FGFR3 inhibitor compounds

Abstract

This invention relates to FGFR3 inhibitor compounds, and specifically, provides compounds of the following formula for the treatment of systemic sclerosis, fibrosis (e.g., pulmonary fibrosis), achondroplasia, lethal dysplasia (e.g., type I), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer:

Description

[0001] This application is a divisional application of the invention patent application filed on March 3, 2022, with application number 202280019076.1 and entitled "FGFR3 Inhibitor Compound".

[0002] Background Fibroblast growth factor (FGF) has been recognized as an important mediator of many physiological processes, such as morphogenesis, fibrosis, and angiogenesis during development. The fibroblast growth factor receptor (FGFR) family consists of five members, four of which (FGFR 1–4) are glycoproteins composed of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and a cytoplasmic portion containing a tyrosine kinase domain. FGF binding leads to FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient to recruit and activate specific downstream signaling couplers involved in the regulation of various processes such as cell growth, cell metabolism, and cell survival. Therefore, the FGF / FGFR signaling pathway plays a pleiotropic role in many biological processes crucial for tumor cell proliferation, migration, invasion, and angiogenesis.

[0003] Overview This article provides compounds with the following formulas: Or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Z, Z1, R 2 and R 6 As defined in this article.

[0004] This article provides compounds with the following formulas: Or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, Y, Y1, Y2, Z, Z1, R 2 R 3 R 4 R 5 R 6 and R 9 As defined in this article.

[0005] This article provides compounds with the following formulas: Or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, Y, Y1, Y2, Z', R 2 R 3 R 4 R 5 and R6 As defined in this article.

[0006] This document provides pharmaceutical compositions comprising a compound of formula (I), (II), (IIA) or (III) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0007] This article provides methods for treating systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or proliferative disorders such as cancer, particularly FGFR3-related cancers, using compounds of formula (I), (II), (IIA), or (III) or pharmaceutically acceptable salts thereof, in patients in need.

[0008] This document provides compounds of formula (I), (II), (IIA), or (III) or pharmaceutically acceptable salts thereof for use in therapies. This document further provides compounds of formula (I), (II), (IIA), or (III) or pharmaceutically acceptable salts thereof for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer, particularly for the treatment of FGFR3-related cancers. The use of compounds of formula (I), (II), (IIA), or (III) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer, particularly for the treatment of FGFR3-related cancers, is also provided.

[0009] Description This article provides compounds believed to have clinical applications in the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, proliferative disorders such as cancer, and particularly for the treatment of FGFR3-related cancers.

[0010] Some of the compounds presented herein exhibit superior FGFR3 potency compared to certain previously known FGFR inhibitors. Furthermore, some of the compounds presented herein demonstrate superior selectivity for FGFR3 compared to certain previously known FGFR inhibitors, thereby reducing potential dose-limiting toxicities (e.g., hyperphosphatemia) caused by FGFR1 inhibition.

[0011] The compounds presented in this article have the following formula: in A is pyrazole, triazole, thiadiazole, or oxadiazole, which is controlled by R 1 and R 1A replace; R 1 It is hydrogen or C1-C3 alkyl; R 1A It is a C1-C3 alkyl group that is hydrogen, halogen, CN, or optionally substituted with one or more substituents, wherein the substituents are independently selected from halogen, OH, and OCH3; X1 and X2 are independently selected from N and C, where if one of X1 or X2 is N, the other is C; X3 is N or CH; X4 is N or CR 9 ; Y is NH, O, S, or a bond; Y1 is a key, CHR 7 CH2-CHR 7 CHR 7 -CH2, CF2, CH2-CF2 or CF2-CH2; Y2 is a bond, CHR 3 CH2-CHR 3 CHR 3 -CH2, CF2, CH2-CF2 or CF2-CH2; Y3 is CR 4 R 5 Or CF2; Y4 is CR 3 R 4 Or CF2; Z is a key, CHR 9A CR 4 R 4A CR 4 R 4A -CH2, CH2-CR 4 R 4A Cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azacyclobutane, pyrrolidine or piperidine; When Z is a key, CR 4 R 4A CR 4 R 4A -CH2, CH2-CR 4 R 4A When Z1 is a bond in the following cases: cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azacyclobutane, pyrrolidine, or piperidine, Z1 is a bond, or when Z is CHR 9A When Z1 is CH2 or CH2-CH2; Z2 is a bond, C(O), SO2, or -NR. 4 C(O); Z3 is a bond, C(O), SO2, or -NR. 4 C(O); R 2 It is a C1-C5 alkyl or R 8 The C1-C5 alkyl group is optionally substituted with one or more substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z2-R. 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted by one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN; R 3 It is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or an R 3 With R 5 Or R 7 Filamentation to form CH2, CH2-CH2, or CH2OCH2; R 4 It is hydrogen or C1-C3 alkyl; R 4A It is hydrogen, halogen, OH, or C1-C3 alkyl; R 5 It is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or with an R 3 Filamentation to form CH2, CH2-CH2, or CH2OCH2; R 6It is hydrogen, halogen, C1-C5 alkyl, CN, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl and 5-6 membered heteroaryl are optionally substituted by one or more substituents, said substituents being independently selected from halogen, methyl, halomethyl, OH or OCH3, and wherein the C1-C5 alkyl is optionally substituted by one or more substituents, said substituents being independently selected from halogen, OH and OCH3; R 7 It is hydrogen, F, OH, OCH3, C1-C3 alkyl, or with an R 3 Filamentation to form CH2, CH2-CH2, or CH2OCH2; R 8 It is a 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally with R 8A Fusing or being R 8A replace; R 8A It is a 3-6 membered cycloalkyl, a 4-6 membered heterocycloalkyl, a 5-6 membered aryl, or a 5-6 membered heteroaryl; R 9 It is hydrogen, C1-C3 alkyl, or related to R 9A Filamentation to form CH2 or CH2-CH2; R 10 It is a 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally with R 8A Fusing or being R 8A replace; R 11 It is a C1-C4 alkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-C3 alkyl)2, wherein the C1-C4 alkyl, C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted by one or more substituents, said substituents being independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN; R 12 It is a C1-C4 alkyl, C3-C5 cycloalkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl, or N(C1-C3 alkyl)2, wherein the C1-C4 alkyl, C1-C3 alkyl, and C3-C5 cycloalkyl are optionally substituted by one or more substituents, said substituents being independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine, and CN; and R 8 R 10 and R 8AOptionally substituted with one or more substituents, said substituents being independently selected from halogens, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R. 12 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted by one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN; Or its pharmaceutically acceptable salt; and having the formula: Or its pharmaceutically acceptable salt; and having the formula: Or its pharmaceutically acceptable salt. In formula (II), X1 and X2 are independently selected from N and C, where if one of X1 or X2 is N, the other is C; Z is a key, CHR 9A Azacyclic butane, pyrrolidine, or piperidine; When Z is a bond, Z1 is a bond, or Z is a cyclohexane, pyrrolidine, or piperidine; or when Z is a CHR... 9A When Z1 is CH2 or CH2-CH2; and R 9 Is it hydrogen or related to R? 9A They fuse to form CH2 or CH2-CH2.

[0012] In equation (III), X1 and X2 are independently selected from N and C, where if one of X1 or X2 is N, the other is C; and Z' is a bond, an azacyclic butane, apyrrolidine, or piperidine.

[0013] In equations (II) and (III), A is pyrazole, triazole, thiadiazole, or oxadiazole, optionally replaced by R. 1 replace; R 1 It is a C1-C3 alkyl group; Y represents NH, O, or a bond; Y1 is a key, CHR 7 CH2-CHR 7 or CHR 7 -CH2; Y2 is a bond, CH2, CF2, CHR 3 CH2-CHR 3 or CHR 3 -CH2; R 2 It is a C1-C5 alkyl or R 8The C1-C5 alkyl group is optionally substituted with one or more substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 ; R 3 It is hydrogen, C1-C3 alkyl, or an R 3 With R 5 Or R 7 Filamentation to form CH2 or CH2-CH2; R 4 It is hydrogen or C1-C3 alkyl; R 5 It is hydrogen, or with an R 3 Filamentation to form CH2 or CH2-CH2; R 6 It is hydrogen, CH3, CN, Cl, or F; R 7 It is hydrogen, or with an R 3 Filamentation to form CH2 or CH2-CH2; R 8 It is a 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally with R 8A Condensation; R 8A It is a 3-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a 5-6 membered aryl, or a 5-6 membered heteroaryl; R 10 It is a 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally with R 8A Fusing or being R 8A Replace; and R 8 R 10 and R 8A Optionally substituted with one or more substituents, said substituents being independently selected from halogens, CN, methyl, halomethyl, methoxy, ethyl, ethoxy, methylamine, S(O)2CH3, C(O)NH2, N,N-dimethylamine and C(O)N,N-dimethylamine.

[0014] In compounds of formula (I), (II) or (III), X1 can be C and X2 can be N; or X1 can be N and X2 can be C.

[0015] In compounds of formula (I), (II), or (III), X1 can be C and X2 can be N, thus forming: The asterisk (*) indicates the connection point with A in equation (I), (II), or (III).

[0016] In compounds of formula (I), (II), or (III), X1 can be N and X2 can be C, thus forming: The asterisk (*) indicates the connection point with A in equation (I), (II), or (III).

[0017] The specific chemical nomenclature conventions used in this article are intended to be familiar to those skilled in the art of chemistry. Some terms have been specifically defined for clarity.

[0018] As used herein, the term "alkyl" refers to a hydrocarbon chain that can be straight-chain or branched and contains a specified number of carbon atoms. For example, the term "C1-C5 alkyl" as used herein refers to a saturated straight-chain or branched monovalent hydrocarbon group having one, two, three, four, or five carbon atoms. Examples of C1-C5 alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, and neopentyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, and 2-methyl-2-propyl. Examples of C1-C3 alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, or isopropyl.

[0019] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group containing a specified number of carbon atoms. For example, the term "3-6 membered cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having three, four, five, or six carbon atoms. Examples of 3-6 membered cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0020] As used herein, the term "heterocyclic alkyl" refers to a compound containing a specified number of C(O) atoms. 0-1 , N, O and S(O) 0-2 A saturated cyclic group having five or six ring atoms. For example, the term "5-6 membered heterocyclic alkyl" as used herein refers to a saturated cyclic ring system having five or six ring atoms, one, two, or three of which are selected from N, O, and S(O). 0-2 The rest are C(O). 0-1Examples of 4-6 membered heterocyclic alkyl groups include, but are not limited to, azacyclobutyl, pyrrolyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidine-2-one, dioxazolidyl, morpholinyl, oxazolidyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidyl, isothiazolidyl, oxozolid-2-onyl, and isothiazolid-2-onyl. Examples of 5-6 membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, pyrrolidine-2-one, dioxazolidyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidyl, isothiazolidyl, oxozolid-2-one, and isothiazolid-2-onyl.

[0021] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group having a specified number of carbon atoms. For example, the term "5-6 aryl" as used herein refers to an aromatic cyclic hydrocarbon group having five or six carbon atoms. Examples of 5-6 aryl groups include cyclopentadienyl and phenyl.

[0022] As used herein, the term "heteroaryl" refers to an aromatic cyclic group having a specified number of atoms selected from C, N, O, and S. For example, the term "5-6-membered heteroaryl" as used herein refers to an aromatic cyclic group having five or six ring atoms, one, two, or three of which are selected from N, O, and S, with the remainder being C. Examples of 5-6-membered heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrroleyl, thiopheneyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. Examples of 6-membered heteroaryls include, but are not limited to, pyridinyl, pyrimidinyl, and pyridazinyl.

[0023] The term “halogen” or “halogenated” as used in this article refers to F (fluorine), Cl (chlorine), Br (bromine) and I (iodine).

[0024] As used in this article, the term "halomethyl" means -CH3, in which one or more hydrogen atoms are replaced by independently selected halogens.

[0025] As used in this article, the term "oxo" means replacing CH2 with O to form C(O).

[0026] The term “N(C1-C3 alkyl)2” as used herein allows for the independent selection of each C1-C3 alkyl substituent; for example, N can be substituted with methyl and ethyl.

[0027] The substituent -NR used in this article 4 C(O) is connected to R through N. 2 .

[0028] Compounds of the following formula or pharmaceutically acceptable salts thereof are also provided: in A is a pyrazole, triazole, thiadiazole, or oxadiazole, optionally mixed with R. 1 replace; R 1 It is a C1-C3 alkyl group; X 1A and X 2A Independently selected from N and CH, where X 1A or X 2A When one is N, the other is CH; Y represents NH, O, or a bond; Y1 is a key, CHR 7 CH2-CHR 7 or CHR 7 -CH2; Y2 is a bond, CH2, CF2, CHR 3 CH2-CHR 3 or CHR 3 -CH2; Z is a key, CHR 9A Azacyclic butane, pyrrolidine, or piperidine; When Z is a bond, Z1 is a bond, or Z is a cyclohexane, pyrrolidine, or piperidine; or when Z is a CHR... 9A When Z1 is CH2 or CH2-CH2; R 2 It is a C1-C5 alkyl or R 8 The C1-C5 alkyl group is optionally substituted with one or more substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 ; R 3 It is hydrogen, C1-C3 alkyl, or an R 3 With R 5 Or R 7 Filamentation to form CH2 or CH2-CH2; R 4 It is hydrogen or C1-C3 alkyl; R 5 It is hydrogen, or with an R 3 Filamentation to form CH2 or CH2-CH2; R 6 It is hydrogen, CH3, CN, Cl, or F; R 7 It is hydrogen, or with an R 3 Filamentation to form CH2 or CH2-CH2; R 8It is a 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally with R 8A Fusing or being R 8A replace; R 8A It is a 3-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a 5-6 membered aryl, or a 5-6 membered heteroaryl; R 9 Is it hydrogen or related to R? 9A Filamentation to form CH2 or CH2-CH2; R 10 It is a 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally with R 8A Fusing or being R 8A Replace; and R 8 R 10 and R 8A Optionally substituted with one or more substituents, said substituents being independently selected from halogens, CN, methyl, halomethyl, methoxy, ethyl, ethoxy, methylamine, S(O)2CH3, C(O)NH2, N,N-dimethylamine and C(O)N,N-dimethylamine.

[0029] In compounds of formula (IIA), X 1A It can be CH, and X 2A It can be N, thus forming: Where * indicates the connection point with A in formula (IIA), thus forming a compound of the following formula: .

[0030] In compounds of formula (IIA), X 1A It can be N, and X 2A It can be CH, thus forming: Where * indicates the connection point with A in formula (IIA), thus forming a compound of the following formula: .

[0031] In the compound of formula (I), A can be pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, or 1,3,4-oxadiazole, which is controlled by R. 1 and R 1A replace.

[0032] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A replace.

[0033] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace, where R 1A It is hydrogen and R 1 It is a C1-C3 alkyl group.

[0034] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace, where R 1A It is hydrogen and R 1 It is CH3.

[0035] In compounds of formula (II), (IIA), or (III), A can be pyrazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, or 1,3,4-oxadiazole, optionally with R 1 replace.

[0036] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, optionally converted by R. 1 replace.

[0037] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 replace.

[0038] In compounds of formula (II), (IIA) or (III), A can be a pyrazole, a 1,2,3-triazole or a 1,2,4-triazole, which is substituted with CH3.

[0039] In compounds of formula (I), (II), (IIA) or (III), A can be: Where * indicates the connection point with Z or Z' in equations (I), (II), (IIA) or (III), and ** indicates other connection points from A; and R 1 It can be a C1-C3 alkyl group.

[0040] In the compound of formula (I), Z can be CHR.9A Cyclobutyl, aziridine, pyrrolidine, or piperidine.

[0041] In the compound of formula (I), Z can be a bond, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0042] In the compound of formula (I), Z can be a bond, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0043] In compounds of formula (II) or (IIA), Z can be CHR. 9A Azacyclobutane, pyrrolidine, or piperidine.

[0044] In compounds of formula (II) or (IIA), Z can be a bond, Where * indicates the connection point with Z1 in equation (II) or (IIA) and ** indicates the connection point with A.

[0045] In compounds of formula (II) or (IIA), Z can be: Where * indicates the connection point with Z1 in equation (II) or (IIA) and ** indicates the connection point with A.

[0046] In compounds of formula (I), (II), or (IIA), Z can be CHR. 9A Z1 can be selected from CH2 or CH2-CH2, and R 9 Can be used with R 9A They fuse to form CH2 or CH2-CH2.

[0047] In compounds of formula (I), (II), or (IIA), Z can be CHR. 9A Z1 can be CH2, and R 9 Can be used with R 9A They fuse to form CH2 or CH2-CH2.

[0048] In compounds of formula (I), (II), or (IIA), Z can be CHR. 9A Z1 can be CH2-CH2, and R 9 Can be used with R 9A They fuse to form CH2 or CH2-CH2.

[0049] In compounds of formula (I), (II), or (IIA), Z can be CHR. 9A Z1 can be selected from CH2 or CH2-CH2, and R 9 Can be used with R 9A They condense to form CH2.

[0050] In compounds of formula (I), (II), or (IIA), Z can be CHR. 9A Z1 can be selected from CH2 or CH2-CH2, and R 9 Can be used with R 9A They condense to form CH2-CH2.

[0051] In compounds of formula (I), (II), or (IIA), Z can be CHR. 9A Z1 can be CH2, and R 9 Can be used with R 9A They condense to form CH2.

[0052] In compounds of formula (I), (II), or (IIA), Z can be CHR. 9A Z1 can be CH2-CH2, and R 9 Can be used with R 9A They condense to form CH2-CH2.

[0053] In the compound of formula (III), Z' can be: Where ** indicates the connection point with A in equation (III) and * indicates other connection points from Z'.

[0054] In the compound of formula (III), Z' can be: Where ** indicates the connection point with A in equation (III) and * indicates other connection points from Z'.

[0055] In compounds of formula (I), (II) or (IIA), Z can be a bond.

[0056] In the compound of formula (III), Z' can be a bond.

[0057] In compounds of formula (I), (II) or (IIA), Z1 can be a bond.

[0058] In compounds of formula (I), (II), (IIA) or (III), Y can be NH or O.

[0059] In compounds of formula (I), (II), (IIA) or (III), Y can be O.

[0060] In the compound of formula (I), Y1 can be a bond, CHR 7 CH2-CHR 7 or CHR 7 -CH2, where R 7 Selected from hydrogen, F, OH and CH3; and Y2 can be a bond, CHR 3 CH2-CHR 3 or CHR 3 -CH2, where R 3 Selected from hydrogen, F, OH and CH3.

[0061] In compounds of formula (I), Y1 can be a bond or a CHR. 7 , where R 7 It is hydrogen, F, OH, or CH3; and Y2 can be a bond or CHR. 3 , where R 3 It is hydrogen, F, OH or CH3.

[0062] In the compound of formula (I), Y1 can be a bond, CHR 7 CH2-CHR 7 or CHR 7 -CH2, where R 7 It can be hydrogen, F, OH, or CH3; and Y2 can be a bond, CHR 3 CH2-CHR 3 or CHR 3 -CH2, where R 3 It is hydrogen, F, OH or CH3, thus forming: Where * indicates the connection point with Z1 in equation (I).

[0063] In compounds of formula (I), Y1 can be a bond or a CHR. 7 , where R 7 It is hydrogen, F, OH, or CH3; and Y2 can be a bond or CHR. 3 , where R 3 It is hydrogen, F, OH or CH3, thus forming: Where * indicates the connection point with Z1 in equation (I).

[0064] In compounds of formula (II), (IIA), or (III), Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2, or CH2-CH2, thereby forming: Where * indicates the connection point with Z1 in equation (II) or (IIA) or with Z' in equation (III).

[0065] In compounds of formula (II), (IIA), or (III), Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, or CF2, thereby forming: Where * indicates the connection point with Z1 in equation (II) or (IIA) or with Z' in equation (III).

[0066] In the compound of formula (I), R 1A It can be hydrogen or a C1-C3 alkyl group optionally substituted with one or more substituents, said substituents being independently selected from halogens, OH and OCH3.

[0067] In the compound of formula (I), R 1A It can be hydrogen or CH3.

[0068] In the compound of formula (I), R 1A It could be hydrogen.

[0069] In compounds of formula (I), (II), (IIA) or (III), R 1 It can be methyl, ethyl, or propyl.

[0070] In compounds of formula (I), (II), (IIA) or (III), R 1 It can be methyl.

[0071] In the compound of formula (I), R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN.

[0072] In the compound of formula (I), R 2 It can be a C1-C4 alkyl group, optionally substituted with one or more substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R. 10 .

[0073] In the compound of formula (I), R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point with Y in formula (I).

[0074] In the compound of formula (I), R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R. 10 , where * indicates the connection point with Y in equation (I).

[0075] In the compound of formula (I), R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point with Y in formula (I).

[0076] In the compound of formula (I), R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3 and -OC3 cycloalkyl and R. 10 , where * indicates the connection point with Y in equation (I).

[0077] In compounds of formula (II), (IIA) or (III), R 2 It can be a C1-C4 alkyl group, optionally substituted with one or more substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 .

[0078] In compounds of formula (II), (IIA) or (III), R 2 It can be a C1-C3 alkyl group, optionally substituted with one or two substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 .

[0079] In compounds of formula (II), (IIA) or (III), R 2 It can be a C1-C3 alkyl group, optionally substituted with one or more substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 .

[0080] In compounds of formula (II), (IIA) or (III), R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 .

[0081] In compounds of formula (II), (IIA) or (III), R 2 It can be a C1-C2 alkyl group, optionally substituted with one or two substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 .

[0082] In compounds of formula (II), (IIA) or (III), R 2 It could be: It may optionally be substituted with one or two substituents, which are independently selected from OH, CF3 and methoxy, wherein * indicates the connection point with Y in formula (II), (IIA) or (III).

[0083] In compounds of formula (II), (IIA) or (III), R 2 It could be: It may optionally be substituted with one or two substituents, which are independently selected from OH, CF3 and methoxy, wherein * indicates the connection point with Y in formula (II), (IIA) or (III).

[0084] In compounds of formula (II), (IIA) or (III), R 2 It could be: It may optionally be substituted with one or two substituents, which are independently selected from OH, CF3 and methoxy, wherein * indicates the connection point with Y in formula (II), (IIA) or (III).

[0085] In the compound of formula (I), Y3 can be CR 4 R 5 Or CF2, where R 4 It is hydrogen or CH3 and R 5 It is hydrogen, F, OH or CH3; and Y4 is CR. 3 R 4 Or CF2, where R 4 It is hydrogen or CH3, and R 3 It is hydrogen, F, OH or CH3.

[0086] In the compound of formula (I), Y3 can be CR 4 R 5 , where R 4 It is hydrogen and R 5 With an R 3 Fusing to form CH2, CH2-CH2, or CH2OCH2; and Y4 is CR 3 R 4 , where R 4 It is hydrogen, and R 3 With R 5 They fuse to form CH2, CH2-CH2, or CH2OCH2.

[0087] In the compound of formula (I), Y3 can be CR 4 R 5 , where R 4 It is hydrogen and R 5 With an R 3 Fusing to form CH2, CH2-CH2, or CH2OCH2; and Y4 is CR 3 R 4 , where R 4 It is hydrogen, and R 3 With R 5 Fusing to form CH2, CH2-CH2, or CH2OCH2, thereby forming: Where * indicates the connection point with Z1 in equation (I).

[0088] In the compound of formula (I), X4 can be N or CR. 9 , where R 9 It is hydrogen or CH3.

[0089] In the compound of formula (I), X4 can be CR 9 , where R9 With R 9A Fused to form CH2 or CH2-CH2; and Z1 is CH2 or CH2-CH2.

[0090] In the compound of formula (I), X4 can be N or CH.

[0091] In compounds of formula (II), (IIA) or (III), R 3 It can be hydrogen, C1-C3 alkyl, or related to R 5 They fuse to form CH2 or CH2-CH2.

[0092] In compounds of formula (II), (IIA) or (III), R 3 It can be hydrogen, C1-C2 alkyl, or related to R 5 They fuse to form CH2 or CH2-CH2.

[0093] In compounds of formula (II), (IIA) or (III), R 3 It can be hydrogen or methyl.

[0094] In compounds of formula (II), (IIA) or (III), R 4 It can be hydrogen or C1-C2 alkyl.

[0095] In compounds of formula (II), (IIA) or (III), R 4 It can be hydrogen or methyl.

[0096] In compounds of formula (II), (IIA) or (III), R 3 and R 4 It could be hydrogen.

[0097] In compounds of formula (II), (IIA) or (III), R 5 It could be hydrogen.

[0098] In compounds of formula (II), (IIA) or (III), R 5 Can be with an R 3 They condense to form CH2-CH2.

[0099] In the compound of formula (I), R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl.

[0100] In the compound of formula (I), R 6 It can be CN, F, or Cl.

[0101] In compounds of formula (I), (II), (IIA) or (III), R 6It can be CN or Cl.

[0102] In compounds of formula (I), (II), (IIA) or (III), R 6 It can be CN.

[0103] In compounds of formula (II), (IIA) or (III), R 7 It could be hydrogen.

[0104] In compounds of formula (II), (IIA) or (III), R 7 Can be with an R 3 They condense to form CH2.

[0105] In compounds of formula (I), (II), (IIA) or (III), R 8 It can be a 5-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a 5-6 membered aryl, or a 5-6 membered heteroaryl, optionally with R 8A Fusing or being R 8A replace.

[0106] In compounds of formula (I), (II), (IIA) or (III), R 8 It can be a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, optionally with R 8A Condensation.

[0107] In compounds of formula (I), (II), (IIA) or (III), R 8 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, or pyridyl, optionally with R 8A Condensation.

[0108] In compounds of formula (I), (II), (IIA) or (III), R 8 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, which reacts with R 8A Condensation.

[0109] In compounds of formula (I), (II), (IIA) or (III), R 8 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, which reacts with R 8A Condensation, where R 8A It can be phenyl or a 6-membered heteroaryl group.

[0110] In compounds of formula (I), (II), (IIA) or (III), R 9 It could be hydrogen.

[0111] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be a 3-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a 5-6 membered aryl, or a 5-6 membered heteroaryl, optionally with R 8A Condensation.

[0112] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be a 3-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a phenyl, or a 5-6 membered heteroaryl, optionally with R 8A Condensation.

[0113] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidine-2-one, dioxacyclohexyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolyl, isothiazolyl, oxazolidine-2-one, isothiazolidine-2-one, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, optionally with R 8A Condensation.

[0114] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, optionally with R 8A Condensation.

[0115] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, optionally with R 8A Condensation.

[0116] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopropyl, cyclobutyl, phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, optionally with R 8A Condensation.

[0117] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazine, pyrrolyl, pyrrolidine-2-one, dioxacyclohexyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl, oxazolyl, isothiazolyl, oxazolidine-2-one, isothiazolidine-2-one, phenyl, pyridinyl, pyrazine, pyrimidinyl, pyranyl, pyrroleyl, thiophene, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiazolyl.

[0118] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0119] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiazolyl.

[0120] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopropyl, cyclobutyl, phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl.

[0121] In compounds of formula (II), (IIA) or (III), R 10 It can be a 5-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a phenyl, or a 5-6 membered heteroaryl, which reacts with R 8A Condensation.

[0122] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, which, together with R 8A Condensation.

[0123] In compounds of formula (I), (II), (IIA) or (III), R 10It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, or pyridinyl, and it reacts with R 8A Condensation.

[0124] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, or pyridinyl, and it reacts with R 8A Condensation.

[0125] In compounds of formula (I, (II), (IIA) or (III), R 10 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, or pyridinyl, and it reacts with R 8A Condensation.

[0126] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be cyclopentyl, cyclohexyl, phenyl, or pyridyl, and it reacts with R 8A Condensation.

[0127] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be phenyl or pyridyl, which reacts with R 8A Condensation, where R 8A It can be a 5-6 membered heterocyclic alkyl or a 5-6 membered heteroaryl.

[0128] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be phenyl or pyridyl, which reacts with R 8A Condensation, where R 8A It can be pyrrolidinyl, pyrrolidin-2-keto, dioxacyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolyl, isothiazolyl, oxazolyl-2-keto, isothiazolyl-2-keto, furanyl, pyrrolidinyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiazolyl.

[0129] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be phenyl or pyridyl, which reacts with R 8A Condensation, where R 8A It can be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolyl, isothiazolyl, oxazolidine-2-one, isothiazolidine-2-one, furanyl, pyrroleyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0130] In compounds of formula (I), (II), (IIA) or (III), R 10 It can be phenyl or pyridyl, which reacts with R 8A Condensation, where R 8A It can be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxazolidin-2-one, or isothiazolidin-2-one.

[0131] In compounds of formula (I), (II) or (IIA), when Z and Z1 are both bonds, they together form a single bond.

[0132] In the compound of formula (I), Z can be CHR. 9A Z1 can be CH2, and X4 can be CR. 9 And R 9 Can be used with R 9A Fusing together to form CH2, thus forming: The asterisk (*) indicates the connection point with A.

[0133] In compounds of formula (II) or (IIA), Z can be CHR. 9A Z1 can be CH2, and R 9 Can be used with R 9A Fusing together to form CH2, thus forming: The asterisk (*) indicates the connection point with A.

[0134] In compounds of formula (I), (II), (IIA) or (III), R 5 Can be with an R 3 Fusing to form CH2-CH2, for example, forming: Where * indicates the connection point with Z1 in equation (I) or with Z' in equations (II), (IIA) or (III).

[0135] In compounds of formula (I), (II), (IIA) or (III), R 8 It can be cyclopentyl, which is related to R 8A Condensation, where R 8A It can be pyridyl, for example, forming: The asterisk (*) indicates the connection point with Y.

[0136] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Substitution; and Y can be NH or O.

[0137] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace, where R 1A It is hydrogen and R 1 It is a C1-C3 alkyl group; and Y can be NH or O.

[0138] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Substitution; and Y can be NH or O.

[0139] In compounds of formula (I), (II), (IIA) or (III), A can be: Where * indicates the connection point with Z or Z' in equations (I), (II), (IIA) or (III), and ** indicates other connection points from A; R 1 It can be a C1-C3 alkyl group; and Y can be NH or O.

[0140] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; and Y can be O.

[0141] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace, where R 1A It is hydrogen and R 1 It is a C1-C3 alkyl group; and Y can be O.

[0142] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Replace; and Y can be O.

[0143] In compounds of formula (I), (II), (IIA) or (III), A can be: Where * indicates the connection point with Z or Z' in equations (I), (II), (IIA) or (III), and ** indicates other connection points from A; R 1 It can be a C1-C3 alkyl group; and Y can be O.

