. The mixture was stirred at -5-5°C until the reaction mixture was completely converted. EA (560 mL) and 560 mL of 5% Na2SO4 aqueous solution were added and then stirred and separated. The aqueous phase was extracted with 240 mL EA and 400 mL THF. The organic phases were combined and then washed with 7% NaHCO3 (560 mL) and water (560 mL). The obtained organic phase was decolorized by CUNO (12 g active cake), then switched to EtOH (560 mL), and then water (800 mL) was added dropwise at 15-25° C. The mixture was stirred at 15-25° C. for 2-4 hours, then filtered and washed with water (400 mL). The wet cake was dissolved with 400 mL THF at 45-55° C., and then water (800 mL) was added dropwise at 20-30° C. The mixture was stirred at 20-30° C. for 4-10 hours, then filtered and washed with water (400 mL). The filter cake was vacuum dried at 45-60° C. for 16-24 hours to obtain 36.9 g of the target compound 112 with a purity of 99.85%, and the yield converted according to the analytical results was 78.8%. The results were analyzed by LCMS and 1 H-NMR structure check. 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).

[0851] In some cases, the condensation reagent T3P can be replaced with a commercially available condensation reagent, such as HATU, EDCI, PyBOP, HBTU, DPPA, CDI, and the like.

[0852] The T3P / EA solution can be replaced with other T3P solutions, such as T3P, T3P / THF solution, T3P / 2-MeTHF solution, T3P / IPAc solution.

[0853] Example 6: New route 4 for compound 112 can also be used for the synthesis of compound 120.

[0854]

[0855] Compound D1 reacts with isonitrile of compound B2 and 2,2,2-trifluoroethylamine to give compound E1. The CF3 group is hydrolyzed to a carboxylic acid group, which is then condensed with compound A13 to give the target compound, compound 120.

[0856] Step 6-1: General procedure for the preparation of 5′-(4-fluorophenyl)-3′-neopentyl-4-(trifluoromethyl)-1H,3′H-2,4′-biimidazole (Compound E1)

[0857]

[0858] Compound D1 was prepared according to the procedure reported in WO2009084614A1.

[0859] To a solution of compound D1 (100 g, 0.61 mol, 1.0 equiv) in THF (1 L) was added 2,2,2-trifluoroethylamine (362 g, 3.7 mol, 6.0 equiv). The mixture was stirred at 15-25 ° C for 3-4 hours, 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 hours, then 2,2,2-trifluoroethylamine (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 judged 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 obtained aqueous phase was extracted with MTBE (500 g) again. The obtained organic layers were combined and washed with water (500 g), then concentrated and switched to toluene (100 mL) by distillation. The obtained mixture was heated and stirred at 40-45 ° C for 1 hour, and 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, and then stirred for 6-14 hours. The mixture was filtered. The filter cake was washed with MCH (150 mL). The filter cake was vacuum dried at 45-55 ° C to obtain solid A. The yield converted according to the analytical results was 85%. The structure was checked with LCMS. LCMS: (M+H) = 367.2.

[0860] Step 6-2: General procedure for preparing 5′-(4-fluorophenyl)-3′-(2,2,2-trifluoroethyl)-1H,3′H-[2,4′-biimidazole]-4-carboxylic acid (Compound E2)

[0861]

[0862] To a mixture of compound E1 (100 g, 0.27 mol, 1.0 equivalent) in MeOH (600 mL) was added 9.56% aqueous NaOH solution (697 g, 1.67 mol, 6.1 equivalents). The mixture was heated and stirred at 50-55 ° C until the reaction was completely converted as determined by HPLC. Water (500 mL) was added and the mixture was adjusted to pH 4-5 using 35% aqueous HCl solution. The mixture was stirred at 15-25 ° C for 2-4 hours and filtered. The filter cake was washed twice with water (200 mL) and then vacuum dried at 40-50 ° C for 12-18 hours to obtain solid compound E2. The yield converted according to the analytical results was 90%. The structure was checked by LCMS. LCMS: (M+H) = 355.2.