[0144] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; and R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl.

[0145] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace, where R 1A It is hydrogen and R 1 It is a C1-C3 alkyl group; and R 6 It can be CN, F, Cl or CF3.

[0146] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; and R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl.

[0147] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; and R 6 It can be CN, F, Cl or CF3.

[0148] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Replace; and R 6 It can be CN or Cl.

[0149] In compounds of formula (I), (II), (IIA) or (III), A can be: Where * indicates the connection point with Z or Z' in equations (I), (II), (IIA) or (III), and ** indicates other connection points from A; R 1 It can be a C1-C3 alkyl group; and R 6 It can be CN or Cl.

[0150] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be NH or O.

[0151] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace, where R 1A It is hydrogen and R 1 It is a C1-C3 alkyl group; R 6 It can be CN, F, Cl or CF3; and Y can be NH or O.

[0152] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be NH or O.

[0153] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl or CF3; and Y can be NH or O.

[0154] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Replace; R 6 It can be CN or Cl; and Y can be NH or O.

[0155] In compounds of formula (I), (II), (IIA) or (III), A can be: Where * indicates the connection point with Z or Z' in equations (I), (II), (IIA) or (III), and ** indicates other connection points from A; R 1 It can be a C1-C3 alkyl group; R 6 It can be CN or Cl; and Y can be NH or O.

[0156] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; and Y can be O.

[0157] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace, where R 1A It is hydrogen and R 1 It is a C1-C3 alkyl group; R 6 It can be CN, F, Cl, or CF3; and Y can be O.

[0158] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; and Y can be O.

[0159] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, or CF3; and Y can be O.

[0160] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Replace; R 6 It can be CN or Cl; and Y can be O.

[0161] In compounds of formula (I), (II), (IIA) or (III), A can be: Where * indicates the connection point with Z or Z' in equations (I), (II), (IIA) or (III), and ** indicates other connection points from A; R 1 It can be a C1-C3 alkyl group; R 6 It can be CN or Cl; and Y can be O.

[0162] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R1A Replace; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; and R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN.

[0163] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; and R 2 It can be a C1-C4 alkyl group, optionally substituted with one or more substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R. 10 .

[0164] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point with Y in formula (I).

[0165] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R. 10 , where * indicates the connection point with Y in equation (I).

[0166] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point with Y in formula (I).

[0167] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R. 10 , where * indicates the connection point with Y in equation (I).

[0168] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; and R 2It can be a C1-C3 alkyl group, optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN.

[0169] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; and R 2 It can be a C1-C4 alkyl group, optionally substituted with one or more substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R. 10 .

[0170] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point with Y in formula (I).

[0171] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R. 10 , where * indicates the connection point with Y in equation (I).

[0172] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, which are independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point with Y in formula (I).

[0173] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R. 10 , where * indicates the connection point with Y in equation (I).

[0174] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Replacement; Y can be O; R 6 It can be CN or Cl; and R 2It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 .

[0175] In compounds of formula (II), (IIA), or (III), A can be: Where * indicates the connection point with Z or Z' in equation (II), (IIA) or (III) and ** indicates other connection points from A; Y can be O; R 6 It can be CN or Cl; and R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 .

[0176] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Replacement; Y can be O; R 6 It can be CN or Cl; and R 2 It could be: It may optionally be substituted with one or two substituents, which are independently selected from OH, CF3 and methoxy, wherein * indicates the connection point with Y in formula (II), (IIA) or (III).

[0177] In compounds of formula (II), (IIA), or (III), A can be: Where * indicates the connection point with Z or Z' in equation (II), (IIA) or (III) and ** indicates other connection points from A; Y can be O; R 6 It can be CN or Cl; and R 2 It could be: It may optionally be substituted with one or two substituents, which are independently selected from OH, CF3 and methoxy, wherein * indicates the connection point with Y in formula (II), (IIA) or (III).

[0178] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; R2 It can be a C1-C3 alkyl group, optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, said substituents being independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine, and CN; and Z can be a bond, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0179] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; R 2 It can be a C1-C4 alkyl group, optionally substituted with one or more substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R. 10 And Z can be a key, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0180] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, said substituents being independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine, and CN, wherein * indicates the connection point with Y in formula (I); and Z can be a bond, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0181] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R. 10 Where * indicates the connection point with Y in equation (I); and Z can be a key, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0182] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, said substituents being independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine, and CN; and Z can be a bond, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0183] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; R 2It can be a C1-C4 alkyl group, optionally substituted with one or more substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R. 10 And Z can be a key, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0184] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, said substituents being independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine, and CN, wherein * indicates the connection point with Y in formula (I); and Z can be a bond, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0185] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R. 10 Where * indicates the connection point with Y in equation (I); and Z can be a key, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A.

[0186] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, three, or four substituents, said substituents being independently selected from halogens, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents, said substituents being independently selected from halogens, OH, OCH3, methylamine, N,N-dimethylamine, and CN; Z can be a bond, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A; Y1 can be a key or CHR. 7 , where R 7 It is hydrogen, F, OH, or CH3; and Y2 can be a bond or CHR. 3 , where R 3 It is hydrogen, F, OH or CH3.

[0187] In the compound of formula (I), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is reacted with R 1 and R 1A Replace; R 6 It can be CN, F, Cl, CH3, CF3, or cyclopropyl; Y can be NH or O; R 2 It can be a C1-C4 alkyl group, optionally substituted with one or more substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R. 10 Z can be a key, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A; Y1 can be a key or CHR. 7 , where R 7 It is hydrogen, F, OH, or CH3; and Y2 can be a bond or CHR. 3 , where R 3 It is hydrogen, F, OH or CH3.

[0188] In the compound of formula (I), A can be: Where * indicates the connection point with Z or Z' in equation (I) and ** indicates other connection points from A; R 6 It can be CN, F, Cl, or CF3; Y can be NH or O; and R 2 It could be: It is optionally substituted with one, two, three, or four substituents, said substituents being independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R. 10 * indicates the connection point with Y in equation (I); Z can be a key, Where * indicates the connection point with Z1 in equation (I) and ** indicates the connection point with A; Y1 can be a key or CHR. 7 , where R 7 It is hydrogen, F, OH, or CH3; and Y2 can be a bond or CHR. 3 , where R 3 It is hydrogen, F, OH or CH3.

[0189] In compounds of formula (II), (IIA), or (III), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Replacement; Y can be O; R 6 It can be CN or Cl; R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2, or CH2-CH2.

[0190] In compounds of formula (II), (IIA), or (III), A can be: Where * indicates the connection point with Z or Z' in equation (II), (IIA) or (III) and ** indicates other connection points from A; Y can be O; R 6 It can be CN or Cl; R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2, or CH2-CH2.

[0191] In compounds of formula (II) or (IIA), A can be a pyrazole, a 1,2,3-triazole, or a 1,2,4-triazole, which is controlled by R. 1 Replacement; Y can be O; R 6 It can be CN or Cl; R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 Y1 can be a bond, CH2, or CH2-CH2; Y2 can be a bond, CH2, CF2, or CH2-CH2; Z can be CHR. 9A Z1 can be CH2; and R 9 Can be used with R 9A They condense to form CH2.

[0192] In compounds of formula (II) or (IIA), A can be: Where * indicates the connection point with Z in equation (II) or (IIA) and ** indicates other connection points from A; Y can be O; R 6 It can be CN or Cl; R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2, or CH2-CH2; Z can be CHR. 9A Z1 can be CH2; and R 9 Can be used with R 9A They condense to form CH2.

[0193] In compounds of formula (III), A can be pyrazole, 1,2,3-triazole, or 1,2,4-triazole, which is reacted with R 1 Replacement; Y can be O; R 6 It can be CN or Cl; R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 Y1 can be a bond, CH2, or CH2-CH2; Y2 can be a bond, CH2, CF2, or CH2-CH2; and Z' can be: The ** indicates the connection point with A, and the * indicates other connection points from Z'.

[0194] In the compound of formula (III), A can be: Where * indicates the connection point with Z' in equation (I) and ** indicates other connection points from A; Y can be O; R 6 It can be CN or Cl; R 2 It can be a C1-C3 alkyl group, optionally substituted with one, two, or three substituents, said substituents being independently selected from OH, methoxy, halomethyl, and R. 10 Y1 can be a bond, CH2, or CH2-CH2; and Y2 can be a bond, CH2, CF2, or CH2-CH2; and Z' can be: The ** indicates the connection point with A, and the * indicates other connection points from Z'.

[0195] In one embodiment, the compound of formula (I) is selected from: Or its pharmaceutically acceptable salt. The key at the * position is represented as follows: .

[0196] For example, for compounds with the following formula: If the key at the * position represents the following: Then a compound is formed: .

[0197] In another embodiment, the compound of formula (I) is selected from: Or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is represented as follows: .

[0198] In another embodiment, the compound of formula (I) is selected from: Or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is represented as follows: .

[0199] In another embodiment, the compound of formula (I) is selected from: Or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is represented as follows: .

[0200] In another embodiment, the compound of formula (I) is selected from: Or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is represented as follows: .

[0201] In another embodiment, the compound of formula (I) is selected from: Or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is represented as follows: .

[0202] In another embodiment, the compound of formula (I) is selected from: Or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is represented as follows: .

[0203] In another embodiment, the compound of formula (I) is selected from: Or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is represented as follows: .

[0204] In another embodiment, the compound of formula (I) is selected from: Or its pharmaceutically acceptable salt.

[0205] In another embodiment, the compound of formula (I) is selected from: Or its pharmaceutically acceptable salt.

[0206] The compounds of formulas (I), (II), (IIA), or (III) provided herein, or their pharmaceutically acceptable salts, wherein any or all hydrogens present in or within a specific group or portion of the compound may be substituted with deuterium or tritium. Thus, the statement of alkyl includes deuterated alkyl groups in which one to a maximum number of hydrogens present may be substituted with deuterium. For example, ethyl represents C2H5 or C2H5 in which 1 to 5 hydrogens are substituted with deuterium, such as in C2D. x H 5-x middle.

[0207] The compounds of formulas (I), (II), (IIA), or (III) provided herein can form pharmaceutically acceptable salts. The examples provided herein can form pharmaceutically acceptable salts. It is intended to include such pharmaceutically acceptable salts. Pharmaceutically acceptable salts and common methods for preparing them are well known in the art (see, e.g., P. Stahl, et al.). Handbook of Pharmaceutical Salts: Properties, Selection and Use , 2nd revised edition (Wiley-VCH, 2011); SM Berge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences Volume 66, Issue 1, January 1977.

[0208] The compounds of formula (I), (II), (IIA), or (III) or pharmaceutically acceptable salts thereof provided herein can be mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. More specifically, the compounds of formula (I), (II), (IIA), or (III) or pharmaceutically acceptable salts thereof provided herein can be formulated into pharmaceutical compositions. Such pharmaceutical compositions and methods of their preparation are well known in the art (see, for example, Remington:The Science and Practice of Pharmacy (A. Gennaro et al., eds., 21st edition, Mack Publishing Co., 2005).

[0209] The compounds of formula (I), (II), (IIA) or (III) provided herein, or their pharmaceutically acceptable salts and pharmaceutical compositions thereof, may be administered via a variety of routes. Such routes of administration include oral and intravenous administration.

[0210] The compounds of formula (I), (II), (IIA) or (III) provided herein, or their pharmaceutically acceptable salts, may be combined with one or more other therapeutic agents.

[0211] The compounds of formula (I), (II), (IIA) or (III) provided herein, or their pharmaceutically acceptable salts, may be components in pharmaceutical compositions for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer, said compositions containing one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally containing one or more additional therapeutic agents.

[0212] The compounds of formula (I), (II), (IIA) or (III) provided herein, or their pharmaceutically acceptable salts, may be components in pharmaceutical compositions for treating cancer, said compositions containing one or more pharmaceutically acceptable carriers, diluents or excipients, and optionally one or more additional therapeutic agents.

[0213] The compounds of formula (I), (II), (IIA) or (III) provided herein, or their pharmaceutically acceptable salts, may be used in combination with one or more other therapeutic agents for simultaneous, separate or sequential administration.

[0214] The compounds of formula (I), (II), (IIA) or (III) provided herein, or their pharmaceutically acceptable salts and pharmaceutical compositions thereof, may be used in the methods described herein.

[0215] The compounds of formulas (I), (II), (IIA), or (III) or their pharmaceutically acceptable salts provided herein are generally effective over a wide dose range. For example, daily doses typically fall within the range of about 0.5 to about 100 mg / kg body weight. In some cases, dose levels below the lower limit of the above range may be more than sufficient, while in others, even higher doses may be used without causing any harmful side effects, and therefore the above dose range is not intended to limit the scope of the invention in any way. It should be understood that the actual dosage of the compound will be determined by a physician taking into account relevant circumstances, including the condition to be treated, the route of administration chosen, one or more actual compounds administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0216] Certain compounds of formula (I), (II), (IIA), or (III), or pharmaceutically acceptable salts thereof, selectively target FGFR3. For example, certain compounds of formula (I), (II), (IIA), or (III), or pharmaceutically acceptable salts thereof, selectively target FGFR3 relative to another FGFR. For example, certain compounds of formula (I), (II), (IIA), or (III), or pharmaceutically acceptable salts thereof, selectively target FGFR3 relative to FGFR1. For example, the selectivity of certain compounds of formula (I), (II), (IIA), or (III), or pharmaceutically acceptable salts thereof, to FGFR3 is at least about 3 times (e.g., at least about 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 times or more) to FGFR1.

[0217] The term "selectivity" as used herein refers to a compound that exhibits more potent activity against a first target compared to a second target. Selectivity folds can be calculated using any method known in the art. For example, by measuring the IC50 of the compound against a second target (e.g., FGFR1). 50 The value divided by the IC50 of the same compound against the first target (e.g., FGFR3) 50 The value can be used to calculate the selectivity factor. The IC can be determined using any method known in the art. 50 Value. For example, IC can be determined as described in the following determinations. 50 value.

[0218] The term "cancer" as used in this article refers to or describes a physiological condition in a patient that is typically characterized by disordered cell proliferation. This definition includes both benign and malignant cancers.

[0219] As used in this article, the term "FGFR3-associated cancer" refers to cancers that are associated with, or have, abnormal regulation related to, the expression, activity, or level of the FGFR3 gene, FGFR3 kinase protein, or any of them. This article describes non-limiting examples of FGFR3-associated cancers. "FGFR3-associated cancer" as used in this article includes, but is not limited to, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer), urothelial carcinoma, bladder cancer (e.g., urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), upper urinary tract cancer (e.g., urothelial upper urinary tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., oral cancer), thyroid cancer, kidney cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0220] The term “treating” (or “treatment”) as used in this article means to suppress, slow down, stop, or reverse the progression or severity of existing symptoms, conditions, or disorders.

[0221] The term “patient” as used in this article refers to mammals, particularly humans.

[0222] This article provides compounds of formula (I), (II), (IIA) or (III) or pharmaceutically acceptable salts thereof for use in therapeutics.

[0223] This article provides compounds of formula (I), (II), (IIA) or (III) or pharmaceutically acceptable salts thereof for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer.

[0224] This article provides compounds of formula (I), (II), (IIA) or (III) or pharmaceutically acceptable salts thereof for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer.

[0225] This article provides compounds of formula (I), (II), (IIA) or (III) or pharmaceutically acceptable salts thereof for the treatment of cancer.

[0226] This document provides the use of compounds of formula (I), (II), (IIA) or (III) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome or cancer.

[0227] This document provides the use of compounds of formula (I), (II), (IIA) or (III) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of cancer.

[0228] This article provides a method for treating systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer, said method comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I), (II), (IIA), or (III) or a pharmaceutically acceptable salt thereof.

[0229] This article provides a method for treating cancer, which includes administering to a patient in need of such treatment an effective amount of a compound of formula (I), (II), (IIA) or (III) or a pharmaceutically acceptable salt thereof.

[0230] In the methods and uses provided herein, the cancers are selected from breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer), urothelial carcinoma, bladder cancer (e.g., urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), upper urinary tract cancer (e.g., urothelial upper urinary tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., oral cancer), thyroid cancer, kidney cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer. Specifically, the cancer is selected from breast cancer (e.g., aggressive ductal carcinoma, aggressive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer), urinary tract epithelial carcinoma, bladder cancer (e.g., urinary tract epithelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), upper urinary tract cancer (e.g., upper urinary tract epithelial carcinoma), urethral cancer, pancreatic cancer, prostate cancer, colorectal cancer, melanoma (e.g., cutaneous melanoma), kidney cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, and ovarian cancer. More specifically, the cancer is selected from breast cancer (e.g., aggressive ductal carcinoma, aggressive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer), urinary tract epithelial carcinoma, bladder cancer (e.g., urinary tract epithelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), upper urinary tract cancer (e.g., upper urinary tract epithelial carcinoma), and glioblastoma. Most specifically, the cancer in question is bladder cancer (e.g., urinary tract epithelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer).

[0231] The compounds provided herein can be prepared as shown in the following preparation and examples.

[0232] Some abbreviations are defined as follows: "ACN" represents acetonitrile; "AcOH" represents acetic acid; "Ac2O" represents acetic anhydride; "aq." represents aqueous; "AIBN" represents azobisisobutyronitrile; "BINAP" represents 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; "Pd(DtBPF)Cl2" represents [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride; "NBS" represents N-bromosuccinimide; "n-BuOH" represents n-butyl alcohol or n-butanol; "BOC" represents tert-butyloxycarbonyl; "Boc2O" represents di-tert-butyl dicarbonate; "BuLi" represents... Butyllithium; "CuSO45H2O" represents copper sulfate pentahydrate; "CsF" represents cesium fluoride; "F-TEDA" represents 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane; "CuI" represents cuprous iodide; "DMP" represents Desmartin periodide; "DCE" represents 1,2-dichloroethane; "DCM" represents dichloromethane (or methylene chloride); "DMEA" represents dimethylethylamine; "NDM" represents 1-dodecanethiol; "DEA" represents diethanolamine; "DEAD" represents azobis(2,2-dichloroethane). Diethyl formate; "DIAD" indicates diisopropyl azodicarbonate; "DIEA" or "DIPEA" indicates N,N-diisopropylethylamine; "DMA" indicates N,N-dimethylaniline; "DMAP" indicates 4-dimethylaminopyridine; "DMF" indicates N,N-dimethylformamide; "DPPA" indicates diphenyl azidophosphate; "EAA" indicates ethyl acetoacetate; "EtOAc" indicates ethyl acetate; "FA" indicates formic acid; "hr" indicates hours; "i-PrMgCl" indicates isopropyl magnesium chloride; "IPA" indicates isopropylamine; "T3P" indicates propylphosphonic anhydride; "KOAc" indicates... "Potassium acetate"; "LiBH4" indicates lithium borohydride; "LDA" indicates lithium diisopropylaminodimethylamine; "MsCl" indicates methanesulfonyl chloride; "MTBE" indicates methyl tert-butyl ether; "NCS" indicates N-chlorosuccinimide; "NIS" indicates N-iodosuccinimide; "MeMgBr" indicates methyl magnesium bromide; "NMP" indicates N-methyl-2-pyrrolidone; "-OAc" indicates acetate; "-OMs" indicates methanesulfonate, also known as methanesulfonate; "min" or "min." indicates minutes; "N2" indicates nitrogen; "sat." or "sat'd" indicates saturated; "soln"." indicates solution; "-OTf" indicates trifluoromethanesulfonate, also known as trifluoromethylsulfonate; "PCy3" indicates tricyclohexylphosphine; "Pd(AcO)2" indicates palladium(II) acetate; "Pd(dba)2" indicates bis(dibenzylacetone)palladium(O); "Pd2(dba)3" indicates tris(dibenzylacetone)dipalladium(O); "Pd2(dba)3.CHCl3" indicates tris(dibenzylacetone)dipalladium-chloroform adduct; "Pd(dppf)Cl2" indicates [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; "Pd(dppf)Cl2.CH2Cl2" indicates 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride Methane complex; "PE" represents petroleum ether; "K3PO4" represents potassium phosphate; "RT" represents room temperature; "PPh3" represents triphenylphosphine; "Pd(PPh3)4" represents tetra(triphenylphosphine)palladium(O); "Ph" represents phenyl; "NaH" represents sodium hydride; "TBAF" represents tetra-n-butylammonium fluoride; "TEA" represents triethylamine; "TFA" represents trifluoroacetic acid; "Tf2O" represents trifluoromethanesulfonic anhydride; "THF" represents tetrahydrofuran; "TsCl" represents 4-toluenesulfonyl chloride; "TMSCF3" represents (trifluoromethyl)trimethylsilane; "TMSOTf" represents trimethylsilyl trifluoromethanesulfonate; "(CF3SO2)2O" represents trifluoromethanesulfonic anhydride; "t". (R) " indicates retention time; "Xantphos" indicates 4,5-bis(diphenylphosphino)-9,9-dimethylxanthanyl; "X-Phos" indicates 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl; "XPhos Pd G2" indicates chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); and "XPhos Pd G4" indicates CAS #1599466-81-5; "ZnCl2" indicates zinc chloride.

[0233] For clarity, certain stereochemical centers are left unspecified and certain substituents are omitted in the following schemes, but this is not intended to limit the teachings of the schemes in any way. Furthermore, those skilled in the art can, at any convenient point in the synthesis of the compounds of the present invention, separate or resolve individual isomers, enantiomers, and diastereomers by methods such as selective crystallization or chiral chromatography (see, for example, J. Jacques et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). The designations “Isomer 1” and “Isomer 2” respectively denote the compounds eluted first and second from chiral chromatography under the conditions described herein, and the same designations apply to subsequent intermediates and examples if chiral chromatography is initiated first in the synthesis. When more than one chiral chromatography is performed in the preparation, further nomenclature of “A” and “B” is provided, where “A” indicates the compound eluted first and “B” indicates the compound eluted second. For example, “Isomer 2A” indicates the compound eluted first from the chiral chromatography of a compound previously named “Isomer 2”. Furthermore, the intermediates described in the following schemes contain a number of nitrogen or oxygen protecting groups. These variable protecting groups may be the same or different each time they appear, depending on the specific reaction conditions and the specific transformation to be performed. Protecting and deprotecting conditions are well known to those skilled in the art and are described in the literature (see, for example, “Greene’s Protective Groups in Organic Synthesis,” 4th edition, Peter GM Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0234] In the following schemes, unless otherwise specified, all substituents are as defined above. “PG” indicates a protecting group developed for an amino group, such as a urethane or amide, an example being a BOC protecting group. Such protecting groups are well known and understood in the art. Reagents and starting materials are generally readily available to those skilled in the art. Others can be prepared using standard techniques of organic and heterocyclic chemistry, similar to the synthesis of known structurally similar compounds and the procedures described in the subsequent preparations and examples, including any new procedures. This specification intends to include intermediates and methods that can be used to synthesize compounds of formula (I), (II), (IIA), or (III).

[0235] Option 1 Scheme 1 describes the preparation of compounds (4) and (8), which produce compound 13 via different pathways and will be further processed into formula (I). Those skilled in the art will recognize that alcohol (1) can react with methanesulfonyl chloride to provide methanesulfonate (2), which can further react with (3) to provide (4). Treatment of compound (4) with LDA and a suitable alkylating agent yields compound (8). Alternatively, those skilled in the art can begin with compound (3) (i.e., the substituted bromide (3)), which directly yields compound (8) upon reaction with methanesulfonate (2).

[0236] Compound (8) can also be synthesized via the alternative route shown in Scheme 1. Furthermore, those skilled in the art will understand that the alcohol (1) can be reacted under Mitsunobu conditions to provide an azide (5). The azide (5) can be condensed with a β-keto ester to provide a triazole ester (6), which can undergo saponification to provide a carboxylic acid (7). Treatment of the carboxylic acid (7) with bromine in the presence of a base yields compound (8).

[0237] Scheme 1 further describes the preparation of compounds (12) and (13), which will be further processed into formula (I). Those skilled in the art will recognize that compounds (4) and (8) can be deprotected to produce (9) and (11), which, when reacted with trifluoromethanesulfonate (10), produce bromide compounds of (12) and (13). Compound (12) can be further alkylated to produce compound (13). Those skilled in the art will understand that a ketone compound can replace the trifluoromethanesulfonate compound of (10). Alternatively, reacting compound (9) or (11) with a suitable ketone under reductive amination conditions can also provide compound (12) or (13).

[0238] Option 2 Scheme 2 describes another method for preparing compounds (12) and (13), which will be further processed into formula (I). Those skilled in the art will recognize that the alcohol (14) can react with methanesulfonyl chloride to provide a methanesulfonate ester (15), which can further react with compound (3) to provide (12). Compound (12) can be further alkylated to provide compound (13). Alternatively, the substituted compound (3) can react with (15) to directly obtain compound (13).

[0239] Alternatively, compound (13) can be synthesized via the alternative route shown in Scheme 2. An alcohol (14) can be reacted under Mitsunobu conditions to provide an azide (16). The azide (16) can be condensed with a β-keto ester to provide a triazole ester (17), which can undergo saponification to provide a carboxylic acid (18). Treatment of the carboxylic acid (18) with bromine in the presence of a base provides a bromide (13). Alternatively, the azide (16) can be reacted with a suitably substituted trimethylsilyl alkyne to provide a trimethylsilyl analog (19). The reaction of (19) with NBS in the presence of silica provides compound (13).

[0240] Option 3 Scheme 3 describes the preparation of the compound of formula (I). The reaction of (20) with chloroacetaldehyde provides a heteroaryl chloride (21), which can be demethylated to produce (22). Compound (22) can be reacted with an alcohol (23) under Mitsunobu conditions to provide R. 2 Substituted heteroaryl chlorides (24). A skilled technician will recognize that when R... 2 When it is methyl, it is not necessary to demethylate (22) to obtain R. 2 Substituted (24). The conversion of heteroaryl chloride (24) to boric acid (25) is achieved by treatment of (24) with dipentanoyl diboron under palladium-catalyzed conditions. Boric acid (25) can be reacted with bromide (13) via Suzuki coupling to generate compound (26). Iodization of compound (26) in the presence of NIS provides (27), which can be further processed to provide R. 6 Alternative compound (28). Alternatively, as known to those skilled in the art, compound (26) can react with reagents such as NCS or NBS to directly provide R as chlorine or bromine. 6 (28) can be obtained without an intermediate iodination step. Compound (28) is deprotected to provide compound (29). N-cyanoylation of (29) produces an N-cyanoamino compound of formula (I).

[0241] Alternatively, a skilled technician will understand that, prior to converting (24) to boric acid (25), compound (24) can first be iodinated and then reacted with copper cyanide in DMF to provide R. 6 Substituted heteroaryl chlorides (24). Next, R 6 Substituted heteroaryl chlorides (24) can be converted to R 6 Substituted boric acid R 6 The substituted (25) can react with bromide (13) to provide compound (28). Deprotection of (28) followed by N-cyanoation produces an N-cyanoamino compound of formula (I).

[0242] Option 4 Scheme 4 describes the preparation of compound (37a). Reaction of (30) in the presence of 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-dionium tetrafluoroborate provides a fluorinated bicyclic analog (31). Reaction of (31) with dipentanoyl diborone under palladium catalysis provides a borate ester (32). Reaction of (32) with bromide (13) under palladium catalysis provides (34). Demethylation of (34) with aqueous sodium hydroxide and dodecane-1-thiol provides a hydroxy bicyclic analog (35). Alkylation of (35) with a suitable bromide gives compound (36). Deprotection of (36), followed by N-cyanoation, yields the N-cyanoamino compound (37a).

[0243] Option 5 Scheme 5 describes another method for preparing the cyanoamino compound of formula (I). Those skilled in the art will recognize that compound (30) can be demethylated to provide (38). The demethylated (38) can then be reacted with an alcohol (22) under Mitsunobu conditions to provide R. 2 Substituted bromide compound (39). Alternatively, compound (39) can be prepared by using the corresponding iodinated analog R of (22). 2 I replace R 2 OH (22) is used for alkylation. R 2 The conversion of the substituted bromide (39) to the borate ester (40) can be achieved by treating (39) with dipentanoyl diboron under palladium-catalyzed conditions. The borate ester (40) reacts with (13) via Suzuki coupling to produce compound (28). Alternatively, those skilled in the art will recognize that, as shown in scheme 5, the methylated compound (30) can first be treated with dipentanoyl diboron under palladium-catalyzed conditions to provide the borate ester (41). The borate ester (41) can react with (13) via Suzuki coupling to produce compound (42). Those skilled in the art will recognize that compound (42) is also compound (28), wherein R 2 It is methyl. Finally, compound (28) can be deprotected to provide an amine (29). N-cyanoation of amine (28) produces an N-cyanoamino compound of formula (I).

[0244] Option 6 Scheme 6 describes compounds (42) from Scheme 5 and compounds (28) from Schemes 3 and 5 (where R 2Another method for preparing compounds of formula (I) starting with methyl is used. Compound (42) is demethylated to provide compound (43), which is then reacted with an alcohol (22) under Mitsunobu conditions to provide R. 2 Substituted compounds (28), wherein R 2 The group is not methyl. R can be... 2 The substituted (28) is deprotected to produce compound (29), and then N-cyano-treated to produce an N-cyanoamino compound of formula (I).

[0245] Those skilled in the art will recognize that alternative reactants can also produce compound (28). For example, alcohol (22) can be converted into a trifluoromethylsulfonate analogue (R) of (22). 2 -OTf), which can then react with compound (43) to produce compound (28). Alternatively, alcohol compound (43) can first be converted to trifluoromethylsulfonate compound (35), which can then react with R of (22). 2 -NH2 analogue reaction to provide amine-R 2 Substituted compounds (28).

[0246] Option 7 Scheme 7 describes the preparation of compound (47), which is further processed in Scheme 8 into a cyanoamino compound of formula (I). The borate ester (40) prepared in Scheme 5 can be reacted with (8) via Suzuki coupling to produce compound (46). Alternatively, those skilled in the art will recognize that the borate ester (41) prepared in Scheme 5 can be reacted with (8) via Suzuki coupling to produce compound (44). Those skilled in the art will recognize that the borate R prepared in Scheme 3... 6 The substituted (25) can be replaced in these reactions with borate esters (40) and (41). Compound (44) can be demethylated to provide compound (45), which, when reacted with alcohol (22) under Mitsunobu conditions, provides compound (46). Finally, compound (44) or (46) can be deprotected to provide amine (47).

[0247] Skilled technicians will recognize that amines (47) can also be prepared by replacing R with an unsubstituted compound (4). 1 The substituted compound (8) produces an amine (47) in which the A group is not substituted.

[0248] Option 8 Scheme 8 describes the preparation of the compound of formula (I). The compound (47) prepared in Scheme 7 is reduced-amined with a ketone (48) to provide the compound of formula (I). Alternatively, (47) is alkylated with a trifluoromethanesulfonate (49) to obtain the compound of formula (I). Those skilled in the art will also understand that the methanesulfonate (-OMs) compound of (49) can be replaced with a trifluoromethanesulfonate (49).

[0249] Furthermore, those skilled in the art will recognize that N-protected ketone compounds (50) and trifluoromethanesulfonate compounds (10) can also be used instead of N-cyanoamino compounds (48) and (49). The compound (47) prepared in Scheme 7 is reductively amination with an N-protected ketone (50) to provide an N-protected (28). Alkylation of compound (47) with an N-protected trifluoromethanesulfonate (10) also provides an N-protected (28). The protected (28) can be deprotected to produce compound (29), which, upon reaction with cyanogen bromide, produces an N-cyanoamino compound of formula (I).

[0250] Option 9 Scheme 9 describes the preparation of compound (54a). R 10 The compound in which R 10 It is a 5-6 aryl or 5-6 heteroaryl group substituted with a halogen, but not limited to a halogen, which can undergo halogen-magnesium exchange with reagents such as iPrMgCl. The resulting Grignard reagent is then reacted with TBDMS-protected alcohol R. 2 The aldehyde (51) is reacted to convert the aldehyde into an alcohol (52). In this step, R can be protected using protecting groups other than TBDMS. 2 Alcohol. Reacting alcohol (52) under Mitsunobu conditions yields compound (53). Treating (53) under acidic conditions yields a compound (54) with double deprotection. Reacting (54) with cyanogen bromide yields an N-cyanoamino compound (54a).

[0251] Option 10 Scheme 10 describes the preparation of compound (60a). 4,6-Dichloropyridin-2-amine is reacted with a solution of 2-bromo-1,1-dimethoxypropane pretreated with aqueous HCl in EtOH to provide 5,7-dichloro-3-methylimidazo[1,2-a]pyridine. The 5,7-dichloro intermediate is treated with sodium methoxide to produce 7-chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine. A borate ester (55) is formed by a Pd-catalyzed reaction of 7-chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine with dipentanoyl diborone. Suzuki coupling of the borate ester (55) with bromide (56) provides compound (57). Hydrolysis of (57) with NaOH yields a hydroxy compound (58). Alkylation of (58) with methanesulfonate ester (59) provides compound (60). (60) is deprotected with cyanogen bromide to provide (61) to provide an N-cyanoamino compound (60a).

[0252] Option 11 Scheme 11 describes the preparation of (65a). R is treated in the presence of a base. 2 OH, followed by the addition of 4,6-dichloropyridin-2-amine, provides compound (61). The reaction of compound (61) with dipentanoyl diborone via Pd catalysis forms a borate ester (62). Suzuki coupling of the borate ester (62) with compound (13) provides compound (63). Chlorination of (63) with 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione provides compound (64), which is then deprotected under acidic conditions to yield compound (65). Treatment of (65) with cyanogen bromide provides an N-cyanoamino compound (65a).

[0253] Option 12 Scheme 12 describes the preparation of (71a). Treatment of 7-chloro-6H-imidazo[1,2-c]pyrimidin-5-one with borate ester (67) under palladium-catalyzed conditions yields (68). Reacting (68) under Mitsunobu conditions yields (70). Halogenating (70) in the presence of NCS yields (69). Deprotection of (69) yields (71). Subsequent treatment of (71) with cyanogen bromide yields compound (71a).

[0254] The compounds of the present invention or pharmaceutically acceptable salts thereof can be prepared according to the following preparations and examples using methods well known and understood in the art. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitutions of solvents and auxiliary reagents are within the scope of the art. Similarly, those skilled in the art will understand that synthetic intermediates can be isolated and / or purified as needed or desired by various well-known techniques, and often, various intermediates may be used directly in subsequent synthetic steps with little or no purification. As an example, the compounds of the preparations and examples can be isolated, for example, by silica gel purification, or directly by filtration or crystallization. Furthermore, those skilled in the art will understand that, in some cases, the order of the introduced moieties is not important. The specific order of steps required to produce the compounds of the present invention depends on the specific compound being synthesized, the relative susceptibility of the starting compound and the substituted moieties, as is well known to skilled chemists. Unless otherwise indicated, all substituents are as defined above, and all reagents are well known and understood in the art.

[0255] Preparation and Examples Preparation 1 3-Benzyloxycyclobutanol A mixture of 3-(benzyloxy)cyclobutane-1-one (20 g, 113.5 mmol) and NaBH4 (4.29 g, 113.5 mmol) in MeOH (50 mL) was stirred at room temperature under N2 for 2 hours. The reaction mixture was quenched with H2O at 0 °C, extracted with EtOAc (3 x 100 mL), washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to provide the title compound (20 g, 98.9%) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.42-7.21 (m, 5H), 4.45(s, 2H), 3.93-3.85 (m, 1H), 3.71-3.62 (m, 1H),2.82-2.63(m,2H), 1.97-1.92(m, 2H).

[0256] Preparation 2 (2S,4S)-2-cyclopropyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester Under N2 at 0°C, NaOH (2.03 g, 50.7 mmol) was added fractionally to trans-2-cyclopropylpiperidine-4-ol hydrochloride (3.00 g, 16.9 mmol) in H2O (15.00 mL) and DCM (15.00 mL). The mixture was stirred at room temperature for 10 min, followed by fractional addition of Boc2O (4.05 g, 18.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with H2O (100 mL) and extracted with DCM (2 x 120 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to provide the title compound (5 g, crude) as a yellow solid, which was used for the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 4.69 (d,1H), 3.98-3.79 (m, 2H), 3.40-3.33 (m, 1H), 2.99-2.85 (m, 1H), 1.94-1.74 (m,2H), 1.37 (s, 9H), 1.31-1.18 (m, 2H), 1.15-1.08 (m, 1H), 0.54-0.45 (m, 1H), 0.42-0.26 (m, 2H), 0.22-0.12 (m, 1H).

[0257] Preparation 3 N-diazo-1,1,1-trifluoro-methanesulfonamide A solution of (CF3SO2)2O (8.00 g, 28.4 mmol) in heptane (25 mL) was slowly added to a solution of NaN3 (9.22 g, 142 mmol) and tetra(butyl-1-yl)ammonium bisulfate (481 mg, 1.42 mmol) in distilled H2O (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1–2 hours. Heptane (25 mL) was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with heptane (3 x 10 mL). The combined organic layers were dried over NaOH beads. The organic layers were decanted, and the solution was used immediately for subsequent reactions.

[0258] Preparation 4 (1r,3r)-3-azidocyclobutanol A solution of (1r,3r)-3-aminocyclobutane-1-ol (1.23 g, 14.2 mmol), NaHCO3 (4.05 g, 48.2 mmol), and CuSO4·5H2O (1.77 g, 7.08 mmol) in MeOH (15 mL) and H2O (15 mL) (v / v) was treated with a freshly prepared stock solution of N-diazo-1,1,1-trifluoro-methanesulfonamide in heptane (4.96 g, 28.3 mmol). Additional MeOH was added to the reactants in 5 mL increments until a homogeneous mixture was obtained (total 20 mL). The reactants were stirred overnight at room temperature. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were concentrated under vacuum to provide a deep green solution. Assume quantitative yield. 1 H NMR (400 MHz, DMSO-d6) δ 2.05 -2.31 (m, 4 H) 4.07 - 4.18 (m, 1 H) 4.29 (br s, 1 H) 5.14 - 5.32 (m, 1 H).

[0259] Preparation 5 4-(2-Azide-1,1-Dimethyl-ethyl)piperazine-1-carboxylic acid tert-butyl ester DPPA (7.67 g, 27.89 mmol) was added dropwise to a stirred solution of tert-butyl 4-(1-hydroxy-2-methylpropane-2-yl)piperazine-1-carboxylate (6.00 g, 23.22 mmol) and DBU (4.24 g, 27.87 mmol) in toluene (100 mL) at 0 °C under N2. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with PE:EtOAc (20:1 to 10:1) to provide the title compound (6 g, 91.2%) as a pale yellow oil. ES / MS m / z: 284.3 [M+H] + .

[0260] Preparation of 6 2-Azide-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester DEAD (10.10 g, 58.01 mmol) was added dropwise to tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (10 g, 41.44 mmol) and PPh3 (15.22 g, 58.01 mmol) in THF (150 ml) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 hour, and then DPPA (13.68 g, 49.72 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and then purified by silica gel chromatography, eluting with PE:EtOAc (30:1 to 20:1) to provide the title compound (14.5 g, crude) as a colorless oil, which was used without further purification. 1 H NMR (300 MHz, CDCl3) δ 3.98 -3.84 (m, 1H), 3.39 -3.28 (m, 4H), 2.32 -2.20 (m, 2H), 1.94 -1.80 (m, 2H), 1.60 -1.52 (m, 4H), 1.47 (s, 9H).

[0261] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to tert-butyl 2-azido-7-azaspiro[3.5]nonane-7-carboxylate. DIAD can be used in place of DEAD.

[0262] Table 1 1 PE:EtOAc (6:1 to 4:1) was purified by preparative TLC.

[0263] 2 Purified by silica gel chromatography, eluted with PE:EtOAc (2:1).

[0264] 3 Purified by reversed-phase chromatography; C18 column; eluted with 40% to 50% ACN in H2O.

[0265] 4 1 H NMR (300 MHz, DMSO-d6).

[0266] 5 Purified by silica gel chromatography, eluted with PE:EA (20:1).

[0267] 6 Purified by silica gel chromatography, eluted with PE:EA (15:1).

[0268] 7 1 H NMR (400 MHz, DMSO-d6).

[0269] 8 Purified by silica gel chromatography, eluted with PE / EA (30:1 to 20:1).

[0270] a The material is used without further purification.

[0271] Preparation of 17 (3S,4S)-4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester Imidazole-1-sulfonyl azide (3.75 g, 21.63 mmol) was added to a mixture of (3S,4S)-4-amino-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.9 g, 18.03 mmol), K₂CO₃ (1.25 g, 9.02 mmol), and CuSO₄·5H₂O (0.45 g, 1.80 mmol) in MeOH (25 mL) at room temperature under N₂. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with H₂O and the mixture was extracted with EA (2 x 500 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (4.3 g, crude product) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 5.67 (d, 1H), 3.95 -3.77 (m, 2H), 3.48-3.35 (m, 1H), 3.33 -3.17 (m, 1H), 2.67 (d, 2H), 1.89 -1.80 (m, 1H), 1.39 (s,9H), 1.24 -1.16 (m, 1H).

[0272] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to tert-butyl (3S,4S)-4-azido-3-hydroxy-piperidine-1-carboxylate. DIAD can be used in place of DEAD.

[0273] Table 2 .

[0274] Preparation 21 (2S)-2-hydroxypropanehydrazine A mixture of ethyl lactate (3.00 g, 25.40 mmol), hydrazine hydrate (7.63 g, 152.37 mmol, 80% in H2O), and EtOH (10.00 mL) was heated at 50 °C for 12 hours under N2. After cooling to room temperature, the reaction mixture was concentrated under vacuum to provide the title compound (3.0 g, crude). The title compound was used for the next step without further purification. ES / MS m / z: 105.2 [M+H] + .

[0275] Preparation 22 (2S)-N-[(E)-dimethylaminomethyleneamino]-2-hydroxypropionamide A mixture of (2S)-2-hydroxypropanehydrazine (3.0 g, crude), (dimethoxymethyl)dimethylamine (6.44 g, 43.22 mmol), and i-PrOH (15 mL) was heated at 50 °C for 5 hours under N2. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with DCM:MeOH (10:1 to 8:1) to provide the title compound (3.0 g, 62.1%) as a white solid. ES / MS m / z: 160.2 [M+H] + .

[0276] Preparation 23 4-(4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylic acid tert-butyl ester TEA (605 mg, 5.98 mmol) was added to a solution of 1-(4-methyl-4H-1,2,4-triazol-3-yl)piperazine (500 mg, 2.99 mmol) in THF (3 mL) and H₂O (0.25 mL). After stirring for 15 minutes, BOC₂O (783 mg, 3.59 mmol) was added. The reaction mixture was stirred at 50 °C for 15 minutes. After cooling to room temperature, the pH was adjusted to ~14 by adding 19N NaOH (aqueous solution). The mixture was extracted with 3:1 CHCl₃:iPrOH. The organic layers were combined, washed with brine (ensuring pH was kept close to 12), dried over Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (647 mg, 2.42 mmol) as a pale yellow solid. ES / MS m / z 168.1 [M+2H-BOC] + .

[0277] Preparation 24 2-(1-Bromoethyl)-N,N-Dimethylbenzamide A reaction flask containing 2-ethyl-N,N-dimethylbenzamide (0.81 g, 4.6 mmol), AIBN (75 mg, 0.46 mmol), and NBS (0.89 g, 5.0 mmol) was evacuated and backfilled with N2 (3X). CCl4 (5 mL) was added, and the reaction mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the insoluble matter was washed with CCl4 (2 x 10 mL). The mixture was then concentrated under vacuum to give the title compound (0.8 g, 70%) as a clear oil, which was used without further purification. 1 H NMR (400 MHz, CdCl3), δ 7.67 (m, 1H), 7.40 (m, 1H), 7.30 (m,1H), 7.25 (m, 1H), 5.45 (m, 1H), 3.18 (3H), 2.91 (3H), 2.08 (3H).

[0278] Preparation 25 2-Fluoro-N-methoxy-N-methyl-acetamide DCM (40 mL) was added to dimethylhydroxylamine hydrochloride (3.68 g, 37.70 mmol) under N2 and the solution was cooled to -10 °C. 2M trimethylaluminum in hexane (2.72 g, 37.70 mmol) was slowly added to the reactants. Once the addition was complete, the reactants were allowed to warm to room temperature and stirred at room temperature for 1 hour. In a separate flask, ethyl 2-fluoroacetate (2.00 g, 18.85 mmol) and DCM (20 mL) were added under N2, and the reaction mixture was cooled to -10 °C. The solution prepared from trimethylaluminum and dimethylhydroxylamine was then slowly transferred to the reactants containing ethyl 2-fluoroacetate, warmed to room temperature, and stirred for 18 hours. The reactants were quenched by slowly adding 1M Rochelle salt (10 mL). The mixture was stirred for 1 hour, diluted with H2O, the layers were separated, and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic matter was washed with brine, dried over Na2SO4, and concentrated under vacuum to produce the title compound (1.6 g, 13 mmol) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ 3.15 (m, 3H), 3.63 (s, 3H), 5.01 (d, J=47.6Hz, 2H).

[0279] Preparation 26 7-Fluoro-N-methoxy-N-methyl-isoquinoline-4-carboxamide DIEA (2.43 g, 18.8 mmol) was added dropwise to a mixture of 7-fluoroisoquinoline-4-carboxylic acid (900 mg, 4.71 mmol) and dimethylhydroxylamine hydrochloride (551 mg, 5.65 mmol) in DCM (5 mL). The solution was stirred for 5 min, followed by dropwise addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane-2,4,6-trioxide (4.49 g, 14.1 mmol). The mixture was stirred at room temperature for 3 h, diluted with H2O, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with 0% to 100% EtOAc in heptane to provide the title compound (1.03 g, 93.4%). 1 H NMR (400 MHz, CDCl3) δ 3.47 (brs, 6 H), 7.50 - 7.61 (m, 1 H), 7.65 (dd, J=8.44, 2.20 Hz, 1 H), 7.97 (dd, J=9.11, 5.07 Hz, 1 H), 8.60 (s, 1 H), 9.26 (s, 1 H).

[0280] The following compounds were prepared essentially as described with respect to 7-fluoro-N-methoxy-N-methyl-isoquinoline-4-carboxamide, using appropriate reagents and adjusting the reaction time to determine the end of the reaction.

[0281] Table 3 1 Dimethylhydroxylamine was used instead of HCl salt. EtOAc was used as the solvent.

[0282] 2 Purified by silica gel column chromatography, eluted with PE:EtOAc (10:1 to 4:1).

[0283] 3 Purified by silica gel column chromatography, eluted with PE:EtOAc (10:1 to 1:1).

[0284] 4 Purified by silica gel column chromatography, eluted with PE:EtOAc (10:1 to 5:1).

[0285] a The material is used in the next step without being characterized.

[0286] b1 H NMR (400 MHz, CDCl3) δ 3.43 (br s, 3 H), 3.84 (br s, 3 H), 7.78 (br s, 1 H), 9.24 (br s, 1 H).

[0287] c1 H NMR (400 MHz, CDCl3) δ 2.59 (br s, 3 H), 3.37 (br s, 3 H), 3.79 (br s, 3 H), 8.30 (br s, 1 H).

[0288] d Sodium 2-(trifluoromethoxy)acetate was used.

[0289] e 1 H NMR (400 MHz, CdCl3) δ 1.45 (s, 3 H) 1.51 (s, 3 H) 3.23 (s, 3 H)3.73 (s, 3 H) 4.04 - 4.11 (m, 1 H) 4.24 - 4.33 (m, 1 H) 4.84 - 4.92 (m, 1 H).

[0290] Preparation of 35 4-Oxoperidin-1-carboxynitrile A solution of BrCN (256 mg, 2.42 mmol) in DCM (3.00 mL) was added dropwise to a stirred mixture of 4-piperidinone (200 mg, 2.02 mmol) and NaHCO3 (509 mg, 6.05 mmol) in H2O (4.50 mL) and DCM (1.50 mL). The mixture was stirred at 0 °C for 30 min, and then stirred overnight at room temperature. The mixture was quenched with H2O (10 mL) and extracted with DCM (3 x 15 mL). The combined organic extracts were washed with saturated NaHCO3 (3 x 5 mL) and brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (120 mg, 48%) as a yellow oil.1 H NMR (400 MHz, d 6 -DMSO) δ 3.54 (t, 4H), 2.47 (t, 4H).

[0291] Preparation of 36 ethyl 1-methylpyrrolo[2,3-c]pyridine-4-carboxylate A mixture of 4-bromo-1-methylpyrrolo[2,3-c]pyridine (500 mg, 1 mmol), diethyl oxalate (415 mg, 2.84 mmol), PdCl₂(PPh₃)₂ (9.98 mg, 14.2 μmol), and N,N-dimethylpyridin-4-amine (347 mg, 2.84 mmol) in EtOH (327 mg, 7.11 mmol) was heated by microwave irradiation at 170 °C for 1 hour. The mixture was diluted with EtOAc (10 mL) and washed with saturated NH₄Cl aqueous solution (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL), and the combined organic layers were concentrated under vacuum. The residue was purified by reversed-phase chromatography, eluting with an ACN gradient from 0% to 100% in water to provide the title compound (265 mg, 54.8%). ES / MS m / z 205.1 [M+H] + .

[0292] Preparation of 37 (1-Methylpyrrolo[2,3-c]pyridin-4-yl)methanol A 1M solution of LiAlH4 (73.9 mg, 1.95 mmol) in Et2O was added to a solution of ethyl 1-methylpyrrolo[2,3-c]pyridine-4-carboxylate (265 mg, 1.30 mmol) in THF (3 mL) at -78 °C. The reaction mixture was stirred for 20 min, then allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with Et2O and, after cooling to 0 °C, H2O (0.1 mL) was slowly added. Then, a 15% aqueous solution of NaOH (0.07 mL) was added, followed by H2O (0.2 mL), and the mixture was warmed to room temperature. After stirring for 15 min, MgSO4 was added, and the mixture was stirred for another 15 min. The solids were removed by filtration, and the filtrate was concentrated under vacuum to provide the title compound (190 mg, 90.3%). ES / MS m / z 163.1 [M+H] + .

[0293] Preparation of 38 1-Methylpyrrolo[2,3-c]pyridine-4-carboxaldehyde DMP (646 mg, 1.52 mmol) was added to a solution of (1-methylpyrrolo[2,3-c]pyridin-4-yl)methanol (190 mg, 1.17 mmol) in DCM (4 mL) at 0 °C, and the reaction mixture was stirred for 1 hour. The mixture was diluted with DCM (10 mL) and washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL). The volatiles were removed under vacuum, and the residue was purified by reversed-phase chromatography, eluting with an ACN gradient from 0% to 100% in water to provide the title compound (70 mg, 37%). ES / MS m / z 161.1 [M+H] + .

[0294] Preparation 39 2-Morphyrin-5-(trifluoromethyl)pyridine-3-carboxaldehyde 2-Chloro-5-(trifluoromethyl)nicotinaldehyde (700 mg, 3.34 mmol) and morpholine (291 mg, 3.34 mmol) were dissolved in EtOH (10 mL) at room temperature and treated with TEA (338 mg, 3.34 mmol). The reaction mixture was heated to 80 °C and held for 6 hours. The mixture was cooled to room temperature, concentrated under vacuum, and purified by rapid silica gel chromatography, eluting with a MeOH gradient from 0% to 20% in DCM to provide the title compound (0.7 g, 80%) as a clear oil. ES / MS m / z 261.1 [M+H] + .

[0295] Preparation of 40 5,7-Dichloroimidozolo[1,2-a]pyridine Under N2 conditions at room temperature, 4,6-dichloropyridin-2-amine (100.00 g, 614 mmol), NaHCO3 (154.6 g, 1840 mmol), chloroacetaldehyde (180.5 g, 920 mmol, 40% in water) and [other ingredients] were added to a 1 L pressure vessel. n-BuOH (500 mL). The resulting mixture was stirred overnight at 80 °C. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (8:1 to 5:1) to yield the title compound (88 g, 76.7%) as a yellow solid. ES / MS m / z 187.0 [M+H] + .

[0296] Preparation 41 5,7-Dichloro-3-methylimidazo[1,2-a]pyridine 12M HCl (33.55 g, 920 mmol) was added to a solution of 2-bromo-1,1-dimethoxypropane (16.84 g, 92 mmol) in EtOH (50 mL) at room temperature under N2. The reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the pH of the mixture was adjusted to approximately pH 8 with NaHCO3 (90.19 g, 1074 mmol). Then, 4,6-dichloropyridin-2-amine (5.0 g, 30.68 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with PE:EtOAc (10:1) to yield the title compound (2.5 g, 40.5%) as a yellow solid. ES / MS m / z 201.1 [M+H] + .

[0297] The following compounds were prepared by using appropriate reagents and adjusting the reaction temperature and time to determine the end of the reaction, essentially as described with respect to 5,7-dichloro-3-methylimidazo[1,2-a]pyridine.

[0298] Table 4 .

[0299] Preparation 43 7-Chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine NaOMe (4.03 g, 74.61 mmol) was added to 5,7-dichloro-3-methylimidazo[1,2-a]pyridine (1.5 g, 7.46 mmol) in MeOH (20 mL) at room temperature under N2. The reaction mixture was stirred at 80 °C for 1 h and then concentrated under vacuum. The residue was diluted with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to yield the title compound (1.35 g, 92.0%) as a yellow solid. ES / MS m / z 197.1 [M+H] + .

[0300] Preparation of 44 5,7-Dichloro-3-iodo-imidazo[1,2-a]pyridine NIS (12.03 g, 53.47 mmol) was added fractionally to 5,7-dichloroimidazolo[1,2-a]pyridine (5.00 g, 26.73 mmol) in DCM (50.00 mL) at room temperature under N2. The reaction mixture was stirred for 2 hours and then quenched with H2O (100 mL). The mixture was extracted with DCM (3 x 50 mL), the organic layer was washed with brine (3 x 50 mL), and dried over Na2SO4. After filtration, the filtrate was concentrated under vacuum to provide the title compound (12.0 g, crude product) as a deep yellow solid. ES / MS m / z 312.9 [M+H] + .

[0301] Preparation of 45 6-Bromo-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine 6-Bromo-4-methoxypyrazolo[1,5-a]pyridine (0.41 g, 1.81 mmol) and NIS (609 mg, 2.71 mmol) were dissolved in ACN (8 mL) and stirred at room temperature for 1 hour. The suspension was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a linear gradient of EtOAc in heptane from 0% to 100%. The fraction containing the title compound was concentrated under vacuum and combined with the filtered solid to provide the title compound (0.60 g, 94.1%). ES / MS m / z ( 79 Br / 81Br) 352.6 / 354.6 [M+H] + .

[0302] Preparation of 46 6-Bromo-3-fluoro-4-methoxy-pyrazolo[1,5-a]pyridine A solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5 g, 22.02 mmol) and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate) (7.04 g, 22.021 mmol) in ACN (50 mL) was stirred overnight at room temperature under N2. The mixture was diluted with H2O (50 mL) and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions: column, C18; mobile phase, 30% to 40% ACN in H2O (0.1% FA), for a 10-min phase to provide the title compound (810 mg, 15.01%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.56 (t, 1H), 8.04 (d, 1H), 6.77 (d, 1H), 3.97 (s, 3H).

[0303] Preparation 47 6-Bromo-4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine A mixture of 6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine (0.6 g, 1.7 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.5 g, 2.6 mmol), and CuI (0.4 g, 2.1 mmol) in DMF (6 mL) was heated to 80 °C for 6 hours. The suspension was filtered and the filtrate was concentrated under vacuum. The residue was purified by normal-phase chromatography, eluting with a linear gradient of EtOAc in heptane from 0% to 100% to provide the title compound (0.125 g, 20%) as a white solid. ES / MS m / z 249.9 [M+H] + .

[0304] Preparation of 48 5,7-Dichloroimidozolo[1,2-a]pyridine-3-carboxynitrile CuCN (6.30 g, 70.31 mmol) was added fractionally to 5,7-dichloro-3-iodoimidazolo[1,2-a]pyridine (11.00 g, 35.15 mmol) in DMF (50.00 mL) at room temperature under N2. The reaction mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, NH4OH (100 mL) was added dropwise over 5 minutes. The mixture was diluted with H2O (300 mL), stirred for 2 hours, and then extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (5:1 to 1:2) to provide the title compound (3.5 g, 47.0%) as a yellow solid. ES / MS m / z ( 35 Cl / 37 Cl) 211.9 / 213.9 [M+H] + .

[0305] Preparation 49 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carboxylonitrile A stirred solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile (5.60 g, 22.22 mmol) and NDM (5.39 g, 26.66 mmol) in DMA (20.0 mL) was treated with NaOH (5.33 g, 66.65 mmol, 50% in H2O) at room temperature under N2, and the mixture was stirred at 50 °C for 2 h under N2. The mixture was diluted with H2O (200 mL), acidified to pH 4–5 with concentrated HCl, and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine (3 x 100 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (3:1) to yield the title compound (4.6 g, 90.7%) as a yellow solid. ES / MS m / z 235.9 / 237.9 [MH] - .

[0306] Preparation of 50 6-Bromo-4-isopropoxy-pyrazolo[1,5-a]pyridine-3-carboxylonitrile A mixture of 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carboxynitrile (200 mg, 0.84 mmol) and Cs₂CO₃ (410.63 mg, 1.26 mmol) in DMF (2 mL) was treated with 2-iodopropane (0.1 mL, 1 mmol) and stirred for 7.5 h. The reaction mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc (0-100%) to yield the title compound (174.2 mg, 0.62 mmol, 74.02%) as a pale yellow solid. ES / MS m / z 282.00 [M+H] + .

[0307] Preparation 51 2-[3-[tert-butyl(dimethyl)silyl]oxyazinobutan-1-yl]-5-(trifluoromethyl)pyridine-3-carboxaldehyde 2-Chloro-5-(trifluoromethyl)nicotinaldehyde (575 mg, 2.74 mmol) and 3-((tert-butyldimethylsilyl)oxy)azacyclobutane (566 mg, 3.02 mmol) were dissolved in EtOH (8 mL) at room temperature and treated with NEt3 (305 mg, 3.02 mmol). The reaction mixture was heated at 80 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel chromatography, eluting with 0% to 100% EtOAc in heptane to give the title compound (0.73 g, 2.03 mmol, 74%) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 8.51 (s, 1H), 8.09 (s,1H), 4.75 (m, 1H), 4.50 (m, 2H), 4.08 (m, 2H), 0.91 (s, 9H), 0.09 (s, 6H).

[0308] Preparation of 52 1-(4-Isoquinolinyl)ethanol 3M methylmagnesium bromide (455 mg, 3.82 mmol) was added to a solution of isoquinoline-4-carboxaldehyde (500 mg, 3.18 mmol) in anhydrous THF (7 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min, allowed to warm to room temperature, and then stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl, extracted with EtOAc (3 x 30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0% to 100% in heptane to yield the title compound (540 mg, 98.0%). 1 H NMR (400 MHz, CDCl3) δ 1.73 (d, J=6.48 Hz, 3H), 2.72 (br s, 1H), 5.59 (q, J=6.48 Hz, 1H), 7.63 (ddd, J=8.10, 7.00, 1.04 Hz, 1H), 7.75 (ddd, J=8.47, 6.94, 1.34 Hz, 1H), 7.99 (d, J=8.07 Hz, 1H), 8.18 -8.22 (m, 1H), 8.61 (s, 1H), 9.15 (s, 1H).

[0309] The following compounds were prepared essentially as described with respect to 1-(4-isoquinolinyl)ethanol, using appropriate reagents and adjusting the reaction temperature and time to determine the end of the reaction.

[0310] Table 5 a1 H NMR (400 MHz, CDCl3) δ 1.55 -1.67 (m, 9H), 2.80 (br s, 1 H), 4.14(q, J=6.77 Hz, 1H), 4.84 (dt, J=12.96, 6.36 Hz, 1H), 5.11 (q, J=5.91 Hz, 1H),7.50 (s, 1H).

[0311] b1 H NMR (400 MHz, d 6 -DMSO) δ 1.35 - 1.46 (m, 6H), 4.37 (m, 2H), 4.81 (m, 1H), 5.30 (br s, 1H), 7.61 (br s, 1H).