[0863] Step 6-3: General procedure for preparing 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)

[0864]

[0865] A suspension of compound E2 (100 g, 0.28 mol, 1.0 eq.) and THF (850 mL) was distilled twice to reduce the water content. Et3N (114 g, 1.13 mol, 4.0 eq.) and compound A13 (80.9 g, 0.42 mol, 1.5 eq.) were added to a suspension of compound E2 in THF (1 L). The mixture was stirred at 15-25° C. for 30-60 minutes, and then cooled to -5-5° C. Compound A13 (72.8 g, 0.38 mol, 1.35 eq.) was added, and then 50% T3P EA solution (121 g, 0.38 mol, 1.35 eq.) was added dropwise at -5-5° C. The mixture was stirred at -5-5° C. until the reaction mixture was completely converted. EA (630 mL), 5% Na2SO4 aqueous solution (354 g) and water (320 g) were added, and then stirred and separated. The aqueous phase was extracted with EA (250mL) and THF (450mL). The organic phases were combined and then washed with 7% NaHCO (700g*2) and water (475g*2). The washed aqueous phases were combined and extracted with EA (70g*2). The organic phases were combined and decolorized by CUNO (15g active cake). CUNO (0.15g active cake) was washed with THF (450g), and compound 120EA / THF solution was combined. The compound 120EA / THF solution was concentrated and switched to EtOH (700mL), and then water (1050mL) was added dropwise at 15-25°C. The mixture was stirred at 15-25°C for 2-4 hours, then filtered and washed with water (200g). The filter cake was dried at 30-60°C for 10-18 hours under vacuum and 20-50%RH. The yield converted according to the analysis result was 75%. The structure was checked with LCMS. LCMS: (M+H)=528.2.

[0866] As described above, the procedures of Examples 2-6 can provide short synthetic routes, relatively high yields and are easy to scale up. In addition, the procedures of Examples 2-6 do not require the Sn reagents required for Stille coupling to form the biimidazole core.

[0867] Additionally, the procedures of Examples 2-6 are amenable to quality control.

[0868] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and that those skilled in the art will think of various modifications or changes in view of them, which are included in the spirit and scope of the present application and within 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 preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in: R 1 Selected from: N(R 5 )2, where each R 5 independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence 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 Carbocyclic and 3- to 12-membered heterocyclic rings; Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2; R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; R 4 Selected from: hydrogen; Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Halogenated alkyl, OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, The method comprises making a compound represented by formula (A) or a pharmaceutically acceptable salt thereof Among them, ring W, R 3 and R 4 defined above, and R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-6 alkyl; subjected to a hydrolysis step to produce a compound represented by formula (B) or a pharmaceutically acceptable salt thereof, Among them, ring W, R 3 and R 4 Defined above.

2. The method according to claim 1, wherein R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-3 alkyl.

3. The method according to claim 1, wherein R A1 , R A2 and R A3 Each of is independently selected from halogen.

4. The method according to claim 1, wherein R A1 , R A2 and R A3 Each of which is independently selected from -OC 1-6 alkyl.

5. The method according to claim 1, wherein R A1 , R A2 and R A3 Each of is independently selected from F, Cl, Br, OMe and OEt.

6. The method according to claim 1, It is CBr3, CCl3, CF3, CF2Cl, CFCl2, CF2Br, CFBr2, C(OMe)3 or C(OEt)3.

7. The method according to claim 1, It is CF3.

8. The process according to 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 (eg, MeOH / water).

9. The method according to 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. The process of claim 8, wherein the hydrolysis step is performed in a mixture of methanol and water.

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

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

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

14. The method of claim 12, wherein the base is selected from NaOH, KOH, LiOH, Ca(OH)2, K2CO3, KHCO3, Na2CO3, NaHCO3, K3PO4, K2HPO4, KH2PO4, Na3PO4, Na2HPO4, NaH2PO4, or a combination thereof.

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

16. The method according to any one of claims 1 to 15, 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, Where R 1 As defined above in formula (I).

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

18. The method of claim 16, wherein the condensation step is performed in the presence of a condensation reagent (e.g., T3P, HATU, EDCI, PyBOP, HBTU, DPPA, CDI).

19. The method according to any one of claims 1 to 18, wherein the compound represented by formula (I) has a structure of formula (Ia), in: R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected from oxo and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and R 4 is a substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by one or more halogens.

20. The method according to any one of claims 1 to 18, wherein the compound represented by formula (I) has a structure of formula (Ia), in, R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and R 4 It is an unsubstituted C1-C6 alkyl group.

21. A method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in: R 1 Selected from: N(R 5 )2, where each R 5 independently selected from hydrogen and optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence 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 Carbocyclic and 3- to 12-membered heterocyclic rings; Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2; R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; R 4 Selected from: hydrogen; Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic rings and 3 to 12 membered heterocyclic rings; and Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings, The method comprises making a compound represented by formula (E) or a pharmaceutically acceptable salt thereof in, Ring W is defined above, En is 0 or 1, R EN is a protecting group, and 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; and a compound represented by formula (F) or a pharmaceutically acceptable salt thereof Where R 3 defined above, and R F is a substituted or unsubstituted phenyl group, reacting in the presence of a compound of formula (K) or a pharmaceutically acceptable salt thereof, R 4 -NH2 (K), Thus producing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof, Where R 3 , R 4 、Ring W、En、R EN and R E1 Defined above.