[0312] c1 H NMR (300 MHz, d 6 -DMSO) δ 7.58 (s, 1H), 5.50 (d, 1H), 4.95-4.85 (m,1H), 4.50 - 4.32 (m, 2H), 1.56 - 1.38 (m, 6H)。

[0313] d1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.39 (s, 1H), 4.91 - 5.02 (m,1H), 2.59 (s, 3H), 1.56 (br d, J=6.36 Hz, 3H)。

[0314] e1 H NMR (400 MHz, CDCl3) δ 1.57 (br d, J=6.11 Hz, 3H), 3.24 (br s,4H), 3.48 (br s, 1H), 3.87 (br s, 4H), 5.08 - 5.19 (m, 1H), 7.92 (br s, 1H),8.51 (br s, 1H)。

[0315] f1 H NMR (400 MHz, CDCl3) δ 1.66 (br d, J=6.11 Hz, 3 H), 2.73 - 2.80(m, 3 H), 2.97 - 3.27 (m, 1 H), 5.21 - 5.35 (m, 1 H)。

[0316] g 1H NMR (400 MHz, CDCl3) δ 8.41-8.29(m, 1H), 7.13-7.03 (m, 1H), 5.34-5.21(m, 1H), 1.62 (t,3H)。

[0317] h1H NMR (400 MHz, CDCl3) δ 1.55 (d, J=6.7 Hz, 3H), 3.08 (s, 3 H), 4.96- 5.07 (m, 1 H), 7.52 - 7.61 (m, 1 H), 7.68 (br t, J=6.8 Hz, 1 H), 7.78 -7.91 (m, 1 H), 7.96 - 8.01 (m, 1 H).

[0318] i1 H NMR (400 MHz, CDCl3) δ 8.36 (t, 1H), 8.32 (d, 1H), 7.62-7.39 (m,1H), 4.99 (q, 1H), 2.82 (s, 1H), 1.53 (d, 3H).

[0319] j 1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.32 (s, 1H), 5.28 (m, 1H), 1.54 (d, 3H).

[0320] k 1 H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.84 (s, 1H), 4.95 (m, 1H), 4.73 (m, 1H), 4.39 (m, 2H), 4.04 (m, 2H), 1.50 (d, 3H), 0.90 (s, 9H), 0.09(s, 6H).

[0321] Preparation of 66 1-(5-fluoro-3-methyl-2-pyridyl)acetone i-PrMgCl (12 mL, 23.7 mmol, 2 M in THF) was added dropwise to 2-bromo-5-fluoro-3-methylpyridine (3 g, 15.8 mmol) in toluene (50 mL) at room temperature under N2. After stirring at room temperature for 3 h, N-methoxy-N-methylacetamide HCl (2.4 g, 23.7 mmol) was added. The reaction mixture was stirred for 2 h and then quenched with H2O (100 mL). The mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to yield the title compound (2 g, 83%). ES / MSm / z 154.1 [M+H] + .

[0322] The following compounds were prepared by using appropriate reagents and adjusting the reaction temperature and time to determine the end of the reaction, essentially as described with respect to 1-(5-fluoro-3-methyl-2-pyridyl)acetone.

[0323] Table 6 1 Purified by silica gel column chromatography, eluted with PE:EA (12:1 to 10:1).

[0324] 2 Purified by silica gel column chromatography, eluted with PE:EA (20:1 to 4:1).

[0325] Preparation 71 1-(7-fluoro-4-isoquinolinyl) ethyl ketone A solution of 3M MeMgBr in Et2O (255 mg, 2.13 mmol, 0.71 mL) was added dropwise to a solution of 7-fluoro-N-methoxy-N-methylisoquinoline-4-carboxamide (500 mg, 2.13 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min, then allowed to warm to room temperature and stirred for another 2 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a MeOH gradient from 0% to 10% in DCM to yield the title compound (389 mg, 96.3%). 1 H NMR (400 MHz, CDCl3) δ 2.81 (s, 3 H), 7.59 - 7.67 (m, 2 H), 8.99 (dd, J=9.11, 5.32 Hz, 1 H), 9.05 (s, 1 H), 9.33 (s, 1 H).

[0326] The following compounds were prepared essentially as described with respect to 1-(7-fluoro-4-isoquinolinyl)acetone, using appropriate reagents and adjusting the reaction temperature and time to determine the end of the reaction.

[0327] Table 7 1Rapid chromatographic purification was achieved by elution with 0% to 100% EtOAc in heptane.

[0328] a 1 H NMR (400 MHz, d 6 -DMSO) δ 2.42 (s, 3H), 2.77 (s, 3H), 7.96 (br s,1H), 9.31 (br s, 1H).

[0329] b1 H NMR (300 MHz, d 6 -DMSO) δ 9.63 (br s, 1H), 8.26 (br s, 1H), 2.79 (brs, 3H).

[0330] c 1 H NMR (400 MHz, CDCl3) δ 2.54 (br s, 3H), 2.60 (br s, 3H), 8.35 (brs, 1H).

[0331] Preparation of 75 2-Fluoro-1-(5-Fluoro-2-pyridyl)ethyl ketone A solution of 2-bromo-5-fluoropyridine (1.1 g, 6.3 mmol) in toluene (6 mL) was cooled to -78 °C under N2, and then a solution of n-BuLi (0.44 g, 2.8 mL, 6.9 mmol, 2.5 M in hexane) was slowly added. The reaction mixture was then stirred at -78 °C for 30 min. 2-Fluoro-N-methoxy-N-methylacetamide (0.83 g, 6.9 mmol) in toluene (2.0 mL) was added to the reactants. After stirring at -78 °C for 30 min, the cooling bath was removed, and the reactants were quenched with a saturated aqueous NH4Cl solution and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (0.9 g, 90%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ5.77 (d, J=47.6 Hz, 2 H) 7.46 - 7.55 (m, 1 H) 8.05 - 8.12 (m, 1 H) 8.39 -8.44 (m, 1 H).

[0332] Preparation of 76 1-[5-Fluoro-6-(2-Methoxyethoxy)-2-pyridyl]acetone Under N2 at -78°C, n-BuLi (2.72 mL, 6.80 mmol, 2.5 M in hexane) was added dropwise to 6-bromo-3-fluoro-2-(2-methoxyethoxy)pyridine (1.7 g, 6.80 mmol) in THF (50 mL, 617.2 mmol). The reaction mixture was stirred at -78°C for 0.5 h. Then, N-methoxy-N-methylacetamide (2.10 g, 20.39 mmol) was added and stirring continued at -78°C for another 1 h. The reaction mixture was quenched at -78°C by adding H2O (50 mL). After warming to room temperature, the reaction mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with brine (3 x 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was used directly in subsequent steps without further purification. ES / MS m / z 213.9 [M+H] + .

[0333] The following compounds were prepared by using appropriate reagents and adjusting the reaction temperature and time to determine the end of the reaction, essentially as described with respect to 1-[5-fluoro-6-(2-methoxyethoxy)-2-pyridyl]acetone.

[0334] Table 8 a 1 H NMR (400 MHz, CdCl3) δ 1.43 (s, 3H) 1.47 (s, 3H) 3.92 (dd, J =8.56,6.48 Hz, 1H) 4.50 - 4.59 (m, 1H) 5.61 - 5.68 (m, 1H) 7.45 - 7.54 (m, 1H)8.08 - 8.15 (m, 1H) 8.39 - 8.44 (m, 1H).

[0335] Preparation of 78 (1E)-2-bromobenzaldehyde oxime A mixture of 2-bromobenzaldehyde (10 g, 54.05 mmol) and NH₂OH·HCl (4.1 g, 59.45 mmol) in EtOH (100 mL) was stirred at 80 °C for 2 hours under N₂. The reaction mixture was concentrated under vacuum. The residue was dissolved in EtOAc (100 mL) and washed with H₂O (3 x 50 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound (12 g) as a grayish-white solid, which was used without further purification. ES / MS m / z ( 79 Br / 81 Br) 200 / 202 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.32 (s, 1H), 7.80 (dd, 1H), 7.67 (dd, 1H), 7.45 -7.38 (m, 1H), 7.34 (td, 1H).

[0336] Preparation 79 3-(2-Bromophenyl)isoxazole Calcium carbide (11.19 g, 175.00 mmol) and H₂O (6.30 g, 349.93 mmol) were added dropwise to a stirred solution of (E)-N-[(2-bromophenyl)methylene]hydroxylamine (5 g, 25.00 mmol) and NCS (4.33 g, 32.49 mmol) in CCl₄ (50 mL) under N₂ at room temperature. The reaction mixture was stirred overnight. The suspension was filtered, and the filter cake was washed with DCM (3 x 30 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (12:1) to provide the title compound (3.5 g, 62.50%) as an off-white solid. ES / MS m / z ( 79 Br / 81 Br) 224 / 226 [M+H] + .

[0337] Preparation of 80 2-(1-ethoxyvinyl)-6-(trifluoromethyl)pyrazine Pd(PPh3)4 (1266.16 mg, 1.096 mmol) was added to a stirred solution of 2-chloro-6-(trifluoromethyl)pyrazine (2000 mg, 10.957 mmol) and tributyl(1-ethoxyvinyl)stanane (4748.68 mg, 13.148 mmol) in dioxane (25 mL) under N2 at room temperature. The resulting mixture was stirred at 80 °C for 4 hours. The mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (8:1 to 4:1) to provide the title compound (1.8 g, 75.29%) as a yellow oil. 1 H NMR (300 MHz, d 6 -DMSO) δ 9.18- 9.16 (m, 2H), 5.47 - 5.41 (m, 1H), 4.75 - 4.69 (m, 1H), 4.03 (q, 2H), 1.40 (t, 3H).

[0338] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to 2-(1-ethoxyvinyl)-6-(trifluoromethyl)pyrazine.

[0339] Table 9 1 Purified by silica gel column chromatography, eluted with PE:EtOAc (20:1 to 5:1).

[0340] Preparation of 82 1-(2-Isoxazol-3-ylphenyl)ethyl ketone 3-[2-(1-ethoxyvinyl)phenyl]-1,2-oxazole (2.20 g, 10.22 mmol) in MeOH (20 mL) was added to 4M HCl (20 mL) in MeOH at room temperature. The reaction mixture was stirred under N2 for 1 hour. The reaction mixture was quenched with H2O (100 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (3:1) to provide the title compound (1.6 g, 83.6%) as a yellow oil. ES / MS m / z 188.1 [M+H] + .

[0341] Preparation of 83 1-[6-(trifluoromethyl)pyrazin-2-yl]acetone A mixture of 2-(1-ethoxyvinyl)-6-(trifluoromethyl)pyrazine (1.20 g, 5.50 mmol) and 12 M HCl (2.29 mL, 27.50 mmol) in THF (20 mL) was stirred for 2 hours at room temperature under N2. The resulting mixture was concentrated under vacuum to provide the title compound, which was then used without further purification. 1 H NMR (400 MHz, d 6 -DMSO) δ 9.45 (s, 1H), 9.41 (s, 1H), 2.67 (s, 3H).

[0342] Preparation of 84 2-Methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]acetone At 0°C under N2 conditions i A solution of PrMgCl (3.3 mL, 6.61 mmol) was added dropwise to a solution of 3-bromo-5-(trifluoromethyl)pyridine (1.00 g, 4.42 mmol) in dry THF (40 mL). The solution was stirred at 50 °C under N2 for 1 hour. N-2-dimethoxy-N-methylacetamide (1.18 g, 8.86 mmol) in dry THF (1 mL) was added to the above solution at room temperature under N2. The solution was stirred at room temperature under N2 for 2 hours. The residue was acidified to pH 6 with concentrated aqueous HCl. The mixture was diluted with H2O (50 mL), the pH was adjusted to 11 with solid Na2CO3, and extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with brine (3 x 50 mL), and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product (5.00 g) was used without further purification. 1 H NMR (300 MHz, CDCl3) δ 9.38 -9.30 (d, 1H), 9.14 - 9.05 (m, 1H), 8.56 - 8.48 (m, 1H), 4.69 (s, 2H), 3.55 -3.53 (m, 3H).

[0343] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]acetone.

[0344] Table 10 1 2.5 M BuLi was used instead of iPrMgCl. The reaction was carried out in toluene at -78 °C.

[0345] 2 Purified by silica gel column chromatography, eluted with PE:EtOAc (12:1).

[0346] a 1 H NMR (400 MHz, CDCl3) δ 5.83 (d, J=47.6 Hz, 2H), 7.54 -7.61 (m,1H), 8.15 (dd, J=8.68, 4.65 Hz, 1H), 8.47 (s, 1H).

[0347] b The material is used without further purification.

[0348] Preparation of 89 2-Methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanol NaBH4 (860 mg, 22.73 mmol) was added fractionally to a stirred mixture of 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]acetone (5.00 g) in MeOH (20 mL) at room temperature under N2. The reaction mixture was quenched with H2O (5 mL) at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 2:1) to yield the title compound (500 mg, 9.91%) as a yellow liquid. ES / MS m / z 222.0 [M+H] + .

[0349] The following compounds were prepared essentially as described with respect to 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanol, by using appropriate reagents and adjusting the reaction time to determine the end of the reaction.

[0350] Table 11 1 Purified by silica gel column chromatography, eluted with 0% to 100% EtOAc in heptane.

[0351] 2 Purified by silica gel column chromatography, eluted with PE:EtOAc (6:1 to 2:1).

[0352] 3 Purified by silica gel column chromatography, eluted with PE:EtOAc (9:1).

[0353] 4 Purified by silica gel column chromatography, eluted with PE:EtOAc (1:1).

[0354] 5 Purified by silica gel column chromatography, eluted with 0% to 100% EtOAc in heptane.

[0355] a 1 H NMR (400 MHz, d 6 -DMSO) δ 1.41 (d, J=6.60 Hz, 3H), 2.33 (s, 3H), 4.93 (qd, J=6.56, 4.65 Hz, 1H), 5.59 (d, J=4.65 Hz, 1H), 7.58 (d, J=0.98 Hz, 1H), 8.97 (d, J=2.08 Hz, 1H).

[0356] b 1 H NMR (400 MHz, CdCl3) δ ppm 4.61 (dd, J=47.2, 5.3 Hz, 2 H) 5.02 (dt, J=16.1, 5.3 Hz, 1H) 7.46 - 7.53 (m, 2 H) 8.46 (s, 1 H).

[0357] c 1 H NMR (400 MHz, CDCl3) δ 1.73 (d, J=6.48 Hz, 3H), 2.42 (br s, 1H), 5.56 (q, J=6.56 Hz, 1H), 7.50 - 7.57 (m, 1H), 7.61 (br d, J=8.68 Hz, 1H), 8.29 (dd, J=9.23, 5.20 Hz, 1H), 8.59 (s, 1H), 9.13 (s, 1H).

[0358] d 1H NMR (400 MHz, d 6 -DMSO) δ 9.11 (s, 1H), 9.07 (s, 1H), 5.82 (d, 1H), 4.95 - 4.88 (m, 1H), 1.44 (d, 3H).

[0359] e The material is used without further purification.

[0360] f1 H NMR (400 MHz, CDCl3) δ 1.51 (br d, J=6.11 Hz, 3H), 2.34 (s, 3H), 2.75 - 2.90 (m, 1 H), 4.87 - 4.97 (m, 1H), 7.55 (br s, 1H), 8.31 (br s, 1H),8.36 (br s, 1H).

[0361] g1 H NMR (400 MHz, CDCl3) δ 1.56 (br d, J=6.24 Hz, 3H), 2.54 (br s,1H), 5.04 (q, J=5.79 Hz, 1H), 6.72 (t, J=55.8 Hz, 1H,) 7.91 (br s, 1H), 8.65(br s, 1H), 8.72(br s, 1H).

[0362] h1 H NMR (400 MHz, CDCl3) δ 1.55 (d, J=6.6 Hz, 3H) 4.95 (q, J=6.6 Hz,1H) 7.37 - 7.46 (m, 1H) 7.46 - 7.52 (m, 2H) 7.53 - 7.59 (m, 1H) 7.66 (br d, J=7.58 Hz, 1H) 8.79 (d, J=4.65 Hz, 1H).

[0363] i 1 H NMR (400 MHz, CdCl3) δ 2.54 - 2.58 (m, 3H), 2.61 - 2.64 (m, 3 H), 3.39 (m, 1H), 3.80 (m, 1H), 8.37 (br s, 1H).

[0364] j 1H NMR (400 MHz, CdCl3) δ 1.35 (s, 3H) 1.44 (s, 3H) 3.92 - 3.98 (m,1H) 4.00 - 4.07 (m, 1H) 4.40 - 4.47 (m, 1H) 4.76 - 4.80 (m, 1H) 7.42 - 7.55 (m, 2H) 8.41 - 8.46 (m, 1H).

[0365] Preparation of 113 cis-3-benzyloxycyclobutanol A mixture of 3-(benzyloxy)cyclobutane-1-one (20 g, 113.5 mmol) and NaBH4 (4.29 g, 113.5 mmol) in MeOH (50 mL) was stirred for 2 hours at room temperature under N2. The reaction mixture was quenched with H2O at 0 °C, extracted with EtOAc (3 x 100 mL), washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to provide the title compound (20 g, 98.9%) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.42-7.21 (m, 5H), 4.45(s, 2H), 3.93-3.85 (m, 1H), 3.71-3.62 (m, 1H),2.82-2.63(m,2H), 1.97-1.92(m, 2H).

[0366] Preparation of 114 3-(5-fluoro-2-pyridyl)-3-hydroxy-2,2-dimethylpropionitrile Lithium diisopropylamino (2.57 g, 24.0 mmol, 2M in THF) was slowly added to a cooled solution of isobutyronitrile (1.66 g, 24.0 mmol) in THF (25 mL) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 30 min. Then, 5-fluoropyridinecarboxaldehyde (2.00 g, 16.0 mmol) in THF (6 mL) was slowly added to the reaction mixture. After stirring for another 1 h, the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with saturated NH4Cl, extracted into EtOAc, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane to provide the title compound (1.60 g, 51.5%) as a white solid. 1 H NMR (400 MHz, CdCl3) δ 8.46 (s, 1H), 7.55-7.47 (m, 2H), 4.68 (s,1H), 4.54 (brs, 1H), 1.44 (s, 3H), 1.21 (s, 3H).

[0367] Preparation 115 2,2,2-Trifluoro-1-(5-fluoropyridin-2-yl)ethanol TBAF (3.20 mL, 3.200 mmol) was added dropwise to 5-fluoropyridine-2-carboxaldehyde (2 g, 15.99 mmol) and TMSCF3 (3.41 g, 23.98 mmol) in THF (5.00 mL) at 0 °C under N2. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 50% EtOAc in PE to provide the title compound (2 g, 64.12%) as a white solid. ES / MS m / z 196.1 [M+H] + .

[0368] Preparation of 116 2-[tert-butyl(dimethyl)silyl]oxy-1-(4-isoquinolinyl)ethanol 2M isopropyl magnesium chloride (1.48 g, 14.42 mmol) was added dropwise to 4-bromoisoquinoline (2.00 g, 9.61 mmol) dissolved in THF (8 mL) at room temperature under N2. The reaction mixture was stirred at room temperature for 30 min, followed by dropwise addition of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (3.35 g, 19.23 mmol). The reaction mixture was stirred at room temperature for 2 h, followed by quenching with a saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in heptane. The separated material was further purified by silica gel chromatography, eluting with 20% DCM in EtOAc to provide the title compound (400 mg, 13.7%) contaminated with isoquinoline byproducts. 1 H NMR (400 MHz, CDCl3) δ 0.07(s, 6H), 0.93 (s, 9H), 3.72 - 3.91 (m, 1H), 3.99 (dd, J=10.27, 3.42 Hz, 1H), 5.47 (dd, J=8.38, 3.36 Hz, 1H), 7.58 - 7.78 (m, 7H), 7.84 (d, J=8.31 ​​Hz, 2H), 7.96 - 8.04 (m, 2H), 8.12 (d, J=8.44 Hz, 1H), 8.54 (d, J=5.62 Hz, 1H), 8.70(s, 1H), 9.22 (s, 1H), 9.27 (s, 1H).

[0369] Preparation of 117 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol At 0°C under N2 conditions i-PrMgCl solution (5.11 mL, 10.23 mmol, 2 M in THF) was added dropwise to a stirred solution of 2-bromo-5-fluoropyridine (1.2 g, 6.82 mmol) in toluene (10.00 mL). The mixture was stirred at 0 °C under N2 for 30 min. 2-[(tert-butyldimethylsilyl)oxy]acetaldehyde (1.78 g, 10.23 mmol) was added dropwise to the mixture at 0 °C for 10 min. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 5:1) to yield the title compound (420 mg, 22.69%) as a colorless oil. ES / MS m / z 272.2 [M+H] + The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol.

[0370] Table 12 1 Purified by silica gel column chromatography, eluted with PE:EtOAc (20:01 to 10:1).

[0371] 2 Purified by silica gel column chromatography, eluted with PE:EtOAc (5:1-3:1).

[0372] 3 Quenching with saturated NH4Cl.

[0373] a 1 H NMR (400 MHz, DMSO-d6) δ 0.78 - 1.04 (m, 4 H), 4.56 - 4.64 (m, 1H), 6.00 (d, J=5.01 Hz, 1 H), 7.52 - 7.78 (m, 2 H), 8.52 (d, J=2.69 Hz, 1H.).

[0374] Preparation 125 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 1 and 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 2 The enantiomers of 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (70 g, 257.915 mmol) were separated under the following conditions: column: CHIRALPAK IG, 7*25 cm, 10 μm; eluted with 60% ACN in H2O (0.05% diethylamine); flow rate: 200 mL / min; 266 / 204 / 208 nm; to provide 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 1, t (R) It is 7.5 min (20.0 g) and 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 2, t (R) It is 11.2 min (20.5g).

[0375] 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 1, was further purified by silica gel column chromatography, eluting with PE / EA (20:1 to 4:1) to provide 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 1 (15.0 g, 21% yield) with 98.6% ee, ES / MS m / z 272.1 [M+H]+.

[0376] 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 2 was further purified by silica gel column chromatography, eluted with PE / EA (30:1 to 20:1) to provide 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 2 (14.0 g, 20% yield) with 93.1% ee, ES / MS m / z 272.1 [M+H]+.

[0377] Preparation 126 2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethyl] ester of 4-methylbenzenesulfonic acid, isomer 2 TsCl (27.8 g, 146 mmol) was added to a solution of 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, isomer 2 (30.4 g, 112 mmol), DMAP (1.37 g, 11.2 mmol), and Et3N (22.7 g, 224 mmol) in DCM (0.2 L) cooled to 0 °C. The reaction mixture was stirred at 0 °C for 3 h and then stored at 0 °C overnight. The resulting suspension was filtered and the insoluble matter was washed with MTBE. H2O (5 ml) was added to the filtrate. The filtrate was then concentrated under vacuum and the substance was purified by silica gel chromatography, eluting with EA in heptane from 0% to 100% to provide the title compound (39.8 g, 93.5 mmol) as a white waxy solid. ES / MS m / z 426.0 [M+H] + .

[0378] Preparation 127 2,2,2-Trifluoro-1-(oxacyclohexane-4-yl)ethanol TMSCF3 (3.74 g, 26.28 mmol) and TBAF (3.50 mL, 3.50 mmol, 1 mol / L) were added dropwise to a stirred solution of oxadiazon-4-carboxaldehyde (2.00 g, 17.52 mmol) in THF (20.00 mL) at 0 °C under N2, and the mixture was stirred at room temperature under N2 for 4 h. The reaction mixture was quenched by adding MeOH (5 mL), and the mixture was dried under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of PE:EtOAc (4:1) to yield the title compound (3.1 g, 96.07%) as a yellow solid. 1 H NMR (300 MHz, d 6 -DMSO) δ 6.16 (d, 1H),3.93 - 3.81 (m, 2H), 3.81 - 3.68 (m, 1H), 3.39 - 3.20 (m, 2H), 1.92 - 1.72(m, 1H), 1.60 (d, 1H), 1.56 - 1.35 (m, 3H).

[0379] Preparation 128 2,2-Dimethyl-1-(pyridin-2-yl)propane-1-ol, isomer 1 and 2,2-Dimethyl-1-(pyridin-2-yl)propane-1-ol, isomer 2 Add dropwise to a stirred solution of 2-iodopyridine (10.0 g, 48.78 mmol) in THF (150.0 mL) under N2 at -75°C. n - A solution of BuLi in hexane (21.4 mL, 53.65 mmol, 2.5 M). The resulting mixture was stirred at -75 °C for 1 hour. Pteropentanal (5.0 g, 58.51 mmol) was added dropwise to the mixture in 10-minute increments. After stirring at -75 °C for 1 hour, the reaction mixture was allowed to warm to room temperature and then quenched with H₂O (100.0 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (20:1 to 15:1) to provide the title compound (2.6 g, 32%) as a white solid. ES / MS m / z 166.3 [M+H] + .

[0380] The enantiomers of 2,2-dimethyl-1-(pyridin-2-yl)propane-1-ol (1.1 g, 6.7 mmol) were separated under the following conditions: column: CHIRALCEL AY-H, 2*25 cm, 5 μm; eluted with 5% EtOH in Hex (10 mM NH3 in MeOH); 260 / 216 nm; to provide 2,2-dimethyl-1-(pyridin-2-yl)propane-1-ol as a pale yellow solid, isomer 1 (400 mg, 36%). (R) =5.3 min, and 2,2-dimethyl-1-(pyridin-2-yl)propane-1-ol, isomer 2 (440 mg, 40%) as a white solid. t (R) =6.2 min. Analytical column used for Rt: CHIRALCEL AY-3, 4.6*50cm; eluted with 5% EtOH in hexane; 254 nm.

[0381] Preparation 129 1-(2-pyridyl)propyl acetate, isomer 2 TEA (4.43 g, 43.74 mmol) was added to a stirred solution of 1-(pyridin-2-yl)propane-1-ol (2.00 g, 14.58 mmol) and Ac₂O (2.98 g, 29.16 mmol) in DCM (10.00 mL) at room temperature under N₂. The reaction mixture was stirred overnight, quenched with H₂O (20 mL), and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions: column, C18; elution with a 40% to 50% ACN gradient in water; UV 254 nm to provide a brown oil (2.50 g, 95.7%). ES / MS m / z 180.3.

[0382] Brown oil (1.00 g, 5.58 mmol) was treated under the following conditions: column: CHIRALPAK IG, 20*250 mm, 5 μm; eluted with 15% EtOH in CO2; 203 nm; to provide 1-(pyridin-2-yl)propyl acetate, isomer 2 (400 mg), t (R) It is 3.86 min, ee=100%; ES / MS m / z 180.3 [M+H] + .

[0383] Using appropriate reagents and adjusting the reaction time to determine the end of the reaction, the following compounds were prepared essentially as described with respect to 1-(2-pyridyl)propyl acetate, isomer 1.

[0384] Table 13 1 Column: CHIRALPAK IG, 2*25cm, 5 μm; eluted with 15% EtOH in CO2, 254 nm.

[0385] Preparation of 131 1-(2-pyridyl)propane-1-ol, isomer 2 Under N2 at room temperature, LiOH (101.55 mg, 4.24 mmol) was added fractionally to 1-(pyridin-2-yl)propyl acetate, isomer 2 (380 mg, 2.12 mmol) in MeOH (3.00 mL) and H2O (3.00 mL). The reaction mixture was stirred for 1 hour. The mixture was diluted with H2O (20 mL) and then extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (260 mg, 90%) as a pale yellow oil. ES / MS m / z 138.1 [M+H] + .

[0386] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to 1-(2-pyridyl)propane-1-ol, isomer 2.

[0387] Table 14 .

[0388] Preparation of 133 1-[2-(2-methoxyethylamino)-5-(trifluoromethyl)-3-pyridyl]ethanol 1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethane-1-ol (0.200 g, 0.89 mmol), 2-methoxyethane-1-amine (200 mg, 2.66 mmol), and DIPEA (573 mg, 4.43 mmol) were prepared in... i The solution in -PrOH (4 mL) was stirred at 100 °C for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a linear gradient of 0% to 30% MeOH in DCM to provide the title compound (30 mg, 13%) as brown oil. ES / MS m / z 265.1 [M+H] + .

[0389] Preparation of 134 (1S)-1-[4-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]ethanol A mixture of (2S)-N'-[(1E)-(dimethylamino)methylene]-2-hydroxypropanehydrazine (3.0 g, 18.8 mmol), ACN (10.0 mL), and HOAc (2.26 g, 37.7 mmol) was heated at 90 °C under N2. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was used for the next step without further purification. ES / MS m / z 196.1 [M+H]+.

[0390] Preparation of 135 (1S)-1-(5-Fluoropyridin-2-yl)ethyl mesylate MsCl (608.69 mg, 5.313 mmol) was added dropwise to a stirred solution of (1S)-1-(5-fluoropyridin-2-yl)ethanol (500.0 mg, 3.54 mmol) and TEA (1.07 g, 10.63 mmol) in DCM (10.0 mL) under N2 at room temperature. The reaction mixture was stirred at room temperature for 1 h, diluted with water (20 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (740 mg, 95.2%) as a pale yellow oil. ES / MS m / z 220.0 [M+H] + .

[0391] Preparation of 136 Trifluoromethanesulfonate [2,2,2-trifluoro-1-(5-fluoro-2-pyridyl)ethyl] ester Tf₂O (2.02 g, 7.17 mmol) was added dropwise to 2,2,2-trifluoro-1-(5-fluoropyridin-2-yl)ethanol (700.00 mg, 3.59 mmol) and TEA (1.09 g, 10.76 mmol) in DCM (5.00 mL) at 0 °C under N₂. The resulting mixture was stirred at room temperature for 3 hours, diluted with water (5 mL), and separated. The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were concentrated under vacuum to yield the title compound (1 g) as a crude product, which was used without further purification. ES / MS m / z 328.0 [M+H] + .

[0392] Preparation of 137 2,2,2-trifluoro-1-(oxacyclohexane-4-yl)ethyl trifluoromethanesulfonate Tf₂O (766.02 mg, 2.715 mmol) was added dropwise at 0 °C under N₂ to a stirred solution of 2,2,2-trifluoro-1-(oxacyclohexane-4-yl)ethanol (500.00 mg, 2.72 mmol) and DIEA (1052.71 mg, 8.14 mmol) in DCM (10.00 mL). The mixture was stirred at room temperature under N₂ for 1 hour and then used directly without further purification.

[0393] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to 2,2,2-trifluoro-1-(oxacyclohexane-4-yl)ethyl trifluoromethanesulfonate. Temperature varied from -70°C to 0°C.

[0394] Table 15 .

[0395] Preparation 142 4-(methanesulfonyloxy)-2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester TEA (940.02 mg, 9.29 mmol) was added dropwise to a stirred mixture of tert-butyl 4-hydroxy-2,2-dimethylpyrrolidine-1-carboxylate (800.00 mg, 3.72 mmol) in DCM (10.00 mL) at room temperature under N2. MsCl (553.35 mg, 4.83 mmol) was added dropwise to the solution at 0 °C for 2 min, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H2O (150 mL), and the mixture was extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (1.1 g, crude product) as a brownish-yellow solid, which was used directly without further purification. 1 H NMR (400 MHz, d 6 -DMSO) δ 5.23-5.18 (m, 1H), 3.66-3.60 (m, 1H), 3.51-3.45 (m, 1H), 3.22 (s,3H), 2.40-2.14 (m, 2H), 1.41 (s, 9H), 1.23 (d, 3H).