22. The method according to claim 21, wherein R E1 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

23. The method according to claim 21, wherein R E1 It is ethyl.

24. The method according to claim 21, wherein R E1 It 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 method according to any one of claims 21 to 24, wherein the compound of formula (E) has a structure of formula (E-1), Where R EN' is hydrogen or R EN .

28. The method according to claim 27, wherein the compound of formula (E-1) has structure.

29. The method according to any one of claims 21 to 23 or 26 to 28, wherein R EN Selected from (trimethylsilyl)ethoxymethyl (SEM), methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl (CBz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), p-toluenesulfonyl (Tos), 2,2,2-trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (Pmb) and benzyl (Bn).

30. The method according to claim 29, wherein R EN For SEM.

31. The method according to any one of claims 21 to 30, wherein RF is optionally substituted by one or more RF1, and each RF1 is independently selected from 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 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.

32. The method of claim 31, wherein RF is optionally substituted with one or more RF1, and each RF1 is independently selected from F, Cl, Br, methyl and methoxy.

33. The method according to claim 31 or 32, wherein the compound of formula (F) has the structure of Wherein Fn is 0, 1, 2, 3, 4 or 5.

34. The method according to claim 31, wherein the compound of formula (F) is 35. The method according to any one of claims 21 to 34, wherein the compound represented by formula (G) has a structure of formula (G-1): Where R EN' is hydrogen or R EN .

36. The method according to claim 35, wherein the compound represented by formula (G-1) has structure.

37. The method according to any one of claims 21 to 36, further comprising subjecting the compound represented by formula (G) or a pharmaceutically acceptable salt thereof to a hydrolysis reaction to produce a compound of formula (H) or a pharmaceutically acceptable salt thereof, Where R 3 , R 4 , Ring W, En and R EN Defined above.

38. The method according to claim 37, wherein the compound represented by formula (H) has a structure of formula (H-1), 39. The method according to claim 38, wherein the compound represented by formula (H-1) has structure.

40. The method according to any one of claims 21 to 39, 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, Where R 1 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 method of claim 41, wherein the deprotection reaction comprises replacing R with hydrogen EN .

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

44. The method according to any one of claims 21 to 43, wherein the compound represented by formula (I) has a structure of formula (Ia), in: R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected from oxo and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and R 4 is a substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by one or more halogens.

45. The method according to any one of claims 21 to 43, wherein the compound represented by formula (I) has the structure of formula (Ia), in, R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and R 4 It is an unsubstituted C1-C6 alkyl group.

46. ​​A method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in: R 1 Selected from: N(R 5 )2, where each R 5 are independently selected from hydrogen and optionally substituted C 1 -C6 alkyl, wherein the C 1 -C6 alkyl is optionally substituted with one or more substituents independently selected at each occurrence 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 Carbocyclic and 3- to 12-membered heterocyclic rings; Substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and An optionally substituted 3 to 8 membered heterocyclic ring; wherein the 3 to 8 membered heterocyclic ring is optionally substituted by one or more substituents, the substituents being independently selected at each occurrence from 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 carbocyclic ring, 3 to 12 membered heterocyclic ring and optionally substituted C 1-10 Alkyl, wherein the C 1-10 The alkyl group is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo, -C 1-10 Alkyl halides, -NH2, -CN and -NO2; R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic rings and 3 to 12 membered heterocyclic rings; and R 4 Selected from: hydrogen; Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings, The method comprises making a compound represented by formula (E) or a pharmaceutically acceptable salt thereof in, Ring W is defined above, En is 0, R EN is a protecting group, and 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 with a compound represented by formula (F) or a pharmaceutically acceptable salt thereof, Where R 3 defined above, and R F is a substituted or unsubstituted phenyl group, Thereby producing a compound of formula (Ga) or a pharmaceutically acceptable salt thereof, Where R 3 、Ring W、En、R EN and R E1 In the above definition, And wherein the method further comprises 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) Where R J is the leaving group, Thus producing a compound represented by formula (G) or a pharmaceutically acceptable salt thereof, Where R 3 , R 4 , R EN and R E1 Defined above.