[0396] The following compounds were prepared essentially as described with respect to tert-butyl 4-(methanesulfonyloxy)-2,2-dimethylpyrrolidine-1-carboxylate, using appropriate reagents and adjusting the reaction time to determine the end of the reaction.

[0397] Table 16 a 1 H NMR (400 MHz, CDCl3) δ 5.21-5.15 (m, 1H), 4.05-3.80 (m, 2H), 3.56(dd, 1H), 3.03 (s, 3H), 2.51-2.40 (m, 1H), 1.90-1.81(m, 1H), 1.47 (s, 9H), 1.28 (d, 3H).

[0398] b 1 H NMR (400 MHz, d 6 -DMSO) δ 5.23-5.18 (m, 1H), 3.94-3.84 (m, 1H), 3.66-3.60 (m, 1H), 3.51-3.45 (m, 1H), 3.22 (s, 3H), 2.46-2.34 (m, 1H), 1.93-1.83 (m, 1H), 1.41 (s, 9H), 1.23 (d, 3H).

[0399] c 1 H NMR (300 MHz, d 6 -DMSO) δ 5.23-5.19 (m, 1H), 3.5 - 3.80 (m, 1H),3.63 (dd, 1H), 3.48 (dt, 1H), 3.24 (s, 3H), 2.49-2.34 (m, 1H), 1.87 (d, 1H),1.41 (s, 9H), 1.23 (d, 3H).

[0400] Preparation of 148 2-(1-Bromoethyl)-N,N-Dimethylbenzamide 2-Ethyl-N,N-dimethylbenzamide (0.81 g, 4.6 mmol), AIBN (75 mg, 0.46 mmol), and NBS (0.89 g, 5.0 mmol) were added to a vacuum-sealed tubular flask and backfilled with N2 (3X). CCl4 (5 mL) was added, and the reaction mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the solids were washed with CCl4 (2 x 10 mL). The filtrate was concentrated to give the title compound (0.8 g, 70%) as a clear oil, which was used without further purification.

[0401] Preparation of 149 4-(2-tert-butoxycarbonylhydrazyl)-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester A mixture of tert-butyl 3,3-difluoro-4-oxopiperidin-1-carboxylate (10.00 g, 42.51 mmol), tert-butoxycarbazide (3.09 g, 23.38 mmol), and AcOH (2.55 g, 42.51 mmol) in MeOH (40 mL) was stirred at 50 °C for 30 min under N2. After cooling to room temperature, NaBH3CN (8.01 g, 127.53 mmol) was added fractionally. The reaction mixture was stirred at 50 °C for 2 h. The mixture was alkalized to pH 8 with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc (3 x 150 mL), the organic layers were combined, washed with brine (3 x 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 5:1) to provide the title compound (5 g, 67%) as a grayish-white oil. ES / MS m / z 240.2 [M+H-C8H16] + .

[0402] Prepare 150 3,3-Difluoro-4-(5-methylpyrazol-1-yl)piperidine A mixture of tert-butyl 4-[[(tert-butoxycarbonyl)amino]amino]-3,3-difluoropiperidin-1-carboxylate (5.50 g, 15.7 mmol) and 4,4-dimethoxybutane-2-one (3.10 g, 23.5 mmol) in AcOH (100 mL) was stirred overnight at 50 °C under N2. HBr (25 mL) was added to the mixture at room temperature. The reaction mixture was stirred overnight. No brominated product was detected by LCMS. The mixture was concentrated under vacuum. The residue was used for the next step without further purification. ES / MS m / z 202.3 [M+H] + .

[0403] Preparation of 151 3,3-Difluoro-4-(5-methylpyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester Boc₂O (29.83 g, 136.67 mmol) was added to 3,3-difluoro-4-(5-methyl-1H-pyrazol-1-yl)piperidine (5.50 g, 27.33 mmol) and TEA (27.66 g, 273.3 mmol) in DCM (100 mL) at room temperature under N₂. The reaction mixture was stirred for 2 hours and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (20:1 to 10:1) to give a crude product. The crude product was purified by reversed-phase chromatography under the following conditions: column, C18; mobile phase, eluting with 40% to 60% ACN in water (0.1% FA) to provide the title compound (3 g, 36.4%) as a yellow oil. ES / MS m / z 302.3 [M+H] + .

[0404] Preparation 152 4-[3-(2-methoxy-2-oxo-ethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester At room temperature, tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (16.31 g, 58.39 mmol) was added to methyl 2-(5-methyl-1H-pyrazol-3-yl)acetate (6 g, 38.92 mmol) and Cs₂CO₃ (25.36 g, 77.83 mmol) in DMF (80 mL). The reaction mixture was stirred at 60 °C for 3 hours under N₂. After cooling to room temperature, the reaction mixture was poured into H₂O (400 mL), extracted with EtOAc (3 x 500 mL), the organic layers were combined, washed with brine (3 x 200 mL), dried over Na₂SO₄, filtered, and rinsed with EtOAc (3 x 80 mL). The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC under the following conditions: column: HEXI SpringXB-C18, 50*250, 10 μm; elution with a gradient of 30% to 55% ACN in H2O (0.05% TFA), flow rate: 100 mL / min; to provide the title compound (420 mg, 3.20%) as a yellow oil. ES / MS m / z 338.3 [M+H] + .

[0405] Preparation 153 4-(5-bromo-4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazine-1-carboxylate (538 mg, 2.01 mmol) and NBS (430 mg, 2.41 mmol) in MeOH (5 mL) was heated to 40 °C and held for 20 min. After cooling to room temperature, the reaction mixture was extracted with 3:1 (v / v) chloroform:iPrOH. The organic phase was washed with 10% Na₂S₂O₃, H₂O, and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum to a yellow oil. This oil was purified by silica gel chromatography, eluting with 5 to 20% MeOH in DCM to provide the title compound (620 mg, 89.0%) as a colorless oil. ES / MS m / z 246.1, 248.8 ( 79 Br / 81 Br) [M+2H-Boc] + .

[0406] The following compounds were prepared essentially as described with respect to tert-butyl piperazine-1-carboxylate, using appropriate reagents and solvents and adjusting the reaction time to determine the end of the reaction.

[0407] Table 17 1 DCM is used as a solvent. 2 Purified by silica gel column chromatography, eluted with DCM:MeOH (30:1 to 15:1).

[0408] Preparation of 156 A solution of 1-(azacyclobutan-3-yl)-4-bromo-5-methylpyrazole (4.00 g) in DCM (20 mL) was alkalized to pH ~10 with DIEA (3 mL) under N2 and then cooled to -60 °C.

[0409] (3R)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was added dropwise, and the reaction mixture was stirred at -60°C for 4 hours. The mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions: column, C18; elution with 20% to 30% ACN in H2O (0.1% FA), 220 nm. The result was to provide the title compound (7.00 g) as a pale yellow solid. ES / MS m / z ( 79 Br / 81 Br) 385.1 / 387.1 [M+H] + .

[0410] Preparation of 157 (1R,3r,5S)-3-(4-bromo-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1] tert-butyl octane-8-carboxylate Cs₂CO₃ (19.20 g, 58.941 mmol) was added fractionally to a mixture of 4-bromopyrazole (2.89 g, 19.65 mmol) and (1R,3s,5S)-3-((methanesulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.00 g, 19.65 mmol) in DMF (50 ml) at room temperature, and the mixture was stirred overnight at 70 °C under N₂. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (10:1–5:1) to yield a crude product (5.2 g). The crude product was further purified by reversed-direction Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 40% to 80% in H2O (0.1% FA), 220 nm, to yield the title compound (3.5 g, 47.5%) as a grayish-white solid. ES / MS m / z 341.1 / 343.1 [M+H-tBu+ACN] + .

[0411] Using appropriate reagents and adjusting the reaction time to determine the end of the reaction, the following compounds were prepared essentially as described with respect to (1R,3r,5S)-3-(4-bromo-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. K2CO3 can also be used as a base. The temperature varied from 70°C to 80°C.

[0412] Table 18 1 The mixture was filtered, the filter cake was washed with EtOAc (3 x 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc.

[0413] 2 The crude product is not repurified.

[0414] 3 The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; mobile phase, ACN in H2O (0.1% NH4HCO3). No further purification was performed.

[0415] 4 The mixture was filtered, the filter cake was washed with DCM (2 x 10 mL), and the filtrate was concentrated under reduced pressure and then purified by reverse Combi-flash chromatography.

[0416] 5Purification was performed using only reverse Combi-flash chromatography.

[0417] a 1 H NMR (300 MHz, d 6- DMSO) δ 8.08 (s, 1H), 7.59 (s, 1H), 4.97 - 4.89 (m, 1H), 3.73-3.65 (m, 1H), 3.57 - 3.51 (m, 1H), 3.46-3.37 (m, 2H), 2.36-2.24(m, 2H), 1.40(d, 9H).

[0418] b 1 H NMR (400 MHz, CDCl3) δ 7.55-7.50 (m, 2H), 4.89-4.83 (m, 1H), 3.77-3.51 (m, 4H), 2.38-2.33 (m, 2H), 1.48 (s, 9H).

[0419] c 1 H NMR (300 MHz, CDCl3) δ 7.61 (d, 1H), 7.49 (d, 1H), 4.77-4.61 (m,1H), 4.15-4.01 (m, 1H), 4.05-3.94 (m, 1H), 3.63 (dd, 1H), 2.71-2.55 (m, 1H), 2.25-2.10 (m, 1H), 1.49 (s, 9H), 1.31 (d, 3H).

[0420] d 1 H NMR (300 MHz, d 6- DMSO) δ 8.04 (s, 1H), 7.58 (s, 1H), 5.03-4.93 (m,1H), 3.72-3.57 (m, 1H), 3.68 - 6.58 (m, 2H), 2.55-2.44 (m, 1H), 2.15-1.85 (m,1H), 1.39 (s, 9H), 1.20 (d, 3H).

[0421] Preparation of 165 2-(4-bromopyrazole-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester Cs₂CO₃ (18.36 g, 56.35 mmol) was added fractionally to a stirred mixture of 2-(methanesulfonyloxy)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (6.00 g, 18.78 mmol) and 4-bromopyrazole (2.76 g, 18.78 mmol) in DMF (50.00 mL) at room temperature under N₂, and the mixture was stirred at 100 °C for 2 hours under N₂. The mixture was cooled to room temperature, diluted with H₂O (100 mL), and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18, eluted with a gradient of 40% to 50% ACN in H2O (0.1% FA), 220 nm, to produce the title compound (5 g). The product was dissolved in DCM (100 mL), washed with brine (2 x 150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to produce the title compound (4.5 g, 64.7%) as a grayish-white solid. 1 H NMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 7.45 (s, 1H), 4.80-4.69 (m,1H), 3.47-3.38 (m, 2H), 3.38-3.29 (m, 2H), 2.51-2.38 (m, 2H), 2.38-2.25 (m,2H), 1.69-1.61 (m, 4H), 1.47 (s, 9H).

[0422] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to tert-butyl 2-(4-bromopyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate. Temperatures varied from 70°C to 100°C.

[0423] Table 19 1 The mixture was filtered, the filter cake was washed with DCM (3 x 20 mL), the filtrate was concentrated under reduced pressure, and the residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; 40-60% ACN in H2O.

[0424] 2 The crude product is used directly without further purification.

[0425] 3 The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with (6:1-1:1 PE / EtOAc).

[0426] a 1 H NMR (300 MHz, CDCl3) δ 7.51 (d, 2H), 4.28-4.18 (m, 2H), 4.00-3.89(m, 1H), 3.35-3.25 (m, 1H), 3.05-2.95 (m, 1H), 2.35 - 1.93 (m, 2H), 1.67 -1.56 (m, 2H), 1.48 (s, 9H).

[0427] b 1 H NMR (400 MHz, d 6-DMSO) δ 7.98 (s, 1H), 7.54 (s, 1H), 4.82-4.64 (m,1H), 4.23-4.09 (m, 2H), 2.04 - 1.82 (m, 6H), 1.81-1.72 (m, 2H), 1.42 (s, 9H) c 1 H NMR (300 MHz, CDCl3) δ 7.46 (d, 1H), 7.43 (d, 1H), 4.25 (ddt,1H), 3.75-3.20 (m, 4H), 2.35-1.84 (m, 6H), 1.50 (s, 9H).

[0428] Preparation of 171 3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester A stirred solution of tert-butyl 3-(4-bromopyrazol-1-yl)azacyclobutane-1-carboxylate (7.50 g, 24.82 mmol) in THF (160 mL) at 0 °C under N2 was treated with LDA (2 mmol / L in THF) (37 mL, 74.46 mmol) and stirred for 30 min. CH3I (10.57 g, 74.46 mmol) was added, and the mixture was stirred at room temperature under N2 for 2 h. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of PE:EtOAc (9:1~5:1) to produce the title compound (4.13 g, 52.62%) as a yellow solid, which was used directly without further purification. 1 H NMR (300 MHz, CDCl3) δ7.53 (s, 1H), 5.04-4.93 (m, 1H), 4.48-4.40 (m, 2H), 4.36-4.28 (m, 2H), 2.27 (s, 3H), 1.48 (s, 9H).

[0429] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compounds were prepared essentially as described with respect to tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutane-1-carboxylate. Temperature varied from -78°C to room temperature. The reaction could also be quenched with NH₄Cl.

[0430] Table 20 1 The crude product is used directly without further purification.

[0431] 2 The dried extract was filtered and the filtrate was concentrated under reduced pressure.

[0432] a 1 H NMR (300 MHz, d 6-DMSO) δ 7.53 (s, 1H), 5.00 (d, 1H), 3.67 (d, 1H),3.50 - 3.42 (m, 2H), 2.27 (s, 3H), 2.24 - 2.10 (m, 2H), 1.40 (d, 9H)。

[0433] b 1 H NMR (400 MHz, d 6 -DMSO) δ7.53 (d, 1H), 5.00 (s, 1H), 3.71-3.65 (m,1H), 3.54-3.42 (m, 3H), 2.27 (s, 3H), 2.19-2.06 (m, 2H), 1.41-1.39 (m, 9H)。

[0434] c 1 H NMR (300 MHz, d 6 -DMSO) δ7.53 (s, 1H), 4.91-4.86 (m, 1H), 3.33-3.18(m, 4H), 2.40-2.14 (m, 7H), 1.64-1.59 (m, 2H), 1.52-1.47 (m, 2H), 1.40 (s,9H)。

[0435] d 1 H NMR (300 MHz, CDCl3) δ 7.42 (d, 1H), 4.05 - 3.95 (m, 1H), 3.20-3.00 (m, 1H), 2.77 - 2.68 (m, 1H), 2.29 (s, 3H), 2.20 - 2.10 (m, 3H), 2.07 -2.04 (m, 1H), 1.89 - 1.82 (m, 1H), 1.67-1.57 (m, 1H), 1.45 (s, 9H)。

[0436] e 1 H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 4.05-3.99 (m, 1H), 3.75-3.10(m, 4H), 2.19 (s, 3H), 2.18 -1.81 (m, 6H), 1.41 (s, 9H)。

[0437] f 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 4.64-4.54 (m, 1H), 3.98 -3.90 (m, 2H), 3.62 -3.45 (m, 1H), 2.54-2.45 (m, 1H), 2.35 - 2.21 (m, 4H), 1.48 (s, 9H), 1.37 (d, 3H).

[0438] g 1 H NMR (300 MHz, d 6 -DMSO) δ 7.51 (s, 1H), 5.09 - 4.94 (m, 1H), 4.11 -3.95 (m, 1H), 3.70-3.60 (m, 1H), 3.52 (dd, 1H), 2.50-2.40 (m, 1H), 2.28 (s,3H), 2.02 - 1.91 (m, 1H), 1.39 (s, 9H), 1.22 (d, 3H).

[0439] Preparation of 186 1-(azacyclobutane-3-yl)-4-bromo-5-methylpyrazole A solution of tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutane-1-carboxylate (3.00 g, 9.488 mmol) in TFA (10 mL) and DCM (20 mL) was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure to produce the title compound (4 g, crude, TFA salt) as a brown oil, which was used directly without further purification. 1 ¹H NMR (300 MHz, CDCl₃) δ 7.50 (s, 1H), 5.16–5.06 (m, 1H), 4.30 (t, 2H), 3.88 (t, 2H), 2.25 (s, 3H). The compound was used directly without further purification.

[0440] Using appropriate reagents and adjusting the reaction time to determine the end of the reaction, the following compounds were prepared essentially as described with respect to 1-(azacyclobutane-3-yl)-4-bromo-5-methylpyrazole.

[0441] Table 21 .

[0442] Preparation of 188 (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester Tf₂O (3.62 g, 12.82 mmol) was added dropwise at -40 °C under N₂ to a stirred mixture of (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g, 10.68 mmol) and DIEA (4.14 g, 32.05 mmol) in a DCM (30 mL). The mixture was then added dropwise to a stirred solution of 1-(azacyclobutan-3-yl)-4-bromo-5-methylpyrazole (4 g, crude) in a DCM (30 mL). The mixture was brought to alkalinity to pH ~10 at -40 °C under N₂ with DIEA (3 mL). The mixture was stirred at -40 °C for another 4 hours and then concentrated under vacuum. The solution was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 20% to 30% in H2O (0.1% FA); 220 nm, to produce the title compound (500 mg, 12%) as a pale yellow solid. ES / MS m / z ( 79 Br / 81 Br) 385.1 / 387.1 [M+H] + .

[0443] Preparation of 189 (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (3S)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.05 g, 6.41 mmol, crude) was added dropwise to a stirred solution of 1-(azacyclobutan-3-yl)-4-bromo-5-methylpyrazole (3 g, 13.88 mmol, crude) in DCM (30 mL). The solution was alkaline to pH ~10 with DIEA (3 mL) at -40 °C under N2, and the mixture was stirred at -40 °C for 4 hours. The solution was quenched with H2O (30 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with brine (2 x 80 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 30% to 50% in H2O (0.1% FA) to yield the title compound (520 mg, 38.5%) as a pale yellow oil. ES / MS m / z ( 79 Br / 81 Br)385.0 / 387.0 [M+H] + .

[0444] The following compound was prepared essentially as described with respect to (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester, using appropriate reagents and adjusting the reaction time to determine the end of the reaction. Temperatures varied from -70°C to -40°C.

[0445] Table 22 1 Preparative TLC (EtOAc).

[0446] Preparation of 191 3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]piperidine-1-carboxylic acid tert-butyl ester NaBH3CN (2.18 g, 34.709 mmol) was added fractionally to a stirred mixture of 1-(azacyclobutan-3-yl)-4-bromo-5-methylpyrazole (5.00 g, 23.14 mmol) and tert-butyl 3-oxopiperidinium-1-carboxylate (5.53 g, 27.77 mmol) in MeOH (50 mL) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (5:1 to 1:1) to yield the title compound (4.0 g, 43.2%) as a brown solid. ES / MS m / z ( 79 Br / 81 Br)399.1 / 401.1 [M+H] + .

[0447] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate. Temperatures varied from room temperature to 50°C.

[0448] Table 23 1 TFA and catalytic AcOH were added to the initial solution, followed by the addition of NaBH3CN.

[0449] 2 Purified by silica gel column chromatography, eluted with PE:EtOAc (2:1 to 1:1).

[0450] Preparation of 194 (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]piperidine-1-carboxylic acid tert-butyl ester .

[0451] Preparation of 195 (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]piperidine-1-carboxylic acid tert-butyl ester 1.0 g of tert-butyl 3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]piperidin-1-carboxylate was separated by preparative chiral chromatography under the following conditions: column, Phenomenex Lux 5 μCellulose-4, AXIA Packed, 2.12*25 cm, 5 μm; elution with 20% MeOH in CO2, flow rate 40 mL / min; 210 nm; analytical LC conditions were: column, Lux Cellulose-4, 0.46*10 cm, 3.0 μm, elution with 10% to 50% MeOH (0.1% DEA) in CO2, flow rate 2 mL / min, to produce t (R) (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]piperidine-1-carboxylic acid tert-butyl ester, t (R) It is 1.85 min, 100% ee, as a pale yellow solid (460 mg); (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]piperidine-1-carboxylic acid tert-butyl ester, t (R) It was 2.18 min, 100% ee, as a pale yellow solid (450 mg). ES / MS m / z 399.1 / 401.1 [M+H] + .

[0452] Preparation of 196 (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester A mixture of (3R,4S)-4-azido-3-fluoro-piperidin-1-carboxylic acid tert-butyl ester (1.00 g, 4.09 mmol) and trimethyl(prop-1-yn-1-yl)silane (1.38 g, 12.28 mmol) was irradiated with microwave at 150 °C for 1 hour. The reaction mixture was concentrated under vacuum to provide the title compound (1.5 g) as a white solid, which was used in the next step without further purification. ES / MS m / z 357.1 [M+H] + .

[0453] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester.

[0454] Table 24 1 Purified by silica gel chromatography, eluted with 0% to 100% EtOAc in heptane.

[0455] 2 The reaction is carried out in toluene. 3 Purified by silica gel chromatography, eluted with PE:EA (4:1).

[0456] 4 Purified by silica gel chromatography, eluted with PE:EA (2:1).

[0457] 5 Purified by silica gel chromatography, eluted with PE:EA (5:1).

[0458] 6 Purified by silica gel chromatography, eluted with PE:EA (6:1 to 5:1).

[0459] a 1 H NMR (400 MHz, DMSO-d6) δ 0.26 (s, 9 H) 2.24 (s, 3 H) 2.36 - 2.47 (m, 2 H) 2.65 - 2.75 (m, 2 H) 4.42 - 4.59 (m, 1 H) 4.97 (ttd, J=8.38, 8.38,5.14, 5.14, 0.73 Hz, 1 H) 5.31 (d, J=4.89 Hz, 1 H).

[0460] Preparation of 207 4-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester K₂CO₃ (414.00 mg, 3.00 mmol) was added fractionally to a stirred solution of tert-butyl 4-azidopiperidine-1-carboxylate (226.00 mg, 1.00 mmol) and EAA (130.00 mg, 1.20 mmol) in DMSO (5.00 mL) at room temperature under N₂. The mixture was stirred at 80 °C for 6 hours under N₂. The mixture was cooled to room temperature, H₂O (10 mL) was added, and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (10:1 to 0:1) to yield the title compound (330 mg, 66.8%) as a yellow oil. ES / MS m / z 339.3 [M+H] + .

[0461] Using appropriate reagents and adjusting the reaction time to determine the end of the reaction, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate. DMF can also be used as a solvent. Temperatures varied from room temperature to 80°C.

[0462] Table 25 1 Filter the mixture, wash the filter cake with DCM (3 x 50 mL), and concentrate the filtrate under reduced pressure.

[0463] 2 Purified by silica gel column chromatography, eluted with PE:EtOAc (1:1).

[0464] 3 Purified by silica gel column chromatography, eluted with PE:EtOAc (10:1 to 2:1).

[0465] 4 DMF is used as a solvent.

[0466] 5 Purified by silica gel column chromatography, eluted with PE:EtOAc (2:1 to 1:1).

[0467] 6 Reverse rapid chromatography: column, C18, 55% to 60% ACN in H2O (0.1% NH4HCO3).

[0468] a 1 H NMR (400 MHz, CDCl3) δ 4.86 -4.73 (m, 1H), 4.49 -4.38 (m, 2H), 3.47 -3.40 (m, 2H), 3.38 -3.30 (m, 2H), 2.67 -2.58 (m, 2H), 2.57 -2.47 (m,5H), 1.76 -1.64 (m, 4H), 1.46 (s, 9H), 1.44 -1.39 (m, 3H).

[0469] b1 H NMR (300 MHz, DMSO-d6) δ 7.43 -7.25 (m, 5H), 5.22 -4.99 (m, 1H), 4.50 -4.37 (m, 3H), 4.30 (q, 2H), 2.88 -2.75 (m, 2H), 2.70 -2.58 (m, 2H), 2.47 (s, 3H), 1.30 (t, 3H).

[0470] Preparation 219 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazol-4-carboxylic acid A solution of tert-butyl 4-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]piperidin-1-carboxylate (300.00 mg, 0.890 mmol) and KOH (100.00 mg, 1.780 mmol) in H₂O (5.00 mL) was stirred at 50 °C for 2 hours under N₂. The mixture was acidified to pH 4 with HCl (aqueous solution) (1N) at 0 °C and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (2 x 15 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (250 mg, 90%) as a yellow oil. ES / MS m / z 311.3 [M+H] + .

[0471] The following compounds were prepared essentially as described with respect to 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazol-4-carboxylic acid, using appropriate reagents and adjusting the reaction time to determine the end of the reaction. The solvent may be DMSO, and the base may be NaOH.

[0472] Table 26 1 The precipitated solid was collected by filtration, washed with H2O (3 x 20 mL), and dried in a vacuum.

[0473] Preparation 229 4-[4-bromo-3-(2-hydroxyethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester LiBH4 (24.49 mg, 1.12 mmol) was added to a solution of 4-[4-bromo-3-(2-methoxy-2-oxo-ethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (390 mg, 0.94 mmol) in MeOH (5 mL) at 0 °C under N2. The reaction mixture was stirred at room temperature for 1 h, cooled to 0 °C, and quenched with H2O (10 mL). The mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined, washed with brine (2 x 10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to provide the title compound (350 mg, 96.22%) as a yellow oil. ES / MS m / z ( 79 Br / 81 Br) 388.1 / 390.1 [M+H] + .

[0474] Preparation 230 7-Chloro-5-[[(1R)-1-(5-fluoro-2-pyridyl)ethyl]amino]imidazo[1,2-a]pyridine-3-carboxylonitrile Under N2 at room temperature, Cs2CO3 (5532 mg, 16.98 mmol), BINAP (176.2 mg, 0.28 mmol), and Pd(AcO)2 (4.33 mg, 0.005 mmol) were added to 5,7-dichloroimidozolo[1,2-a]pyridine-3-carboxynitrile (600 mg, 2.83 mmol) and (1R)-1-(5-fluoropyridin-2-yl)ethylamine hydrochloride (749.7 mg, 4.25 mmol) in toluene (10 mL). The reaction mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1 to 1:3) to provide the title compound (250 mg, 28%) as a yellow solid. ES / MS m / z 316.1 [M+H]+ .

[0475] Preparation of 231 7-Chloro-5-methoxyimidazo[1,2-a]pyridine A solution of 4-chloro-6-methoxypyridine-2-amine (7.00 g, 44.14 mmol), chloroacetaldehyde (8.32 g, 52.99 mmol, 50%), and NaHCO3 (11.12 g, 132.42 mmol) in n-butanol (140.00 mL) was aliquoted into fourteen portions and stirred overnight at 65 °C in sealed tubes. The solutions were cooled to room temperature, diluted with H2O (200 mL), and extracted with EtOAc (3 x 200 mL). The organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE:EtOAc 1:1) to yield the title compound (6.1 g, 75.68%) as a light brown solid. ES / MS m / z 183.10 [M+H] + .

[0476] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to 7-chloro-5-methoxyimidazo[1,2-a]pyridine.

[0477] Table 27 .

[0478] Preparation of 233 7-Clonimidazole[1,2-a]pyridine-5-ol A mixture of 7-chloro-5-methoxyimidazo[1,2-a]pyridine (2.00 g, 10.95 mmol), NaOH (50% in H2O) (1.31 g, 16.43 mmol), and NDM (3.33 g, 16.43 mmol) in DMA (10.00 mL) was stirred for 2 hours at 50 °C under N2. The mixture was diluted with H2O (100 mL) and acidified to pH 4–5 with 1 M HCl to produce a precipitated solid, which was collected by filtration and washed with PE (3 x 100 mL) and H2O (3 x 10 mL), and dried under vacuum to give the title compound (1.5 g, 81.24%) as a pale yellow solid. ES / MS m / z 169.2 [M+H] + .

[0479] Preparation of 234 tert-butyl-[2-(7-chloroimidazolo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridinyl)ethoxy]-dimethyl-silane 60% NaH (0.96 g, 24.06 mmol) was added to 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (6.53 g, 24.06 mmol) in THF (50.00 mL) at 0 °C under N2. After stirring at 0 °C for 0.5 h, 5,7-dichloroimidazolo[1,2-a]pyridine (3 g, 16.04 mmol) was added to the mixture. The reaction mixture was stirred at room temperature under N2 for 2 h. The reaction mixture was quenched with H2O (50 mL) and then extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1 to 4:1) to provide the title compound (2.5 g, 36.93%) as a brown solid. ES / MS m / z 422.2. [M+H] + .

[0480] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to tert-butyl-[2-(7-chloroimidazolo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridinyl)ethoxy]-dimethyl-silane.

[0481] Table 28 1 Purified by silica gel column chromatography, eluted with PE:EtOAc (10:1 to 5:1).

[0482] 2 Purification by reversed-phase chromatography: column, C18; eluted with 0% to 100% ACN in H2O (0.1% NH3·H2O).

[0483] Preparation of 237 6-Bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-3-carboxylonitrile A solution of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carboxynitrile (2.00 g, 8.40 mmol), (1S)-1-(pyridin-2-yl)ethanol (1.14 g, 9.24 mmol), and PPh3 (2.64 g, 10.08 mmol) in THF (20.0 mL) was stirred at room temperature under N2 for 10 min. DEAD (1.76 g, 10.08 mmol) was added dropwise to the mixture over 10 min at room temperature. After stirring the mixture at room temperature for another 2 h, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of PE:EtOAc (PE~3:1) to yield the title compound (1.48 g, 51.3%) as the green oil. ES / MS m / z 343.0 / 345.0 [M+H] + .

[0484] Using appropriate reagents and adjusting the reaction time to determine the end of the reaction, the following compounds were prepared essentially as described with respect to 6-bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-3-carboxynitrile. The temperature varied from 0°C to room temperature.

[0485] Table 29 1 Purified by silica gel chromatography, eluted with PE:EtOAc (15:1 to 10:1).

[0486] a1 H NMR (300 MHz, CDCl3) δ 8.32 (d, 1H), 8.15 (s, 1H), 6.75 (d, 1H), 4.22 - 4.12 (m, 1H), 1.53 (d, 3H), 1.35 - 1.27 (m, 1H), 0.75 - 0.60 (m, 2H),0.60 - 0.36 (m, 2H).

[0487] Preparation of 245 (3R,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidin-1-carboxylic acid tert-butyl ester NBS (2.00 g, 11.22 mmol) was added to (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.5 g) and SiO2 (505.58 mg, 8.41 mmol) in ACN (15 mL) at room temperature under N2. The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with H2O. The suspension was filtered and washed with EtOAc (2 x 5 mL). The filtrate was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with PE:EA (3:1) to provide the title compound (1.3 g, 85.1%) as a white solid. ES / MSm / z ( 79 Br / 81 Br) 363.0 / 365.0 [M+H] + .

[0488] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to (3R,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester.

[0489] Table 30 1 Purified by silica gel chromatography, eluted with PE:EA (4:1).

[0490] 2 Purified by silica gel chromatography, eluted with PE:EA (3:1).

[0491] 3 Purified by silica gel chromatography, eluted with 0% to 100% EA in heptane.

[0492] 4 Purified by silica gel chromatography, eluted with PE:EA (5:1).

[0493] 5 Purified by silica gel chromatography, eluted with PE:EA (5:1 to 4:1).

[0494] a 1H NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3 H) 2.37 - 2.47 (m, 2 H) 2.69- 2.77 (m, 2 H) 4.41 - 4.49 (m, 1 H) 4.99 - 5.09 (m, 1 H) 5.09 - 5.67 (m, 1H).

[0495] Preparation 256 2-(4-bromo-5-methyl-triazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester Under N2 conditions at room temperature, KOH (6.59 g, 117.3 mmol) was added to 100 mL of H2O containing 11.1 g (11.1 g, 29.3 mmol) of 2-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester. The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was used directly for the next step without further purification.

[0496] Br2 (6.95 g, 43.99 mmol) was added dropwise to 1-(7-tert-butoxycarbonyl-7-azaspiro[3.5]non-2-yl)-5-methyl-triazol-4-carboxylic acid at room temperature under N2. The reaction mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated Na2S2O3 (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to provide the title compound (8.7 g, 75.35%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 4.84 -4.69 (m, 1H), 3.50 - 3.40 (m, 2H), 3.38 - 3.30 (m, 2H), 2.62 -2.54 (m, 2H), 2.53 - 2.44 (m, 2H), 2.24 (s, 3H), 1.77 - 1.62 (m, 4H), 1.46 (s, 9H).

[0497] Preparation 257 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester Br2 (154.00 mg, 0.96 mmol) was added fractionally to a stirred solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazol-4-carboxylic acid (248 mg, 0.80 mmol) and KOH (54.00 mg, 0.96 mmol) in H2O (6 mL), and the mixture was stirred at room temperature under N2 for 3 hours. A precipitate was formed, and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (2 x 15 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (190 mg, 69%) as a yellow solid. ES / MS m / z ( 79 Br / 81 Br) 345.2 / 347.2 [M+H] + It can be used directly without further purification.

[0498] The following compounds were prepared essentially as described with respect to tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate, using appropriate reagents and adjusting the reaction time to determine the end of the reaction. Temperature was varied from 0°C to room temperature. HBr / AcOH could be used as a solvent.

[0499] Table 31 1 Reverse rapid chromatography: column, C18, 10% to 50% ACN in H2O (0.1% NH4HCO3).

[0500] 2 Silica gel column chromatography, eluted with PE:EtOAc (5:1).

[0501] 3 Reverse rapid chromatography: column, C18, 50% to 80% ACN in H2O (0.1% FA).

[0502] 4 Reverse rapid chromatography: column, C18, 40% to 70% ACN in H2O (0.1% FA).

[0503] 5 Reverse rapid chromatography: column, C18, 50% to 55% ACN in H2O (0.1% NH4HCO3).

[0504] a 1H NMR (400 MHz, DMSO-d6) δ 7.40-7.34 (m, 4H), 7.33 - 7.27 (m, 1H), 5.14 - 5.06 (m, 1H), 4.45 (s, 2H), 4.42-4.34 (m, 1H), 2.81-2.72 (m, 2H), 2.66- 2.56 (m, 2H), 2.22 (s, 3H).

[0505] Preparation of 267 4-[2-(4-bromo-5-methyl-triazol-1-yl)-1,1-dimethyl-ethyl]piperazine-1-carboxylic acid tert-butyl ester Under N2 at 0 °C, BH3 (12.01 mL, 12.01 mol, 1 M in THF) was added dropwise to tert-butyl 4-[2-(4-bromo-5-methyl-triazol-1-yl)-1,1-dimethyl-ethyl]-3-oxo-piperazin-1-carboxylate (1 g, 2.40 mmol) in THF (10.00 mL). The reaction mixture was stirred at room temperature for 2 h, cooled to 0 °C, and quenched with MeOH (10 mL). The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with PE:EtOAc (4:1 to 2:1) to provide the title compound (0.53 g, 54.8%) as a pale yellow oil. ES / MS m / z ( 79 Br / 81 Br) 401.8 / 403.8 [M+H] + .

[0506] Preparation of 268 cis-3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanol A mixture of 1-(3-benzyloxycyclobutyl)-4-bromo-5-methyl-triazole (8.5 g, 26.38 mmol) and FeCl3 (8.56 g, 52.76 mmol) in DCM (100 mL) was stirred at 50 °C for 2 hours under N2. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to provide the title compound (8.00 g, crude product) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 5.09 -4.99 (m, 1H), 4.55 -4.42 (m, 1H), 2.80-2.71 (m, 2H), 2.48 -2.37 (m, 2H), 2.21 (s, 3H).

[0507] Preparation 269 3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanone A mixture of 3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanol (4.00 g, 17.23 mmol) and Dess-Martin (10.97 g, 25.85 mmol) in DCM (40 mL) was stirred at room temperature under N2 for 2 hours. The mixture was diluted with H2O (100 mL), extracted with EtOAc (3 x 100 mL), washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions: column, C18; mobile phase, 20% to 40% ACN in H2O (0.1% FA) to provide the title compound (2.10 g, 52.96%) as a white solid. ES / MS m / z ( 79 Br / 81 Br) 229.9 / 231.9 [M+H] + .

[0508] Preparation 270 1-Bromo-3-[(diphenylmethyl)amino]-3-methylbutane-2-one A mixture of 3-[(diphenylmethyl)amino]-3-methylbutane-2-one (700.00 mg, 2.62 mmol) and Br2 (418.39 mg, 2.62 mmol) in HBr / AcOH (40%, 6.00 mL) was stirred for 2 hours at room temperature under N2. The reaction mixture was quenched at 0 °C with NaHCO3 / ice (300 mL). The mixture was extracted with DCM (2 x 300 mL). The combined organic extracts were washed with brine (1 x 300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (800 mg) as a yellow solid, which was used without further purification. ES / MS m / z ( 79 Br / 81Br)346.0 / 348.0 [M+H] +。

[0509] Preparation 271 1-(diphenylmethyl)-2,2-dimethylazacyclobutane-3-one A mixture of 1-bromo-3-[(diphenylmethyl)amino]-3-methylbutane-2-one (2.10 g, 6.07 mmol) and NaHCO3 (764.21 mg, 9.10 mmol) in DMF (6.00 mL) and H2O (1.50 mL) was stirred at room temperature under N2 for 12 hours. The mixture was diluted with EtOAc (100 mL) and washed with H2O (3 x 80 mL). The organic layer was washed with brine (2 x 80 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 24% to 27% in H2O to produce the title compound (1.30 g, 75.4%) as a yellow solid. ES / MS m / z 284.3 [M+H2O+H] + .

[0510] Preparation of 272 6-(1-[1-[1-(diphenylmethyl)-2,2-dimethylazacyclobutane-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile A mixture of 4-methoxy-6-[5-methyl-1-(piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyridin-3-carboxynitrile (300.00 mg, 0.89 mmol), 1-(phenylmethyl)-2,2-dimethylazacyclobutane-3-one (473.29 mg, 1.78 mmol), AcOH (5.36 mg, 0.089 mmol), and NaBH3CN (140.11 mg, 2.23 mmol) in MeOH (4.00 mL) was stirred for 12 hours at 50 °C under N2. The reaction mixture was quenched with NaHCO3 (50 mL) at room temperature, and the aqueous layer was extracted with EtOAc (2 x 80 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 38% to 40% in H2O (0.1% FA) to yield the title compound (400 mg, 76.57%) as a yellow solid. ES / MS m / z 586.3 [M+H] + .

[0511] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compounds were prepared essentially as described regarding 6-(1-[1-[1-(diphenylmethyl)-2,2-dimethylazacyclobutan-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile). The reaction can also be quenched with H2O, and the filtrate can be washed with EtOAc.

[0512] Table 32 1 Purified by silica gel column chromatography, eluted with 1% to 50% EA in PE.

[0513] Preparation of 275 4-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester, isomer 1 and Preparation 276 4-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester, isomer 2 The isomers of 4-[3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutan-1-yl]-3,3-difluoropiperidin-1-carboxylic acid tert-butyl ester (1.9 g) were separated by chiral preparative HPLC under the following conditions: column, N--CHIRALPAK IG (lot number IG30CS-VL001), 4.6*100 mm, 3.0 μm; elution with a gradient of 10% - 50% MeOH (20 mM NH3); flow rate: 2 mL / min; 210 nm; t (R) Isomer 1 was 2.30 min, 100% ee, as a white solid (810 mg, 42.63%); t (R) Isomer 2 was 2.52 min, 100% ee, as a white solid (788 mg, 41.47%).

[0514] Preparation of 277 6,6-Difluoro-5,6-dihydro-7H-cyclopentadieno[b]pyridin-7-one F-TEDA (23.95 g, 67.61 mmol) was added fractionally to a stirred solution of 5H,6H-cyclopentadieno[b]pyridin-7-one (3.00 g, 22.53 mmol) and Na2SO4 (16.00 g, 112.64 mmol) in ACN (30 mL) at room temperature under N2, and the mixture was stirred at 80 °C for 3 hours under N2. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of PE / EtOAc (3:1) to yield the title compound (2.2 g, 57.73%) as a pale yellow solid. 1 H NMR (400 MHz, d 6 -DMSO) δ 8.88 (dd, 1H), 8.14 (dd, 1H), 7.78 (dd,1H), 3.75 (t, 2H).

[0515] Preparation 278 6,6-Difluoro-6,7-dihydro-5H-cyclopentadieno[b]pyridine-7-ol A stirred solution of 6,6-difluoro-3H,4H,5H-cyclopentadien[b]pyridin-7-one (1 g, 5.84 mmol) in MeOH (10 mL) was treated with NaBH4 (220 mg, 5.82 mmol) and stirred for 2 h at room temperature under N2. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with a gradient elution of PE / EtOAc (3:1) to yield the title compound (800 mg, 80%) as a white solid. ES / MS m / z 172.0 [M+H] + .

[0516] Preparation 279 Trifluoromethanesulfonic acid(R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl ester Tf₂O (597.33 mg, 2.12 mmol) was added dropwise to a stirred solution of (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanol (250 mg, 1.41 mmol) and TEA (428.47 mg, 4.23 mmol) in DCM (10 mL) at 0 °C, and the mixture was stirred at room temperature under N₂ for 4 h. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (1 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (280 mg, crude) as a yellow oil. The product was used directly without further purification. ES / MS m / z 309.8 [M+H] + .

[0517] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to trifluoromethanesulfonic acid (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl ester.

[0518] Table 33 1 The extract was concentrated under vacuum and dried or filtered without washing with brine or anhydrous Na2SO4.

[0519] Preparation of 281 4-Methoxy-6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine KOAc (6.48 g, 66.06 mmol) and Pd(dppf)Cl2 (322.25 mg, 0.44 mmol, 0.02 equivalent) were added to 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5.00 g, 22.02 mmol) and dipentanoyl diborone (6710.27 mg, 26.43 mmol) in dioxane (10 mL) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 hours under N2. The mixture was used without further purification. ES / MS m / z 275.1 [M+H]+.

[0520] Preparation of 282 [5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]boronic acid A mixture of tert-butyl-[2-(7-chloroimidazolo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridinyl)ethoxy]-dimethyl-silane (1.8 g, 4.27 mmol), dipentanoyl diboron (1.62 g, 6.40 mmol), KOAc (1.05 g, 10.67 mmol), XPhos (0.24 g, 0.51 mmol), and Pd2(dba)3 (0.39 g, 0.427 mmol) in dioxane (20 mL) was stirred at 80 °C for 2 hours under N2. After cooling to room temperature, the reaction mixture was used for the next step without further purification. ES / MS m / z 432.1 [M+H] + .

[0521] Preparation of 283 5-Methoxyimidazo[1,2-a]pyridine-7-ylboronic acid A stirred mixture of 7-chloro-5-methoxyimidazo[1,2-a]pyridine (1.00 g, 5.48 mmol) and dipentanoyl diborone (1.67 g, 6.57 mmol) in 1,4-dioxane was treated at room temperature under N2 with KOAc (1.61 g, 16.43 mmol) and Xphos Pd G4 (0.05 g, 0.06 mmol) and stirred at 80 °C for 8 hours. The mixture was diluted with H2O (100 mL), acidified to pH 4 with aqueous HCl solution (1 N), and then... iExtracted with PrOH:CHCl3 (3:1) (3 x 200 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum to yield the title compound (1.4 g, crude product) as a light pink solid. ES / MS m / z 193.0 [M+H] + .

[0522] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to 5-methoxyimidazo[1,2-a]pyridin-7-ylboronic acid. The catalyst may also be XPhos Pd G4.

[0523] Table 34 1 Use 0.1 equivalents of Xantphos Pd G4 and 0.2 equivalents of X-Phos.

[0524] Preparation of 287 4-[(1R)-1-(pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile A solution of 6-bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-3-carboxylonitrile (1.40 g, 4.08 mmol), KOAc (1.20 g, 12.24 mmol), and dipentanoyl diborone (1.24 g, 4.90 mmol) in dioxane (20.00 mL) at room temperature was stirred with Pd(dppf)Cl2. . The mixture was treated with CH2Cl2 (0.17 g, 0.20 mmol) and stirred at 100 °C for 2 hours under N2. The mixture was filtered, the filter cake was washed with EtOAc (3 x 20 mL), and the filtrate was concentrated under reduced pressure to yield the title compound as a black solid (2.5 g, crude product), which was used directly without further purification. ES / MS m / z 391.3 [M+H] + .

[0525] The following compounds were prepared essentially as described with respect to 4-[(1R)-1-(pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile, using appropriate reagents and adjusting the reaction time to determine the end of the reaction. The temperature varied from 80°C to 100°C. The base may also be KF. The catalyst may also be Pd(PPh3)4, Pd2(dba)3, or Pd(dppf)Cl2, and may be used alone or in combination with XPhos Pd G4.

[0526] Table 35 1 The mixture is used directly without further purification.

[0527] 2 The mixture was filtered, washed with 1,4-dioxane, concentrated under reduced pressure, and used directly without further purification.

[0528] 3 The reaction mixture was filtered and purified by reversed-phase C18 chromatography.

[0529] 4 After post-treatment, the organic layers were combined and washed with H2O. The aqueous layer was acidified to pH 3-4 with concentrated HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum.

[0530] 5 Purified by silica gel column chromatography, eluted with PE / EtOAc (20:1 to 3:1).

[0531] a The material is used without further purification.

[0532] Preparation of 302 3-Chloro-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine A mixture of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo[1,5-a]pyridine (5.06 g, 18.46 mmol) and NCS (2.47 g, 18.46 mmol) in CHCl3 (5 mL) was heated at 50 °C for 1 hour. After cooling to room temperature, the reactants were washed with H2O, saturated aqueous NaHCO3 solution, and brine, dried over Na2SO4, and filtered. The filtrate was concentrated to provide the title compound (5.79 g, 18 mmol) as a light brown solid. ES / MS m / z 227.0 [M+H-C6H12] + .

[0533] Preparation of 303 4-[4-(5-chloroimidozolo[1,2-a]pyridin-7-yl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester Pd(PPh3)4 (349.4 mg, 0.30 mmol) and KF (527.0 mg, 9.07 mmol) were added to 7-bromo-5-chloroimidazolo[1,2-a]pyridine (700.0 mg, 3.02 mmol) and 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (946.7 mg, 2.41 mmol) in dioxane / H2O (4:1, 10.0 mL) at room temperature under N2. The reaction mixture was stirred at 100 °C for 2 hours under N2. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (1:2) to provide the title compound (700 mg, 55.6%) as a yellow solid. ES / MS m / z 416.2 [M+H] + .

[0534] Preparation of 304 4-[5-methyl-4-(5-oxo-6H-imidazo[1,2-c]pyrimidin-7-yl)pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester 7-chloroimidazolo[1,2-c]pyrimidin-5(6H)-one (300 mg, 1.77 mmol), tert-butyl 4-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylate (1.04 g, 2.65 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (127 mg, 0.27 mmol) and K3PO4 (1.13 g, 5.31 mmol) in 1,4-dioxane (4 mL) were treated with Pd2(dba)3 (243 mg, 0.27 mmol) and bubbled with N2 for 5 min. The reaction mixture was sealed and refluxed overnight. After cooling to room temperature, the reactants were diluted with H₂O and extracted with EtOAc (3x). The combined organic layers were washed with H₂O, followed by brine, dried over Na₂SO₄, filtered, and concentrated to a yellow oil. The oil was dissolved in DCM and purified by silica gel chromatography, eluting with 0% to 10% MeOH in DCM to provide the title compound as a solid (470 mg, 1.18 mmol, 66.7%). ES / MS m / z 399.2 [M+H] + .

[0535] Preparation of 305 4-(4-[5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester A mixture of tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylate (1.60 g, 4.63 mmol), 5-methoxyimidazo[1,2-a]pyridin-7-ylboronic acid (1.33 g, crude), K₂CO₃ (1.92 g, 13.90 mmol), Pd(PPh₃)₄ (0.27 g, 0.23 mmol), dioxane (8 mL), and H₂O (2.00 mL) was stirred at 90 °C for 8 hours under N₂. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with H₂O (50 mL), and then washed with brine (80 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (3:1 to 1:1) to yield the title compound (520 mg, 18.2%) as a brown solid. ES / MS m / z 413.3 [M+H] +.

[0536] Preparation of 306 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester Under N2 at room temperature, K2CO3 (7.56 g, 54.72 mmol) and Pd(DtBPF)Cl2 (0.24 g, 0.36 mmol) were added to 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine (5 g, 18.24 mmol) in dioxane (80 mL) and water (20 mL). The reaction mixture was stirred overnight at 80 °C. After cooling to room temperature, the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with a 30% to 60% EtOAc gradient in PE to provide the title compound (4.5 g, 59.8%) as a light brown solid. ES / MS m / z 413.2 [M+H] + .

[0537] Preparation of 307 4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylate (16.1 g, 39.02 mmol) in CHCl3 (50 mL) was treated with PPTS (981 mg, 3.90 mmol) followed by NCS (5.21 g, 39.02 mmol). The reaction mixture was stirred at 40 °C for 95 min. After cooling to room temperature, the mixture was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in heptane to provide the title compound (17.7 g, 101%) as a colorless solid. ES / MS m / z391.2 [M+2H-tBu] + .

[0538] Preparation of 308 3-[5-methyl-4-[5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]triazol-1-yl]azacyclobutane-1-carboxylic acid tert-butyl ester Pd(PPh3)4 (0.41 g, 0.35 mmol) was added to 5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-ylboronic acid (1.00 g, 3.53 mmol), 3-(4-bromo-5-methyl-1,2,3-triazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (1.23 g, 3.89 mmol), and K2CO3 (1.46 g, 10.60 mmol) in dioxane (8.00 mL) and H2O (2.00 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 hours under N2. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with a 5% to 10% MeOH gradient in DCM to provide the title compound (550 mg, 32.74%) as a yellow solid. ES / MS m / z 476.1 [M+H] + .

[0539] Preparation of 309 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridinyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A mixture of 5-[2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-ylboronic acid (1.6 g, 3.71 mmol), 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (1.41 g, 4.08 mmol), K₂CO₃ (1.54 g, 11.13 mmol), and Pd(DtBPF)Cl₂ (242 mg, 0.37 mmol) in dioxane (20 mL) and H₂O (5 mL) was stirred at 80 °C for 2 hours under N₂. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc (1:2 to 1:1) to provide the title compound (1.2 g, 49.63%) as a brown solid. ES / MS m / z 652.4 [M+H] + .

[0540] Preparation of 310 3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester A stirred solution of tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azacyclobutane-1-carboxylate (2.50 g, 7.91 mmol) and 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (2.37 g, 7.91 mmol) in dioxane:H₂O (80 mL:20 mL) was treated at room temperature under N₂ with K₂CO₃ (3.28 g, 23.72 mmol) and Pd(PPh₃)₄ (0.09 g, 0.08 mmol), and the mixture was stirred overnight at 100 °C under N₂. The mixture was cooled to room temperature, the reaction mixture was quenched with H₂O (100 mL), and extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with brine (1 x 150 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a gradient elution of PE:EtOAc (10:1–1:1) to yield the title compound (1.88 g, 58.21%) as a white solid. 1 H NMR (300 MHz, d 6-DMSO) δ8.61-8.51 (m, 2H), 7.95 (s, 1H), 7.09 (d, 1H), 5.41-5.26 (m, 1H), 4.37-4.26(m, 2H), 4.18 (d, 2H), 4.06 (s, 3H), 2.41 (s, 3H), 1.43 (s, 9H).

[0541] The following compound was prepared essentially as described with respect to tert-butyl 3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azacyclobutane-1-carboxylate using appropriate reagents and adjusting the reaction time to determine the end of the reaction. The temperature varied from 80°C to 100°C. The solvent could also be toluene:H₂O. The base could also be KOAc, K₃PO₄, or KF. The catalyst could also be CsF, Pd(AcO)₂, PCy₃, Pd(dppf)Cl₂DCM, Pd₂(dba)₃.CHCl₃, or Pd(dppf)Cl₂, used alone or in combination with X-Phos or Xphos Pd G₄. Alternatively, the reaction could be carried out without a catalyst. The mixture could also be PE and CHCl₃: i -PrOH extraction.

[0542] Table 36 1 Preparative TLC (EtOAc:PE=1:1).

[0543] 2 Reverse rapid chromatography using the following conditions: column, C18; ACN in H2O (0.1% NH4HCO3).

[0544] 3 Reverse rapid chromatography using the following conditions: column, C18, ACN in H2O (0.1% FA).

[0545] 4 Reverse rapid chromatography using the following conditions: column, C18; ACN in H2O (0.1% NH3H2O).

[0546] 5 Reverse rapid chromatography using the following conditions: column, C18; ACN in H2O.

[0547] 6 Reverse rapid chromatography using the following conditions: column, C18, H2O (0.1% FA).

[0548] 7 Silica gel column chromatography, using gradient elution with DCM:MeOH.

[0549] 8 Silica gel column chromatography, eluted with PE:EtOAc (1:2) 9 Reverse rapid chromatography: column, C18, 40% to 70% ACN in H2O (0.1% FA).

[0550] 10 Catalyst: Pd(DtBPF)Cl2.

[0551] 11 Silica gel column chromatography, eluted with PE:EtOAc (1:1).

[0552] 13 Silica gel column chromatography, eluted with PE:EtOAc (4:1 to 1:2).

[0553] 14 Rapid silica gel column chromatography, eluted with 10% to 60% EtOAc in PE.

[0554] 15 Preparative TLC (EtOAc).

[0555] 16 Silica gel column chromatography, eluted with a gradient of DCM:MeOH (20:1).

[0556] 17 Reverse rapid chromatography using the following conditions: column, C18; 10% to 50% ACN in H2O (0.1% NH4HCO3).

[0557] 18 Reverse rapid chromatography using the following conditions: column, C18; 50% to 60% ACN in H2O (0.1% NH4HCO3).

[0558] 19 Silica gel column chromatography, eluted with 50% to 100% EtOAc in PE.

[0559] 20Silica gel column chromatography, eluted with gradients of DCM:MeOH (20:1 to 12:1).

[0560] 21 Cs2CO3 is used as a base.

[0561] 22 Pd(DtBPF)Cl2 is used as a catalyst 23 Silica gel column chromatography, eluted with PE:EtOAc (2:1 to 1:1).

[0562] 24 Silica gel column chromatography, eluted with PE:EtOAc (2:1 to 1:1).

[0563] 25 Silica gel column chromatography, eluted with 0% to 100% EtOAc in heptane.

[0564] 26 Reverse rapid chromatography using the following conditions: column, C18; 10% to 50% ACN in H2O.

[0565] a 1H NMR (300 MHz, methanol-d4) δ 7.82 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 6.77 (s, 1H), 4.24 (s, 3H), 3.86 -3.73(m, 1H), 3.65-3.37 (m, 4H), 2.62 (s, 3H), 2.09-2.01 (m, 1H), 1.94 -1.81 (m, 1H), 1.54 (s, 9H), 1.49 -1.14 (m, 4H).

[0566] b ES / MS m / z [M+2H-tBu] + .

[0567] c 1 H NMR (300 MHz, d 6 -DMSO) δ 8.59-8.49 (m, 2H), 8.35 (s, 1H), 7.12 (d,1H), 5.24-5.11(m, 1H), 4.38-4.28(m, 2H), 4.22-4.12 (m, 2H), 4.06 (s, 3H), 2.41 (s, 3H), 1.42 (s, 9H).

[0568] Preparation of 361 4-(4-[3-cyano-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester A solution of 4-[(1R)-1-(pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridin-3-carboxylonitrile (500 mg, 1.28 mmol), tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylate (487 mg, 1.41 mmol), K₂CO₃ (531 mg, 3.84 mmol), Pd(PPh₃)₄ (148 mg, 0.13 mmol), H₂O (2 mL), and dioxane (8 mL) was stirred overnight at 100 °C under N₂. The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-direction Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 50% to 60% in H₂O (0.1% NH₄HCO₃) to yield the title compound (354 mg, 52.27%) as a brown solid. ES / MS m / z 529.3 [M+H] + .

[0569] Preparation of 362 2-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)-7-azaspiro[3,5]nonane-7-carboxylic acid tert-butyl ester A mixture of tert-butyl 2-(4-bromo-5-methylpyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (200.00 mg, 0.52 mmol) and 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (171.24 mg, 0.57 mmol) in dioxane (4.00 mL) and H2O (1 mL) was treated fractionally at room temperature under N2 with K2CO3 (215.77 mg, 1.56 mmol) and Pd(PPh3)4 (120.27 mg, 0.10 mmol). The mixture was stirred at 80 °C for 2 hours under N2. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (3:1 to 2:1) to yield the title compound (110 mg, 44.3%) as a yellow solid. ES / MS m / z 462.3 [M-tBu+ACN+H] + .

[0570] The following compounds were prepared by using appropriate reagents and adjusting the reaction time to determine the end of the reaction, essentially as described with respect to tert-butyl 2-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate. Temperatures varied from 80°C to 100°C. Toluene:H₂O could also be used as a solvent. Pd(AcO)₂, PCy₃, XPhos Pd G₂, XPhos Pd G₄, or Pd(dppf)Cl₂ could also be used as catalysts, or no catalyst was required. K₃PO₄, KF, or CsF could also be used as bases. Pd(DtBPF)Cl₂ could also be used as a catalyst.

[0571] Table 37 1 ISCO column, eluted with hexane: EtOAc (10-100%).

[0572] 2 Purified by silica gel column chromatography, eluted with a gradient of DCM:MeOH (20:1).

[0573] 3Purified by silica gel column chromatography, eluted with a gradient of 0% to 10% MeOH in DCM.

[0574] 4 Purification by preparative TLC (EA) 5 Purified by reverse Combi-flash chromatography under the following conditions: column, C18; ACN in H2O (0.1% NH4HCO3).

[0575] 6 Purified by preparative TLC PE:EtOAc (1:1).

[0576] 7 Purified by preparative TLC (EA).

[0577] 8 Purified by silica gel column chromatography, eluted with PE:EtOAc (1:3).

[0578] 9 Purified by silica gel column chromatography, eluted with PE:EtOAc (2:3).

[0579] 10 Purified by silica gel column chromatography, eluted with a gradient of 0% to 10% MeOH in DCM.

[0580] 11 Purified by silica gel column chromatography, eluted with PE:EA (2:3).

[0581] 12 Purified by silica gel chromatography, eluted with PE:EA (1:1 to 1:2).

[0582] 13 Purification by reversed-phase chromatography: column, C18; eluted with 40% to 50% ACN in H2O (0.1% NH4OH).

[0583] 14 Purified by silica gel column chromatography, eluted with PE:EtOAc (3:1).

[0584] 15 Purified by silica gel column chromatography, eluted with PE:EA (2:1 to 1:1).

[0585] Preparation of 393 (3R)-3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (Trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate (10 mL, 8.32 mmol) was added dropwise over 5 min to a stirred solution of 4-methoxy-6-[5-methyl-1-(piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxynitrile (400.00 mg, 1.18 mmol) and DIEA (307.36 mg, 2.37 mmol) in DCM (5.00 mL). The mixture was stirred at room temperature under N2 for 1 h, washed with H2O (3 x 20 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH (9:1) to yield the title compound (411 mg, 68.36%) as a brown solid. ES / MS m / z 506.3 [M+H] + .

[0586] Preparation of 394 (2S,4R)-4-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azacyclobutan-1-yl]-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester Tf2O (420.55 mg, 1.491 mmol) was added dropwise to a stirred solution of (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (300.00 mg, 1.491 mmol) and DIEA (577.94 mg, 4.472 mmol) in DCM (5.00 mL) at -70 °C under N2 for 1 hour. Then, a solution of (2S,4S)-2-methyl-4-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was added dropwise to a stirred solution of 6-[1-(azacyclobutan-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile, TFA (400.00 mg, 0.95 mmol) and DIEA (367.20 mg, 2.84 mmol) in DCM (20.00 mL) at -70 °C under N2. The solution was stirred overnight at room temperature, quenched with H2O (50 mL), and extracted with DCM (2 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to yield the title compound (80 mg, 17.18%) as a pale yellow solid. ES / MS m / z 492.2 [M+H]+ .

[0587] Preparation of 395 (3S)-3-(4-(4-(3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)tert-butyl pyrrolidine-1-carboxylate A mixture of 4-methoxy-6-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (300.00 mg, 0.89 mmol), (3R)-3-(methanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.37 g, 8.92 mmol), and K₂CO₃ (369.75 mg, 2.68 mmol) in toluene (3.00 mL) was stirred at 150 °C for 4 hours under N₂. The mixture was cooled to room temperature, poured into H₂O (20 mL), and extracted with DCM (2 x 20 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH (95:5–90:10) to yield the title compound (260 mg, 57.66%) as a pale yellow solid. ES / MS m / z 506.4 [M+H] + .