47. The method of claim 46, wherein the compound of formula (E) has structure.

48. The method according to claim 46 or 47, wherein the compound of formula (Ga) has structure.

49. The method of claim 46, wherein the compound of formula (G) has structure.

50. The method of any one of claims 46 to 49, wherein RJ is a halogen (eg, Br, Cl, I).

51. The method according to any one of claims 46 to 49, wherein RJ is an alkyl sulfonate (e.g., trifluoromethanesulfonate (trifluoromethanesulfonate or TfO - )) or an aryl sulfonate (e.g., 4-methylbenzenesulfonate).

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

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

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

55. The method according to any one of claims 46 to 54, further comprising subjecting the compound represented by formula (G) or a pharmaceutically acceptable salt thereof to a hydrolysis reaction to produce a compound of formula (H) or a pharmaceutically acceptable salt thereof, Where R 3 , R 4 , En and R EN Defined above.

56. The method of claim 55, wherein the compound of formula (H) has structure.

57. The method according to claim 55 or 56, 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, Where R 1 Defined above in formula (Ia).

58. The method according to any one of claims 46 to 57, wherein the compound represented by formula (I) has a structure of formula (Ia), in: R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents independently selected from oxo and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and R 4 is a substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group is substituted by one or more halogens.

59. The method according to any one of claims 46 to 57, wherein the compound represented by formula (I) has a structure of formula (Ia), in, R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and R 4 It is an unsubstituted C1-C6 alkyl group.

60. A method for preparing a compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof, in: R 1 is piperazine, wherein the piperazine is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from oxo, -S(O2)NH2 and C 1-10 Alkyl, wherein the C 1-10 Alkyl is optionally substituted with one or more substituents independently selected at each occurrence from the group consisting of hydroxy, halogen, oxo and -NH2; R 3 is phenyl, wherein the phenyl is optionally substituted with one or more halogens; and R 4 is an unsubstituted C1-C6 alkyl group; The method comprises making a compound represented by formula (E-1) or a pharmaceutically acceptable salt thereof in, R EN' is hydrogen or R EN , and where 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 with a compound represented by formula (F) or a pharmaceutically acceptable salt thereof, Where R 3 defined above, and R F is a substituted or unsubstituted phenyl group, Thereby producing a compound of formula (G-1a) or a pharmaceutically acceptable salt thereof, Where R 3 , R EN' and R El In the above definition, And wherein the method further comprises 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) Where R J is the leaving group, Thus, a compound represented by formula (G-1) or a pharmaceutically acceptable salt thereof is produced, Where R 3 , R 4 , R EN' and R E1 Defined above.

61. The method according to claim 60, further comprising subjecting the compound represented by formula (G-1) or a pharmaceutically acceptable salt thereof to a hydrolysis reaction to produce a compound of formula (H-1) or a pharmaceutically acceptable salt thereof, Where R 3 , R 4 and R EN’ The above text is sufficient.

62. The method according to claim 61, further comprising 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, Where R 1 Defined above in formula (Ia).

63. The method according to any one of claims 60 to 62, wherein R EN' For hydrogen.

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

65. The method of claim 64, wherein R EN' Selected from (trimethylsilyl)ethoxymethyl (SEM), methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl (CBz), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2,2,2-trichloroethoxycarbonyl (Troc), p-toluenesulfonyl (Tos), 2,2,2-trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (Pmb) and benzyl (Bn).

66. The method of claim 64, wherein R EN' For SEM.

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

68. The method of claim 67, wherein the deprotection reaction occurs after the condensation reaction, and wherein the deprotection reaction comprises replacing R EN .

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

71. The method of any one of claims 16, 40, 57 or 62, wherein the compound of formula (C) or a pharmaceutically acceptable salt thereof has structure.

72. A compound represented by formula (A) or a pharmaceutically acceptable salt thereof, in R 3 is selected from an optionally substituted C1-C6 alkyl group, an optionally substituted 3- to 10-membered heterocycle, and an optionally substituted C 3-10 wherein each of the alkyl, heterocycle and carbocycle is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; R 4 Selected from: hydrogen; Optionally substituted C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more substituents, the substituents being independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; and Optionally substituted C 3-10 A carbon ring, wherein the C 3-10 The carbocyclic ring is optionally substituted with one or more substituents independently selected at each occurrence from 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 Carbocyclic and 3- to 12-membered heterocyclic rings; Ring W is an optionally substituted 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is optionally substituted by one or more substituents independently selected at each occurrence from halogen, -OH, -CN, -NO2, -NH2, oxo, =S, -S(O2)NH2, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 210 Alkenyl, C 2-10 Alkynyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings; R A1 , R A2 and R A3 Each of which is independently selected from halogen and -OC 1-6 alkyl.

73. The compound of claim 72, wherein the compound has structure.

Images