[0588] Preparation of 396 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazacyclobutane-1-carboxylic acid tert-butyl ester A mixture of 6-(1-[1-[1-(diphenylmethyl)-2,2-dimethylazacyclobutan-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile (400.00 mg, 0.68 mmol), Boc2O (447.11 mg, 2.05 mmol), and Pd(OH)2 / C (287.69 mg) in MeOH (10.00 mL) was stirred at room temperature under H2 for 12 hours. The mixture was filtered, the filter cake was washed with MeOH (2 x 30 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 30% to 33% in H2O (0.1% FA) to yield the title compound (260 mg, 73.27%) as a yellow solid. ES / MS m / z 520.4 [M+H] + .

[0589] Preparation of 397 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazacyclobutane-1-carboxylic acid tert-butyl ester, isomer 1 and Preparation of 398 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazacyclobutane-1-carboxylic acid tert-butyl ester, isomer 2 The isomers of 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazacyclobutane-1-carboxylic acid tert-butyl ester (390.00 mg) were separated by preparative chiral chromatography under the following conditions: column, CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; elution with a 30% iPrOH gradient in hexane (10 mM NH3MeOH); flow rate 20 mL / min; 254 / 220 nm; t (R) Isomer 1 is 10.2 min (110 mg, 28.21%), as a yellow solid with 100% ee; t (R) Isomer 2 was 12.7 min (120 mg, 30.77%), as a yellow solid with 99.6% ee. ES / MSm / z 520.4 [M+H] + .

[0590] Preparation of 399 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]azacyclobutane-1-carboxylic acid tert-butyl ester 3-oxoazacyclobutane-1-carboxylic acid tert-butyl ester (101.18 mg, 0.59 mmol) in MeOH (4.00 mL) was added to 4-methoxy-6-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (100.00 mg, 0.30 mmol). The solution was stirred at 40 °C for 1 hour. After cooling the solution to room temperature, NaBH3CN (37.14 mg, 0.591 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The mixture was diluted with EtOAc (50 mL) and washed with H2O (2 x 50 mL). The organic extract was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 50% to 60% in H2O (0.1% FA) to yield the title compound (130 mg, 89.5%) as a pale yellow solid. ES / MS m / z 492.2 [M+H] + .

[0591] Preparation of 400 (3R)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azacyclobutan-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester 6-[1-(azacyclobutan-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylonitrile (241 mg, 0.78 mmol) was added to a stirred solution of (3S)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.3 mL, 0.78 mmol, 3.4 M in DCM) in DCM (5 mL). After stirring the solution at -50°C for 1 hour, another (3S)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.3 mL, 0.78 mmol, 3.4 M in DCM) was added and stirring was continued at -50°C for another hour. The mixture was diluted with EtOAc (100 mL) and washed with H2O (2 x 20 mL) and brine (20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: C18; elution with an ACN gradient of 35% to 60% in H2O (0.1% NH4HCO3) to yield the title compound (80 mg, 20.6%) as a pale yellow solid. ES / MS m / z 478.4 [M+H] + .

[0592] Preparation of 401 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester A stirred solution of 4-(4-[5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (500 mg, 1.21 mmol) in DCM (6 mL) at room temperature was treated with NIS (300 mg, 1.33 mmol) and stirred at room temperature for 8 hours. The mixture was diluted with EtOAc (100 mL), washed with H2O (20 mL), and then washed with brine (20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to yield the title compound (820 mg, crude), which was used directly without further purification. ES / MS m / z 539.2 [M+H] + .

[0593] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate. The compounds can also be chlorinated with NCS or with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione. The reaction can be quenched with Na₂SO₃, and the mixture can also be extracted with DCM. Temperature varied from -60°C to room temperature.

[0594] Table 38 1 Purification was achieved by rapid silica gel chromatography, eluting with 0% to 100% EtOAc in heptane.

[0595] Preparation of 501 4-[4-(3-cyclopropyl-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-[4-(3-iodo-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (500 mg, 0.929 mmol) in toluene:H₂O 10:1 (6.6 mL), cyclopropylboronic acid (160 mg, 1.86 mmol), K₃PO₄ (986 mg, 4.64 mmol), tricyclohexylphosphine (57.3 mg, 0.204 mmol), and PdOAc₂ (22.9 mg, 0.102 mmol) were added, and the mixture was heated at 100 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL) and H₂O (20 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated under vacuum, and the residue was purified by reversed-phase chromatography, eluting with an ACN gradient from 0% to 100% in H₂O to provide the title compound (79 mg, 19%). ES / MS m / z 452.9 [M+H] + .

[0596] Preparation of 502 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylate (800 mg, crude), DMF (8.00 mL), and CuCN (173.01 mg, 1.93 mmol) was stirred at 100 °C for 2 hours under N2. The mixture was diluted with DCM (100 mL), washed first with H2O (20 mL), and then with brine (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with a gradient of 50% to 70% ACN in H2O (0.1% FA) to yield the title compound (450 mg, 46%). ES / MS m / z 438.3 [M+H] + .

[0597] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate. Temperatures varied from 80°C to 100°C. The reaction could also be quenched with aqueous solutions of H₂O or NH₄OH, and the mixture could be extracted with EtOAc or DCM.

[0598] Table 39 1 Purified by silica gel chromatography, eluted with 0% to 100% EtOAc in DCM.

[0599] Preparation of 510 6-(1-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-chloro-4-methoxypyrazolo[1,5-a]pyridine A solution of (1r,3r)-3-(4-(3-chloro-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutane-1-ol (1.03 g, 3.09 mmol), tert-butyldimethylchlorosilane (930 mg, 6.17 mmol), in DCM (15 mL) and imidazole (420 mg, 6.17 mmol) was stirred at room temperature for 30 min. The reactants were directly loaded onto a silica gel column and eluted with 0% to 100% EtOAc in heptane to provide the title compound as a solid (700 mg, 1.56 mmol). ES / MS m / z 448.2 [M+H] + .

[0600] Preparation of 511 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester Under N2 and at room temperature, NaOH (50% aqueous solution) (8.23 g, 102.856 mmol) was added dropwise to a stirred solution of 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (15.00 g, 34.29 mmol) and NDM (10.41 g, 51.43 mmol) in DMA (200.00 mL). The mixture was stirred under N2 at 50 °C for 2 hours. The mixture was diluted with H2O (1500 mL) and PE (500 mL) and acidified with FA to pH 4. The precipitated solid was collected by filtration, washed with H₂O (2 x 50 mL) and PE (2 x 100 mL), and dried under reduced pressure to yield the title compound (13 g, 89.54%) as a white solid. ES / MS m / z 424.2 [M+H] + .

[0601] Preparation of 512 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester Dodecane-1-thiol (883 mg, 4.36 mmol) was added to 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (900 mg, 2.18 mmol) in DMA (10 mL) and NaOH in water (523.60 mg, 6.55 mmol, 50% in water). The reaction mixture was stirred at 50 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (150 mL) and PE (50 mL). The pH of the mixture was acidified to pH 4 with FA. The mixture was stirred at room temperature under N2 for 3 hours. The resulting precipitate was filtered and then washed with water (3 x 10 mL) and PE (3 x 10 mL). The solid was concentrated under vacuum to provide the title compound (740 mg, 85.12%) as a pale yellow solid. ES / MS m / z 399.2 [M+H] + .

[0602] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate.

[0603] Table 40 1 Purified by silica gel chromatography, eluted with PE:EtOAc (1:2).

[0604] 2 Purification was achieved by rapid silica gel chromatography, eluting with 10% to 70% EtOAc in PE.

[0605] 3 Purification by rapid reversed-phase chromatography: column, C18; eluted with 10% to 70% ACN in H2O (0.1% NH4CO3).

[0606] 4 Post-treatment: Acidify the mixture to pH 6 with FA. Collect the insoluble matter by filtration.

[0607] 5 Purified by silica gel chromatography, eluted with 0% to 10% MeOH in DCM.

[0608] 6Purification by rapid reversed-phase chromatography: column, C18; elution with 0% to 100% ACN in H2O.

[0609] 7 Purification by reversed-phase chromatography: column, C18; eluted with 10% to 50% ACN in H2O.

[0610] 8 Purification by reversed-phase chromatography: column, C18; eluted with 30% to 70% ACN in H2O (0.1% FA).

[0611] a [M+H-C4H8] + 9 After adjusting the pH to 4 with FA, the resulting insoluble matter was collected by filtration.

[0612] Preparation of 529 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester NaOH (50% aqueous solution) (36.57 g, 457.14 mmol) was added dropwise to a stirred mixture of 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (40.00 g, 91.43 mmol) and NDM (55.51 g, 274.28 mmol) in DMA (400 mL) at 0 °C. The mixture was stirred at 50 °C for 8 hours. The mixture was diluted with H2O (400 mL), acidified to pH 6 with FA, filtered, and the filter cake was washed with H2O and dried under vacuum. The solid was ground together with a mixture of hexane (200 mL) and Et2O (200 mL), filtered, and stirred in MeOH (400 mL) at 60 °C for 2 hours. The mixture was filtered, and the filter cake was concentrated under vacuum to yield the title compound (32 g, 82.6%) as a pale yellow solid. ES / MS m / z 424.3 [M+H] + .

[0613] Preparation of 530 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester Under N2 conditions, 10.44 g (130.58 mmol) of 50% aqueous NaOH was added to a stirred mixture of 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (19.00 g, 43.53 mmol) and NDM (26.43 g, 130.58 mmol) in DMA (150 mL), and the mixture was stirred under N2 conditions at 60 °C for 3 hours. The mixture was diluted with H2O (1 L), acidified to pH ~4 with FA, and extracted with EtOAc (3 x 1 L). The combined organic extracts were washed with brine (3 x 800 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized with MTBE:DCM:MeOH (1000 mL: 100 mL: 10 mL). The precipitated solid was collected by filtration and washed with hexane (3 x 50 mL) to yield the title compound (15.03 g, 81.7%) as a gray solid. ES / MS m / z 421.30 [MH] - .

[0614] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compound was prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate. The extraction / washing / drying / crystallization steps can be omitted. The solid can also be washed with H₂O, hexanes, and PE. The solvent can also be 1,4-dioxane. The temperature varies from 50°C to 60°C.

[0615] Table 41 .

[0616] Preparation of 534 (3S)-3-[3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]azacyclobutan-1-yl]tert-butyl pyrrolidine-1-carboxylate TEA (196 mg, 1.94 mmol) and DMAP (7 mg, 0.06 mmol) were added to (S)-3-(3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azacyclobutane-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.64 mmol) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (346 mg, 0.97 mmol) in DCM (10.00 mL) at room temperature under N2. The reaction mixture was stirred at room temperature under N2 for 1 h and then concentrated under vacuum. The residue was purified by preparative TLC with 10% MeOH in DCM to provide the title compound (350 mg, 90%) as a pale yellow solid. ES / MS m / z 596.2 [M+H] + .

[0617] Preparation of 535 4-[4-(3-cyano-4-[[(2S)-1,1,1-trifluoropropane-2-yl]oxy]pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A stirred solution of (2R)-1,1,1-trifluoropropane-2-ol (150.00 mg, 1.32 mmol) and DIEA (509.87 mg, 3.95 mmol) in a DCM (5.00 mL) at 0 °C under N2 was treated with Tf2O (371.02 mg, 1.32 mmol), and the mixture was stirred at room temperature under N2 for 1 h. The mixture was then added directly to a stirred solution of 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.41 mmol) and K2CO3 (168.46 mg, 1.22 mmol) in a CAN (8.00 mL). The mixture was stirred at 80 °C under N2 for 5 h. The mixture was cooled to room temperature, the reactants were quenched with H₂O (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc 2:1) to yield the title compound (60 mg, 48.89%) as a pale yellow solid. ES / MS m / z 504.3 [M-tBu+H] +.

[0618] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate.

[0619] Table 42 .

[0620] Preparation of 537 (3S)-3-[3-[4-[3-cyano-4-[[(1R)-1-(2-pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]azacyclobutan-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester At room temperature, Cs₂CO₃ (765 mg, 2.35 mmol), XantPhos (68 mg, 0.11 mmol), and Pd₂(dba)₃ (53 mg, 0.05 mmol) were added to (3S)-3-[3-[4-[3-cyano-4-(trifluoromethanesulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]azacyclobutane-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (350 mg, 0.58 mmol) and (1R)-1-(pyridin-2-yl)ethylamine (358 mg, 2.93 mmol) in toluene (10 mL). The reaction mixture was stirred overnight at 100 °C under N₂. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (20:1 to 10:1) to provide the title compound (60 mg, 17%) as a green solid. ES / MS m / z 568.4 [M+H] + .

[0621] Preparation of 538 4-[4-[5-[(1R)-1-(5-fluoro-2-pyridinyl)ethoxy]-3-methyl-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester Cs₂CO₃ (1.42 g, 4.37 mmol) was added to tert-butyl 4-(4-{5-hydroxy-3-methylimidazo[1,2-a]pyridin-7-yl}-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylate (600.0 mg, 1.46 mmol) and (1S)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonic acid (382.66 mg, 1.75 mmol) in DMF (10.0 mL) at room temperature under N₂. The reaction mixture was stirred at 120 °C for 2 hours. After cooling to room temperature, the mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM / MeOH 20:1) to provide the title compound (240 mg, 30.8%) as a yellow solid. ES / MS m / z 536.3 [M+H] + .

[0622] Using appropriate reagents, adjusting the reaction time and temperature, and modifying the purification system as appropriate, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate.

[0623] Table 43 1 Methyl 2-(1-bromoethyl)benzoate was used as a starting material.

[0624] 2 Purified by reversed-phase chromatography, eluted with a gradient of 0% to 100% ACN in H2O.

[0625] 3 Purified by reversed-phase chromatography, eluted with a gradient of 10% to 100% ACN in H2O.

[0626] 4 Purified by preparative TLC 2:1 EtOAc:PE.

[0627] 5 Purified by preparative TLC 10:1 DCM:MeOH.

[0628] 6Purified by silica gel chromatography, eluted with a gradient of 0% to 20% MeOH in DCM.

[0629] Preparation of 546 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester To a solution of 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (45 mg, 0.08 mmol) in MeOH (5 mL), NaBH4 (3.7 mg, 0.098 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The residue was treated with EtOAc and H2O. The organic layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to provide the title compound (45 mg, 0.08 mmol) as a white solid. The crude product was used in the next step without further purification. ES / MS m / z 556.2 [M+H] + .

[0630] Using appropriate reagents, adjusting the reaction time and temperature, and modifying the purification system as needed, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate.

[0631] Table 44 .

[0632] Preparation of 548 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-hydroxy-propoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A solution of MeMgBr (3M in Et2O) (50.2 mg, 0.42 mmol) was added to a solution of 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (200 mg, 0.35 mmol) in THF (10 mL) at room temperature. After stirring at room temperature for 60 min, the reaction mixture was quenched with saturated NH4Cl, extracted with EtOAc (2X), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in heptane to provide the title compound (170 mg, 82.7%) as a white solid. ES / MS, m / z 586.4 [M+H] + .

[0633] Preparation of 549 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridinyl)-2-hydroxy-propoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester MeMgBr (3M solution) (58.2 mg, 0.49 mmol) was added to a solution of 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (180 mg, 0.33 mmol) in THF (8 mL) at room temperature, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then quenched with saturated NH4Cl, extracted into EtOAc (2X), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in heptane to provide the title compound (90 mg, 49%) as a white solid. ES / MS, m / z 570.4 [M+H] + .

[0634] Preparation of 550 4-(4-{4-[2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethoxy]-3-cyanopyrazolo[1,5-a]pyridin-6-yl}-5-methylpyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester DIAD (7.66 g, 37.87 mmol) was added dropwise to a stirred mixture of PPh3 (9.93 g, 97.87 mmol) in THF (30 mL) at 0 °C under N2. The reaction mixture was stirred at 0 °C under N2 for 0.5 h. 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (1.93 g, 7.10 mmol) and 4-(4-{3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl}-5-methylpyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (2 g, 4.73 mmol) in THF (20 mL) were added to the mixture. The resulting mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions: column, C18; elution with 80% to 100% ACN in H2O (0.1% NH4HCO3) to yield the title compound (2.7 g, 85.9%) as a white solid. ES / MS m / z 676.4 [M+H] + .

[0635] Preparation of 551 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester DIAD (568.36 mg, 2.811 mmol) was added dropwise to PPh3 (789.88 mg, 3.01 mmol) in THF (15 mL) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 0.5 h. 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.00 mmol) and 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (408.68 mg, 1.51 mmol) in THF (10 mL) were added to the mixture. After stirring at room temperature for 2 h, the reaction mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions: column, C18; elution with 70% to 80% ACN in H2O (0.1% NH4HCO3) to yield the title compound (450 mg, 68.77%) as a light brown oil. ES / MS m / z 652.4 [M+H] + .

[0636] Preparation of 552 4-(4-[3-cyano-5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester DEAD (185.1 mg, 1.06 mmol) was added to a stirred solution of PPh3 (278.7 mg, 1.06 mmol) in THF (5.0 mL) at 0 °C under N2. After stirring the mixture at 0 °C under N2 for 30 min, a solution of 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (150.0 mg, 0.35 mmol) and (1S)-1-(5-fluoropyridin-2-yl)ethanol (60.0 mg, 0.425 mmol) in THF (5.0 mL) was added to the mixture at room temperature under N2, and the mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 50% to 70% in H2O (0.1% NH4HCO3) to yield the title compound (80.0 mg, 41.3%) as a yellow solid. ES / MS m / z 547.2 [M+H] + .

[0637] Preparation of 553 4-[4-[3-cyano-5-[1-[5-(trifluoromethyl)-3-pyridinyl]ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester DIAD (334.25 mg, 1.65 mmol) was added dropwise to a stirred mixture of PPh3 (464.52 mg, 1.77 mmol) in THF (10 mL) at 0 °C under N2, and the mixture was stirred at 0 °C under N2 for 30 min. 1-[5-(trifluoromethyl)pyridin-3-yl]ethanol (135.42 mg, 0.71 mmol) and 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (250.00 mg, 0.59 mmol) in THF (20 mL) were added to the mixture. The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with 0 to 100% ACN in H2O (0.1% FA), yielding the title compound (150 mg, 42.59%) as a grayish-white solid. ES+H, m / z 596.9 [M+H] + .

[0638] Preparation of 554 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester DIAD (171.90 mg, 0.85 mmol) was added dropwise to a stirred mixture of PPh3 (241.55 mg, 0.92 mmol) in THF (10.00 mL) at 0 °C under N2. The mixture was stirred at 0 °C under N2 for 30 min, and then added to 1-(5-fluoropyridin-2-yl)-2-methoxyethanol (133.39 mg, 0.78 mmol) and 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (300.00 mg, 0.71 mmol) in THF (10 mL). The mixture was stirred at room temperature under N2 for 2 h and concentrated under vacuum. The residue was purified by reverse Combi-flash chromatography under the following conditions: elution with 55% to 60% ACN in H2O (0.1% NH4HCO3) to yield the title compound (160 mg, 39.17%) as a grayish-white solid. ES / MS m / z 577.3 [M+H] + .

[0639] Preparation of 555 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridinyl)propoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester DIAD (171.90 mg, 0.85 mmol) was added dropwise to a mixture of PPh3 (241.55 mg, 0.92 mmol) in THF (10.0 mL) at 0 °C under N2, and the mixture was stirred at 0 °C under N2 for 30 min. The mixture was then added to 1-(5-fluoropyridin-2-yl)propane-1-ol (120.92 mg, 0.78 mmol) and 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (300.00 mg, 0.71 mmol) in THF (10 mL). The mixture was stirred at room temperature under N2 for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse Combi-flash chromatography under the following conditions: elution with 55% to 60% ACN in H2O (0.1% NH4HCO3) to yield the title compound (210 mg, 52.87%) as a gray solid. ES / MS m / z 561.5 [M+H] + .

[0640] Preparation of 556 4-[4-[3-cyano-4-[1-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester DIAD (143.25 mg, 0.71 mmol) was added dropwise to a mixture of PPh3 (201.29 mg, 0.77 mmol) in THF (15.00 mL) at 0 °C under N2, and the mixture was stirred at 0 °C under N2 for 30 min. 1-(5-fluoropyridin-2-yl)-2-methoxyethanol (111.16 mg, 0.65 mmol) and 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (250.00 mg, 0.59 mmol) in THF (15 mL) were added to the mixture. The mixture was stirred at room temperature under N2 for 2 h and concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: elution with 55% to 60% ACN in H2O (0.1% NH4HCO3) to yield the title compound (200 mg, 58.75%) as a grayish-white solid. ES / MS m / z 577.1 + .

[0641] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compounds were prepared essentially as described regarding tert-butyl piperidine-1-carboxylate. DIAD, DIEA, and DMAP can also be used instead of DEAD. Temperatures varied from 0°C to 80°C. Polymer-supported PPh3 can be used instead of PPh3.

[0642] Table 45 1 Purified by silica gel column chromatography, eluted with a gradient of PE:EtOAc (2:1 to 1:1).

[0643] 2 Rapid chromatography, eluted with 71% PE in EtOAc.

[0644] 3 Purified by reverse Combi-flash chromatography on a C18 column, eluted with 80% to 100% ACN in H2O (0.1% NH4HCO3).

[0645] 4 Purified by reversed-phase chromatography on a C18 column, eluted with 70% to 80% ACN in H2O (0.1% NH4HCO3).

[0646] 5 Purified by reversed-phase chromatography on a C18 column, eluted with 50% to 60% ACN in H2O (0.1% NH4HCO3).

[0647] 6 Purified by reversed-phase chromatography using a C18 column and eluted with ACN in H2O.

[0648] 7 Purified by reversed-phase chromatography on a C18 column, eluted with 0% to 100% ACN in H2O.

[0649] 8 Purified by preparative TLC, eluted with a gradient of PE:EtOAc (1:1).

[0650] 9 Purified by reversed-phase chromatography on a C18 column, eluted with 10% to 100% ACN in H2O.

[0651] 10 Purified by silica gel column chromatography, eluted with a gradient of PE:EtOAc (8:1).

[0652] 11 Purified by reversed-phase chromatography on a C18 column, eluted with 45% to 50% ACN in H2O (0.1% FA).

[0653] 12 Purified by reversed-phase chromatography on a C18 column, eluted with 56% to 60% ACN in H2O (0.1% NH4HCO3).

[0654] 13 Purified by reversed-phase chromatography on a C18 column, eluted with 70% to 75% ACN in H2O (0.1% NH4OH).

[0655] 14 Purified by reversed-phase chromatography on a C18 column, eluted with 70% to 90% ACN in H2O (0.1% NH4HCO3).

[0656] 15 Purified by reversed-phase chromatography on a C18 column, eluted with 80% to 100% ACN in H2O (0.1% NH4HCO3).

[0657] 16 Purified by preparative TLC and eluted with EtOAc.

[0658] 17 Purified by silica gel column chromatography, eluted with PE:EtOAc (5:1 to 2:1).

[0659] 18 Purified by preparative TLC, eluted with a gradient of PE:EtOAc (2:1).

[0660] 19 Purified by reversed-phase chromatography on a C18 column, eluted with 0% to 100% ACN in H2O (0.1% FA).

[0661] 20 Purified by reversed-phase chromatography on a C18 column, eluted with 60% to 70% ACN in H2O (0.1% NH4HCO3).

[0662] 21 Purified by reversed-phase chromatography on a C18 column, eluted with 30% to 50% ACN in H2O (0.1% NH4OH).

[0663] 22 Purified by reversed-phase chromatography on a C18 column, eluted with 20% to 60% ACN in H2O (NH4HCO3).

[0664] 23 Purified by silica gel column chromatography, eluted with a gradient of DCM:MeOH (9:1).

[0665] 24Purified by silica gel column chromatography, eluted with 10% to 50% EtOAc in PE.

[0666] 25 Purified by reversed-phase chromatography on a C18 column, eluted with 10% to 50% ACN in H2O (0.1% FA).

[0667] 26 Purified by reversed-phase chromatography on a C18 column, eluted with 10% to 50% ACN in H2O (0.1% NH4HCO3).

[0668] 27 Purified by reversed-phase chromatography on a C18 column, eluted with 30% to 45% ACN in H2O (0.1% NH3H2O).

[0669] 28 Purified by reversed-phase chromatography on a C18 column, eluted with 0% to 100% ACN in H2O (0.1% NH4HCO3).

[0670] 29 Purified by reversed-phase chromatography on a C18 column, eluted with 10% to 70% ACN in H2O (0.1% NH4HCO3).

[0671] 30 Purified by reversed-phase chromatography on a C18 column, eluted with 40% to 80% ACN in H2O (0.05% NH4HCO3).

[0672] 31 Purified by reversed-phase chromatography on a C18 column, eluted with 45% to 50% ACN in H2O (0.1% NH4HCO3).

[0673] 32 Purified by reversed-phase chromatography on a C18 column, eluted with 50% to 70% ACN in H2O (0.1% FA).

[0674] 33 Purified by reversed-phase chromatography on a C18 column, eluted with 30% to 50% ACN in H2O (0.1% NH4HCO3).

[0675] 34 Purified by reversed-phase chromatography on a C18 column, eluted with 25% to 50% ACN in H2O (0.1% NH4OH).

[0676] 35 Purified by reversed-phase chromatography using a C18 column, eluted with ACN in H2O (0.1% FA).

[0677] 36 Purified by silica gel chromatography, eluted with EtOAc:heptane.

[0678] 37 Purification was performed by reverse Combi-flash chromatography on a C18 column, eluting with 55% to 60% ACN in H2O (0.1% NH4HCO3).

[0679] 38 Purified by reversed-phase chromatography on a C18 column, eluted with 40% to 50% ACN in H2O.

[0680] 39 Purified by reversed-phase chromatography on a C18 column, eluted with 10% to 50% ACN in H2O.

[0681] 40 Purified by reversed-phase chromatography on a C18 column, eluted with 0% to 50% ACN in H2O.

[0682] 41 Purified by reversed-phase chromatography on a C18 column, eluted with 10% to 100% ACN in H2O.

[0683] 42 Purified by silica gel column chromatography, eluted with a gradient of PE:EtOAc (4:1 to 3:1).

[0684] 43 Purified by reversed-phase chromatography on a C18 column, eluted with 85% to 95% ACN in H2O (0.1% FA).

[0685] 44 Purified by silica gel column chromatography, eluted with a gradient of PE:EtOAc (1:1).

[0686] 45 Purified by reversed-phase chromatography on a C18 column, eluted with 60% to 90% ACN in H2O.

[0687] 46 Purified by reversed-phase chromatography on a C18 column, eluted with 85% to 95% ACN in H2O (0.1% NH4HCO3).

[0688] 47 Purified by reversed-phase chromatography on a C18 column, eluted with 50% to 55% ACN in H2O (0.1% NH4HCO3).

[0689] 48 Purified by silica gel column chromatography, eluted with a gradient of 0% to 100% acetone in DCM.

[0690] a 1 H NMR (400 MHz, CDCl3) δ 1.49 - 1.54 (m, 9 H), 1.91 - 1.97 (m, 3H), 2.00 (s, 3 H), 2.20 - 2.33 (m, 2 H), 2.43 - 2.49 (m, 3 H), 2.89 - 3.01(m, 2 H), 3.25 - 3.34 (m, 4 H), 3.93 - 4.01 (m, 3 H), 4.25 - 4.37 (m, 3 H),5.78 - 5.88 (m, 1 H), 7.35 - 7.42 (m, 1 H,) 8.13 - 8.18 (m, 2 H), 8.18 - 8.24(m, 1 H), 8.48 - 8.54 (m, 1 H).

[0691] b 1 H NMR (400 MHz, CDCl3) δ 0.00 (br s, 6 H) 0.81 (br s, 9 H) 1.39 (brs, 9 H) 1.71 - 1.83 (m, 3 H) 1.92 (br d, J=15.53 Hz, 3 H) 2.08 - 2.21 (m, 2H) 2.26 (br s, 3 H) 2.77 - 2.95 (m, 2 H) 3.91 - 4.12 (m, 2 H) 4.15 - 4.33 (m,4 H) 4.39 - 4.52 (m, 1 H) 4.68 - 4.79 (m, 1 H) 5.43 - 5.54 (m, 1 H) 6.85 -6.99 (m, 1 H) 7.79 - 7.94 (m, 1 H) 8.05 - 8.17 (m, 1 H) 8.22 - 8.37 (m, 2 H).

[0692] Preparation of 675 (3R)-3-(3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azacyclobutane-1-yl)tert-butyl pyrrolidine-1-carboxylate A stirred mixture of (R)-3-(3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azacyclobutan-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.64 mmol) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (346 mg, 0.97 mmol) in DCM (10.00 mL) was treated with TEA (196.00 mg, 1.94 mmol) and DMAP (7.00 mg, 0.06 mmol) and stirred at room temperature under N2 for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with a DCM:MeOH (10:1) gradient to yield the title compound (350 mg, 90.8%) as a pale yellow oil. ES / MS m / z 596.3 [M+H] + .

[0693] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compound was prepared essentially as described regarding (R)-3-(3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azacyclobutan-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester. DMF can also be used as a solvent, and DIEA can be used as a base. The temperature varied from 0°C to room temperature.

[0694] Table 46 1 Purified using a C18 column by reverse Combi-flash chromatography; eluted with 70-75% ACN in H2O.

[0695] 2 Purified by reversed-phase rapid chromatography using a C18 column, eluted with 60-70% ACN in H2O (1% NH4HCO3).

[0696] 3 Purified by silica gel column chromatography, eluted with PE:EtOAc (10:1).

[0697] Preparation of 679 (3R)-3-[4-(3-cyano-4-[[(1R)-1-(pyridin-2-yl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester A stirred mixture of (3R)-3-[4-[3-cyano-4-(trifluoromethanesulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (102.00 mg, 0.19 mmol) and (1R)-1-(pyridin-2-yl)ethylamine (27.67 mg, 0.23 mmol) in toluene (20.00 mL) was treated with the fractionally added Cs₂CO₃ (184.45 mg, 0.57 mmol), Xantphos (65.51 mg, 0.11 mmol), and Pd₂(dba)₃ (86.40 mg, 0.094 mmol). The mixture was stirred at 80 °C for 4 hours under N₂. The solution was cooled to room temperature, filtered, and the filter cake was washed with EtOAc (5 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: C18 silica gel; H₂O (0.1% NH₄HCO₃) in ACN, eluted with a gradient of 70% to 80%. The mixture was concentrated under reduced pressure to yield the title compound (50 mg, 51.69%) as a white solid. ES / MS m / z 513.3 [M+H] + .

[0698] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compounds were prepared essentially as described with respect to (3R)-3-[4-(3-cyano-4-[[(1R)-1-(pyridin-2-yl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester. The catalyst may also be Pd(OAc)₂, Pd(dba)₂. The temperature varied from 80°C to 100°C.

[0699] Table 47 1 After cooling the mixture to room temperature, it was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH (20:1).

[0700] 2 Prior to purification, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure.

[0701] 3Purified by silica gel column chromatography, eluted with DCM:MeOH (20:1).

[0702] 4 Purified by preparative TLC PE:EtOAc (1:1).

[0703] Preparation of 684 7-((1s,3s)-3-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester, isomer 2 A solution of (1S,3r)-3-(4-(4-((S)-2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutane-1-ol (190 mg, 0.33 mmol) and DIPEA (214 mg, 1.66 mmol) in DCM (4.0 ml) was treated with (CF3SO2)2O (1.40 g, 0.50 mmol). The reaction mixture was stirred at -78°C for 15 minutes. The reactants were then treated with a solution of DIPEA (214 mg, 1.66 mmol) and 9-boc-3-oxa-7,9-diazabicyclo[3.3.1]nonane (151 mg, 0.66 mmol) in DCM (4 mL). The mixture was heated to 40 °C and held for 16 hours. The reactants were then cooled to room temperature and stirred for 2 days. The reactants were diluted with H2O and then extracted with 4:1 DCM:IPA. The layers were separated, and the organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in DCM to provide the title compound (100 mg, 38.5%) as a yellowish-brown solid. ES / MS m / z 783.4 [M+H] + .

[0704] Preparation of 685 4-[4-[3-cyano-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridinyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester K₂CO₃ (587.45 mg, 4.25 mmol) was added to tert-butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylate (600.00 mg, 1.42 mmol) and ethyl 2,2,2-trifluoro-1-(5-fluoropyridin-2-yl)trifluoromethanesulfonic acid (0.927 g, 2.83 mmol) in ACN (5.00 mL) at room temperature under N₂. The resulting mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18; elution with an ACN gradient of 50% to 60% in water (0.1% NH4HCO3); UV 254 nm, to provide the title compound (450 mg, 52.88%) as a white solid. ES / MS m / z 601.3 [M+H] + .

[0705] Preparation of 686 4-(4-[3-cyano-4-[2,2,2-trifluoro-1-(oxacyclohexane-4-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester A stirred solution of 2,2,2-trifluoro-1-(oxacyclohexane-4-yl)ethyl trifluoromethanesulfonate (204.12 mg, 0.65 mmol) and K₂CO₃ (267.64 mg, 1.94 mmol) in ACN (5.00 mL) under N₂ at room temperature was treated with tert-butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-carboxylate (300.00 mg, 0.71 mmol), and the mixture was stirred under N₂ at 80 °C for 3 hours. The solution was filtered, the filter cake was washed with DCM (2 x 10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; ACN in H2O, eluted with a gradient of 60% to 65% to yield the title compound (320 mg, 84.22%) as a yellow solid. ES / MS m / z 589.1 [M+H] + .

[0706] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as needed, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate. The filter cake can also be washed with EtOAc.

[0707] Table 48 1 After stirring, the solution was cooled to room temperature, diluted with EtOAc (50 mL), washed with saline (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure.

[0708] 2 Purification by reversed-phase chromatography: column, C18; eluted with 55% to 60% ACN in H2O (0.1% NH4HCO3).

[0709] Preparation of 690 4-[4-[4-[(1R)-1-(2-cyanophenyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A mixture of 4-(4-[4-[(1R)-1-(2-bromophenyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (550 mg, 0.94 mmol), Zn(CN)2 (334 mg, 2.84 mmol), Zn (62 mg, 0.95 mmol), X-Phos (226 mg, 0.47 mmol), and Pd2(dba)3 (434 mg, 0.47 mmol) in DMA (100 mL) was stirred overnight at 100 °C under N2. After cooling to room temperature, the reaction mixture was extracted with EtOAc (500 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography, eluting with 10% to 100% EtOAc in PE to provide the title compound as a yellow solid (390 mg, 78%). ES / MS m / z 527.3 [M+H] + .

[0710] Preparation of 691 4-[4-[3-cyano-4-((1S)-2,2,2-trifluoro-1-phenyl-ethoxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (250 mg, 590 μmol), (R)-2,2,2-trifluoro-1-phenylethane-1-ol (208 mg, 1.18 mmol), PPh3 (310 mg, 1.18 mmol), DCM (4 mL), and (E)-diazepine-1,2-dicarboxylic acid di-tert-butyl ester (299 mg, 1.30 mmol) were added sequentially, and the mixture was stirred at 50 °C for 2 hours. The mixture was concentrated and diluted with NMP. The residue was purified by preparative HPLC with a gradient elution of ACN:H₂O (10–90%, 0.5% HCl) to yield the title compound as a white solid (94 mg, 0.14 mmol, 23%). ES / MS m / z 582.4 [M+H] + .

[0711] Preparation of 692 4-[4-[4-[(1R)-1-(5-fluoro-2-pyridinyl)ethoxy]-3-formyl-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester Under N2 conditions, ZnCl2 (56.1 mg, 0.41 mmol) and NaH (32.9 mg, 60 wt%, 0.82 mmol) in a sealed tubular flask were mixed with (R)-4-(4-(3-cyano-4-(1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (150 mg, 0.27 mmol) in 3 mL of THF. The reaction mixture was stirred at 40 °C for 1.5 hours. At this point, additional ZnCl2 (56.1 mg, 0.41 mmol) and NaH (32.9 mg, 60 wt%, 0.82 mmol) were added, and stirring was continued at 40 °C for 1.5 hours. The reactants were cooled to 0°C, and silica gel (1.0 g) was added. The mixture was diluted with hexane (5 mL) and stirred at room temperature for 1 hour. The suspension was filtered, washed with EtOAc, then with 20% MeOH in DCM, and concentrated under vacuum. The residue was purified by reversed-phase C18 chromatography, eluting with a linear gradient of 10% to 100% ACN in H2O to provide the title compound (30 mg, 20%) as a grayish-white solid. ES / MS 550.8 m / z [M+H] + .

[0712] Preparation of 693 4-[4-[4-[(1R)-1-(5-fluoro-2-pyridinyl)ethoxy]-3-(hydroxymethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester At room temperature, NaBH4 (2.8 mg, 0.07 mmol) was added to a solution of (R)-4-(4-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3-carboxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.04 mmol) in MeOH (3 mL). After stirring for 10 min, the reaction mixture was concentrated under vacuum. The residue was suspended in EtOAC and H2O, and the layers were separated. The aqueous layer was extracted with EtOAC (2X). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was used for subsequent steps without further purification. ES / MS 553.8 m / z [M+H] + .

[0713] Preparation of 694 3-[4-[3-chloro-5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]azacyclobutane-1-carboxylic acid tert-butyl ester Under N2 conditions at room temperature, 1,3-dichloro-5,5-dimethylimidazoline-2,4-dione (41.43 mg, 0.21 mmol) was added to 3-[5-methyl-4-[5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]triazol-1-yl]azacyclobutane-1-carboxylic acid tert-butyl ester (200.00 mg, 0.421 mmol) in DMF (2.00 mL). The reaction mixture was stirred at room temperature for 2 hours, quenched with H2O (10 mL), and extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative TLC (5% MeOH in DCM) to provide the title compound (140 mg, 65.27%) as a yellow solid. ES / MS m / z 510.0 [M+H] + .

[0714] Preparation of 695 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A mixture of 4-(4-{4-[(1R)-2-[(tert-butyldimethylsilyl)oxy]-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl}-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (770 mg, 1.22 mmol) and NCS (146 mg, 1.09 mmol) in DCM (10 mL) was stirred for 3 hours at room temperature under N2. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 50% PE in EA to provide the title compound (700 mg, 86.22%) as a pale yellow solid. ES / MS, m / z668.4 [M+H] + .

[0715] Preparation of 696 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridinyl)ethoxy]-3-chloro-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A mixture of tert-butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridinyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylate (1 g, 1.53 mmol) in DCM (10 mL) was stirred at room temperature under N2 for 2 h. The reaction mixture was quenched with H2O (20 mL) and then extracted with DCM (2 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:1–1:1) to provide the title compound (460 mg, 43.69%) as a grayish-white solid. ES / MS m / z 686.3 [M+H] + .

[0716] Preparation of 697 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridinyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester NCS (64.22 mg, 0.481 mmol) was added to tert-butyl piperidine-1-carboxylate (330 mg, 0.51 mmol) in DCM (5 mL) at room temperature under N2. The reaction mixture was concentrated under vacuum, and the residue was purified by reversed-phase chromatography under the following conditions: column, C18; elution with 65% to 75% ACN in H2O (0.1% FA) to yield the title compound (185 mg, 53.25%) as a pale yellow oil. ES / MS m / z 686.0 [M+H]+ .

[0717] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to tert-butyl piperidine-1-carboxylate.

[0718] Table 49 1 Purification was performed by reversed-phase chromatography under the following conditions: column, C18; elution with 70% to 80% ACN in H2O (0.1% NH4HCO3).

[0719] 2 Purification was performed by reversed-phase chromatography under the following conditions: column, C18; elution with 10% to 100% ACN in H2O.

[0720] 3 Purified by silica gel chromatography, eluted with 0% to 100% EtOAc in DCM.

[0721] 4 Purified by silica gel chromatography, eluted with PE:EA (1:2).

[0722] 5 Purified by preparative TLC PE:EA (2:1).

[0723] 6 Purified by silica gel chromatography, eluted with PE:EA (1:1:1:2).

[0724] 7 Purified by preparative TLC PE:EA (1:1).

[0725] Preparation of 714 4-[4-[3-cyano-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-c]pyrimidin-7-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 4-[4-[5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-iodo-imidazo[1,2-c]pyrimidin-7-yl]-5-methyl-pyrazol-1-yl]piperidin-1-carboxylate (74.0 mg, 0.11 mmol) and CuCN (11.0 mg, 0.13 mmol) in DMF (2.5 mL) was stirred at 100 °C for 1 hour. After cooling to room temperature, the reaction mixture was quenched with aqueous NH4OH and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0% to 100% EtOAc in DCM to provide the title compound (57 mg, 91%) as a colorless foam. ES / MS m / z 547.2 [M+H] + .

[0726] Preparation of 715 4-[4-[3-cyano-4-[1-[2-(1-hydroxy-1-methyl-ethyl)phenyl]ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A solution of MeMgBr (178 mg, 3 mol, 1.50 mmol) in THF was added dropwise to a solution of tert-butyl piperidine-1-carboxylate (292 mg, 0.50 mmol) in THF (3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours.

[0727] H2O (3 mL) was slowly added, and the mixture was allowed to warm to room temperature. The mixture was diluted with DCM (20 mL) and H2O (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (20 mL). The combined organic layers were concentrated under vacuum. The residue was purified by reversed-phase chromatography, eluting with an ACN gradient from 0% to 100% in H2O to provide the title compound (192 mg, 65.7%). ES / MS m / z 585.8 [M+H] + .

[0728] Preparation of 716 2-[1-[6-[1-(1-tert-butoxycarbonyl-4-piperidinyl)-5-methyl-triazol-4-yl]-3-cyano-pyrazolo[1,5-a]pyridin-4-yl]oxyethyl]benzoic acid An aqueous solution of LiOH (112 mg, 4.68 mmol) was added to tert-butyl piperidine-1-carboxylate (274 mg, 468 μmol) in THF (12 mL), and the mixture was stirred for 3 hours. The pH was adjusted to 5 using an aqueous solution of HCl (0.1 M), and then EtOAc (10 mL) was added. The layers were separated, and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum to provide the title compound (260 mg, 97.2%). ES / MS m / z 572.2 [M+H] + .

[0729] Preparation of 717 4-[4-[4-[1-(2-carbamoylphenyl)ethoxy]-3-cyano-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester T3P (868 mg, 50 wt%, 1.36 mmol) in DMF was added to 2-(1-((6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)benzoic acid (260 mg, 455 μmol) and NH4Cl (122 mg, 2.27 mmol) in DMF, followed by DIEA (588 mg, 4.55 mmol), and the reaction mixture was stirred for 3 hours. The mixture was diluted with DCM (10 mL) and H2O (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 x 10 mL) and the combined organic matter was concentrated under vacuum. The residue was purified by reversed-phase chromatography, eluting with 0% to 100% ACN in H2O to provide the title compound (80 mg, 31%). ES / MS m / z 571.3 [M+H] + .

[0730] Preparation of 718 4-[4-[4-[(1R)-1-(5-fluoro-2-pyridinyl)ethoxy]-3-isothiazolyl-4-yl-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester A mixture of tert-butyl piperidine-1-carboxylate (600 mg, 0.93 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,2-thiazole (293 mg, 1.39 mmol), CsF (422 mg, 2.78 mmol), and Pd(DtBPF)Cl2 (60.39 mg, 0.09 mmol) in dioxane (4 mL) was stirred at 60 °C for 3 hours under N2. The reaction mixture was concentrated under vacuum. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reversed-phase chromatography under the following conditions: column, C18; mobile phase, eluted with a linear gradient of 30% to 50% ACN in H₂O, to provide the title compound (400 mg, 71.4%) as a white solid. ES / MS m / z 605.5 [M+H] + .

[0731] Preparation of 719 7-[1-(azacyclobutane-3-yl)-5-methyl-triazol-4-yl]-3-chloro-5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridine. TFA TFA (1.00 mL) was added to a stirred solution of 3-(4-[3-chloro-5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (140.00 mg, 0.28 mmol) in DCM (2.00 mL) under N2 at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to provide the title compound (120 mg, crude product) as a yellow solid, which was used without further purification. ES / MS m / z 410.0 [M+H] + .

[0732] Preparation of 720 4-[1-(5-fluoro-2-pyridinyl)-2-hydroxyethoxy]-6-[5-methyl-1-(4-piperidinyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxynitrile. HCl A mixture of tert-butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridinyl)ethoxy]-3-cyano-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]piperidin-1-carboxylate (2.7 g, 4.00 mmol) in DCM (50 mL) and 4 M HCl / 1,4-dioxane (25 mL) was stirred at room temperature under N2 for 1 hour. The resulting mixture was concentrated under vacuum to yield the title compound (2.3 g, crude, HCl salt), which was used without further purification. ES / MS m / z 462.2 [M+H] + .

[0733] Preparation of 721 2-[3-chloro-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridinyl)ethanol. HCl A solution of tert-butyl piperidine-1-carboxylate (175 mg, 0.26 mmol) in DCM (3 mL) and 4 M HCl / 1,4-dioxane (1.5 mL) was stirred at room temperature under N2 for 1 hour. The resulting mixture was concentrated under vacuum to yield the title compound (165 mg), which was used without further purification. ES / MS m / z 472.2 [M+H] + .

[0734] Preparation of 722 2-[3-chloro-7-[5-methyl-1-(4-piperidinyl)triazol-4-yl]imidazo[1,2-a]pyridin-5-yl]oxy-2-(5-fluoro-2-pyridinyl)ethanol. HCl To 450 mg (0.66 mmol) of 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridinyl)ethoxy]-3-chloro-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester in DCM (4 mL), 4 M HCl / 1,4-dioxane (4 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under vacuum to provide the title compound (300 mg, HCl salt), which was used without further purification. ES / MS m / z 472.2 [M+H] + .

[0735] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to 2-[3-chloro-7-[5-methyl-1-(4-piperidinyl)triazol-4-yl]imidazo[1,2-a]pyridin-5-yl]oxy-2-(5-fluoro-2-pyridinyl)ethanol HCl. For compounds in which the amine salt is isolated, the formation of the monovalent, divalent, or trivalent salt depends on the pKa of the amine and the acid used to form the salt. The exact monovalent, divalent, or trivalent salt forms of each example were not identified.

[0736] Table 50 .

[0737] Preparation of 746 7-[5-methyl-1-(4-piperidinyl)triazol-4-yl]-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridinyl)ethoxy]imidazo[1,2-a]pyridine-3-carboxynitrile. HCl 4M HCl / 1,4-dioxane (2 mL) was added to a stirred solution of 4-[4-[3-cyano-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridinyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (450.00 mg, 0.75 mmol) in DCM (5.00 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum to provide the title compound (300 mg). The title compound was used without further purification. ES / MS m / z 501.2 [M+H]+ .

[0738] Preparation of 747 5-Methoxy-7-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine-3-carboxynitrile.HCl A solution of tert-butyl piperidine-1-carboxylate (450.00 mg, 1.03 mmol), DCM (10 mL), and HCl (4 M) in 1,4-dioxane (10.00 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with EtOAc (3 mL) and hexane (20 mL), and stirred for 5 min. The solid was collected by filtration, and the filter cake was washed with hexane (2 x 10 mL) and lyophilized to yield the title compound (110 mg, 28.6%) as a brown solid. ES / MS m / z 338.0 [M+H] + .

[0739] Preparation of 748 4-Isopropoxy-6-[5-methyl-1-[piperidin-4-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxylonitrile. TFA 4-[4-(3-cyano-4-isopropoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (75 mg, 0.16 mmol) was stirred in TFA (1 mL) at room temperature for 30 min. The mixture was concentrated to dryness to yield the title compound (54.2 mg, 92.12%), which was used without further purification. ES / MS m / z 365.2 [M+H] + Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to 4-isopropoxy-6-[5-methyl-1-[piperidin-4-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxynitrile. Temperatures varied from room temperature to 50°C. The mixture could also be quenched with a saturated aqueous solution of Na₂CO₃ and extracted with EtOAc. For compounds in which the amine salt is separated, the formation of monovalent, divalent, or trivalent salts depends on the pKa of the amine and the acid used to form the salt. The exact monovalent, divalent, or trivalent salt forms of each example were not identified.

[0740] Table 51 1 Reverse Combi-flash chromatography was performed under the following conditions: C18; elution with a gradient of 50-70% ACN in H2O (0.1% FA).

[0741] Preparation of 757 6-[1-(azacyclobutan-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylonitrile.FA A solution of tert-butyl 3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azacyclobutane-1-carboxylate (480 mg, 1.18 mmol) and TFA (20 mL) in DCM (20 mL) was stirred at room temperature under N2 for 30 min. The mixture was concentrated under reduced pressure. The pH of the residue was adjusted to pH 8 with a saturated aqueous solution of NaHCO3 and extracted with DCM:iPrOH (3:1) (3 x 100 mL). The combined organic extracts were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse Combi-flash chromatography under the following conditions: column, C18; elution with an ACN gradient of 0% to 30% in H2O (0.1% FA) to produce the title compound (210 mg, 57%) as a white solid. ES / MS m / z 309.05 [M+H] + .

[0742] Preparation of 758 5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]-7-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine-3-carboxynitrile.HCl A stirred solution of tert-butyl piperidine-1-carboxylate (70.0 mg, 0.128 mmol) in DCM (3.0 mL) was treated with 4 M HCl / 1,4-dioxane (1.0 mL) and stirred at room temperature under N2 for 30 min. The mixture was concentrated under reduced pressure and washed with EtOAc (3 x 20 mL) to yield the title compound (95 mg, crude) as a yellow solid. ES / MS m / z 447.2 [M+H] + .

[0743] Preparation of 759 6-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carboxynitrile. TFA A solution of tert-butyl piperidine-1-carboxylate (354 mg, 0.67 mmol) and TFA (1 mL) was stirred at room temperature under N2 for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by grinding with MTBE (5 mL). The precipitated solid was collected by filtration and washed with MTBE (2 x 2 mL) to yield the title compound (456 mg) as a brown solid, which was used directly without further purification. ES / MS m / z 429.3 [M+H] + .

[0744] Preparation of 760 7-[5-methyl-1-(4-piperidinyl)triazol-4-yl]-5-[1-[5-(trifluoromethyl)-3-pyridinyl]ethylamino]imidazo[1,2-a]pyridine-3-carboxylonitrile.TFA A solution of tert-butyl piperidine-1-carboxylate (150.00 mg, 0.251 mmol), TFA (5 mL), and DCM (10 mL) was stirred at room temperature under N2 for 1 hour. The mixture was concentrated under reduced pressure to yield the title compound. m / z 497.3 [M+H] + .

[0745] Preparation of 761 5-[1-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]-7-[5-methyl-1-(4-piperidinyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carboxynitrile.TFA A mixture of 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (150.00 mg, 0.26 mmol) in TFA (2.00 mL) and DCM (4.00 mL) was stirred at room temperature under N2 for 1 hour. The mixture was concentrated under reduced pressure to obtain the title compound, which was used directly without further purification (140 mg). ES / MS m / z 477.2 [M+H] + .

[0746] Preparation of 762 5-[1-(5-fluoro-2-pyridinyl)propoxy]-7-[5-methyl-1-(4-piperidinyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carboxynitrile.HCl A mixture of 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridinyl)propoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (200.00 mg, 0.36 mmol) in 4 M HCl (gas) / 1,4-dioxane (2.00 mL) and DCM (3.00 mL) was stirred at room temperature under N2 for 1 hour. The mixture was concentrated under reduced pressure to yield the title compound (200 mg), which was used directly without further purification. ES / MS m / z 461.3[M+H] + .

[0747] Preparation of 763 4-[1-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carboxynitrile.HCl A mixture of 4-[4-[3-cyano-4-[1-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidin-1-carboxylic acid tert-butyl ester (180.00 mg, 0.31 mmol) in 4 M HCl (gas) / 1,4-dioxane (2.00 mL) and DCM (4.00 mL) was stirred at room temperature under N2 for 1 hour. The mixture was concentrated under reduced pressure to yield the title compound (160 mg), which was used directly without further purification. ES / MS m / z 477.2 [M+H] + .

[0748] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to 4-[1-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-3-carboxynitrile.HCl. TFA and trifluoroacetaldehyde can be substituted for HCl. The precipitated solid can also be ground with Et2O and DCM. For compounds in which the amine salt is separated, the formation of monovalent, divalent, or trivalent salts depends on the pKa of the amine and the acid used to form the salt. The exact monovalent, divalent, or trivalent salt forms of each example have not been identified.

[0749] Table 52 a The material is used in the next step without further purification.

[0750] Preparation of 833 4-Methoxy-6-(5-methyl-1-[1-[(3S)-pyrrolidone-3-yl]pyridin-290-3-yl]pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile A mixture of (3S)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-ylpyridin-290-1-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (190 mg, 0.42 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield the title compound (260 mg) as a dark green oil. The pH of the crude product (60 mg) was adjusted with NaHCO3 and purified by preparative HPLC under the following conditions: column, Xbridge Shield RP18 OBD, 19*150 mm, 5 μm; elution with a gradient of 20% to 35% ACN in H2O (10 mmol / L NH4HCO3), flow rate: 25 mL / min; t (R) 5.57 min, to produce the title compound (20 mg, 12.7%) as a white solid. ES / MS m / z 378.3 [M+H] + .

[0751] Using appropriate reagents, adjusting the reaction time to determine the end of the reaction, and adjusting the purification system as appropriate, the following compounds were prepared essentially as described with respect to (S)-4-methoxy-6-(5-methyl-1-[1-[(3S)-pyrrolidine-3-yl]pyridin-290-3-yl]pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-carboxynitrile. The crude product can also be dissolved in MeOH, and Na₂CO₃ can also be used as an alternative base. 2,6-dimethylpyridine in DCM can also be used as a base and solvent combination. HCl in 1,4-dioxane can also be used instead of TFA. For compounds in which the amine salt is isolated, the formation of the monovalent, divalent, or trivalent salt depends on the pKa of the amine and the acid used to form the salt. The exact monovalent, divalent, or trivalent salt forms of each example have not been identified.

[0752] Table 53 1Preparative HPLC was performed under the following conditions: column, Xbridge Prep C18 OBD, 19*150 mm, 5 μm; eluted with 38-50% MeOH in H2O (0.05% NH3H2O).

[0753] 2 Reverse Combi-flash chromatography was performed under the following conditions: column, C18, eluted with a gradient of 30-60% ACN in H2O (0.1% NH3H2O).

[0754] 3 Reversed-phase chromatography, eluted with a gradient of 0-100% ACN in H2O.

[0755] 4 Purification by reverse rapid chromatography: column, C18; elution with 50% to 55% ACN in H2O (0.1% NH4OH), gradient of 50% to 55%.

[0756] 5 The reactants were mixed with CHCl3 at a ratio of 3:1. i PrOH was diluted and concentrated under vacuum. The residue was dissolved in a 4:1 DCM solution. i In PrOH, the solution is washed with NaHCO3, then with H2O and brine, dried with Na2SO4, filtered, and concentrated.

[0757] 6 Reversed-phase C18 chromatography, eluted with 10% to 95% ACN in H2O.

[0758] 7 Reversed-phase C18 chromatography, eluted with 10% to 100% ACN in H2O.

[0759] 8 Remove volatiles and filter the residue through a carbonate filter.

[0760] 9 The reactants were quenched by adding an aqueous solution of NaHCO3, and the mixture was extracted with DCM.

[0761] 10 Purification by reversed-phase chromatography: column, C18; eluted with 50% to 60% ACN in H2O (0.1% NH4HCO3).

[0762] 11 Purification by reversed-phase chromatography: column, C18; eluted with 0% to 50% ACN in H2O (0.1% FA).

[0763] 12The reactants were concentrated under vacuum. The residue was dissolved in a 3:1 CHCl3:IPA solution, washed with NaHCO3 aqueous solution, H2O, and brine, dried over Na2SO4, filtered, and concentrated.

[0764] Preparation of 847 5-Methoxy-7-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine-3-carboxynitrile.HCl A solution of tert-butyl piperidine-1-carboxylate (450.00 mg, 1.03 mmol), DCM (10 mL), and HCl (4 M) in 1,4-dioxane (10.00 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with EtOAc (3 mL) and hexane (20 mL), and stirred for 5 min. The solid was collected by filtration, and the filter cake was washed with hexane (2 x 10 mL) and lyophilized to yield the title compound (110 mg, 28.6%) as a brown solid. ES / MS m / z 338.0 [M+H] + .

[0765] Preparation of 848 6-[1-[1-(azacyclobutan-3-yl)piperidin-4-yl]-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile TFA (2 mL) was added dropwise to a stirred solution of 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]azacyclobutane-1-carboxylic acid tert-butyl ester (100.00 mg, 0.20 mmol) in DCM (2.00 mL), and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to yield the title compound (120 mg, crude product). The product was used directly without further purification. ES / MS m / z 392.2 [M+H] + .

[0766] Using appropriate reagents and adjusting the reaction time to determine the end of the reaction, the following compounds were prepared essentially as described with respect to 6-[1-[1-(azacyclobutan-3-yl)piperidin-4-yl]-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile. 2,6-Dimethylpyridine in DCM can also be used as a solvent. HCl or TMSOTf in 1,4-dioxane can also be used instead of TFA. For compounds in which the amine salt is isolated, the formation of the monovalent, divalent, or trivalent salt depends on the pKa of the amine and the acid used to form the salt. The exact monovalent, divalent, or trivalent salt form of each example has not been identified.

[0767] Table 54 1 The crude product was recrystallized from EtOAc:PE (40:40 mL).

[0768] 2 Purification was performed by reverse Combi-flash chromatography under the following conditions: column, C18; elution with a gradient of 20-30% ACN in H2O (0.1% HCl).

[0769] 3 The crude product was recrystallized from EtOAc.

[0770] 4 The mixture was filtered, and the filter cake was washed with EtOAc.

[0771] 5 The crude product was ground together with DCM.

[0772] 6 The crude product was concentrated and recrystallized from EtOAc:MTBE.

[0773] 7The reactants were quenched at room temperature by adding saturated NH4Cl (10.0 mL), and the mixture was extracted with CHCl3 and iPrOH (3:1, 3 x 30 mL).

[0774] 8 The crude product was ground in MTBE:EtOAc (5:1) and collected by filtration.

[0775] 9 The mixture was washed with Et2O.

[0776] 10 The crude product was recrystallized from MeOH / EtOAc.

[0777] 11 The reactants were diluted with MTBE and filtered to collect the title compound as a pale yellow solid.

[0778] 12 Reversed-phase chromatography, eluted with a gradient of 0-100% ACN in H2O.

[0779] Preparation of 923 5-[(1R)-1-(2-fluorophenyl)ethoxy]-7-[5-methyl-1-(4-piperidinyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carboxynitrile Under a nitrogen atmosphere at room temperature, tert-butyl piperidine-1-carboxylate (110 mg, 0.20 mmol) was added dropwise to a solution of 4-(4-[3-cyano-5-[(1R)-1-(2-fluorophenyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidin-1-carboxylate (5.0 mL) in DCM, along with 2,6-dimethylpyridine (216 mg, 2.0 mmol, 10.00 mmol) and TMSOTf (224 mg, 1.0 mmol). The reaction mixture was stirred for 1 hour and then concentrated under vacuum to provide the title compound (400 mg) as a yellow liquid. ES / MS m / z 446.1 [M+H] + .

[0780] Using appropriate reagents and adjusting the reaction time to determine the end of the reaction, the following compounds were prepared essentially as described with respect to 5-[(1R)-1-(2-fluorophenyl)ethoxy]-7-[5-methyl-1-(4-piperidinyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carboxynitrile. For compounds in which the amine salt is isolated, the formation of monovalent, divalent, or trivalent salts depends on the pKa of the amine and the acid used to form the salt. The exact monovalent, divalent, or trivalent salt forms of each example were not identified. The substances were isolated for use in the next step.

[0781] Table 55 1 TEA in DCM will be used as a solvent. The reactants will be quenched by adding MeOH (5 mL).

[0782] Preparation of 934 4-Methoxy-6-[5-methyl-1-[(3R)-pyrrolidine-3-yl]triazo...

Claims

1. Compounds selected from the following group or their pharmaceutically acceptable salts: 。 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer.

4. The use according to claim 3, wherein the cancer is selected from the group consisting of: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

5. The use according to claim 3, wherein the cancer is selected from the group consisting of: breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial urinary tract cancer, and glioblastoma.

6. The use according to claim 3, wherein the cancer is selected from the group consisting of: bladder cancer, urinary tract epithelial bladder cancer, non-muscle-invasive bladder cancer, and muscle-invasive bladder cancer.

7. The use according to any one of claims 3-6, wherein the cancer is an FGFR3-related cancer.

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