FGFR2 inhibitor compounds

Abstract

The present invention relates to a compound of formula (I) for use in the treatment of cancer, [Formula 1] TIFF2025515466000400.tif3560 In formula, A, X1, X2, X3, Y, Z, Z1, Z2, R 2 and R 6 provides a compound, or a pharma- ceutically acceptable salt thereof, as defined herein, and a method of treating cancer.

Description

[Technical Field]

[0001] Fibroblast growth factor (FGF) is recognized as a crucial mediator of many physiological processes during development, including morphogenesis, fibrosis, and angiogenesis. The fibroblast growth factor receptor (FGFR) family consists of five members, four of which (FGFR1-4) are glycoproteins composed of a cytoplasmic portion containing an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane domain, and 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 mobilize and activate specific downstream signaling partners involved in regulating diverse processes such as cell proliferation, cell metabolism, and cell survival. Therefore, the FGF / FGFR signaling pathway has multifaceted effects on many biological processes important for tumor cell proliferation, migration, invasion, and angiogenesis. [Overview of the project]

[0002] Provided herein are compounds of the following formulas:

[0003] [ka] or a pharmaceutically acceptable salt thereof, in the formula A, X1, X2, X3, Y, Z, Z1, Z2, R 2 and R 6 This is as defined herein.

[0004] Provided herein are compounds of the following formulas:

[0005] [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, Y, Z', Z2, R 2 and R 6 are as defined herein.

[0006] Provided herein is a compound of the following formula,

[0007]

Chemical Structure

[0008] Provided herein is a compound of the following formula,

[0009]

Chemical Structure

[0010] Provided herein is a compound of the following formula,

[0011]

Chemical Structure

[0012] Provided herein is a compound of the following formula,

[0013]

Chemical Structure

[0014] Provided herein are pharmaceutical compositions comprising a compound of formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0015] Provided herein are methods for using compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable compositions thereof, for the treatment of proliferative disorders such as cancer, particularly for the treatment of FGFR2-related cancers. The method comprises administering an effective amount of a compound of formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, to a patient in need.

[0016] Provided herein are compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in therapy. Further provided herein are compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in the treatment of cancer, particularly in the treatment of FGFR2-related cancers. Also provided is the use of compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of cancer, particularly in the treatment of FGFR2-related cancers. [Modes for carrying out the invention]

[0017] Provided herein are compounds that are considered to have clinical applications for the treatment of cancer, particularly for the treatment of FGFR2-related cancers.

[0018] Certain compounds provided herein have superior FGFR2 efficacy compared to certain previously known FGFR inhibitors. Certain compounds provided herein have superior selectivity for FGFR2 compared to FGFR1 compared to certain previously known FGFR inhibitors, and reduce potential dose-limiting toxicities (e.g., hyperphosphatemia) caused by FGFR1 inhibition.

[0019] The compounds provided herein are compounds of formula (I),

[0020] [ka] During the ceremony, The Z2

[0021] [ka] And, A, R 1 and R 1A A pyrazole, triazole, thiadiazole, or oxadiazole substituted with, R 1 However, it is hydrogen or C1-C3 alkyl, R 1A However, it is a C1-C3 alkyl group optionally substituted with one or more substituents independently selected from hydrogen, halo, CN, or halo, OH, and OCH3. X1 and X2 are selected independently from N and C, and if either X1 or X2 is N, then the other is C. X3 is N or CH, X4 is N or CR 9 And, Y is NH, O, S or a bond. Y1 is bonded, CHR 7 CH2-CHR 7, CHR 7 -CH2, CF2, CH2-CF2, or CF2-CH2, Y2 is bonded, 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, Y5 is CR 13 R 14 , CR 13 R 14 CH2 or CH2CR 13 R 14 And, Y6 is CR 13 R 14 , CR 13 R 14 CH2 or CH2CR 13 R 14 And, Z bond, CHR 9A , CR 4 R 4A , CR 4 R 4A -CH2, CH2-CR 4 R 4A These are cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine, or piperidine. Z is bonded, CR 4 R 4A , CR 4 R 4A -CH2, CH2-CR 4 R 4A If Z1 is a bond or Z is CHR 9A In that case, Z1 is CH2 or CH2-CH2, Z3 is a bond, C(O), SO2, or -NR4 C(O) and Z4 is a bond, C(O), SO2, or -NR 4 C(O) and R 2 However, C1-C5 alkyl or R 8 The C1-C5 alkyl groups are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R. 11 , and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN. R 3 However, it is either hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R 3 However, R 5 Or R 7 It condenses with to form CH2, CH2-CH2, or CH2OCH2, R 4 However, it is hydrogen or C1-C3 alkyl, R 4A However, it is hydrogen, halo, OH, or C1-C3 alkyl. R 5 However, it is either hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R 3 It condenses with to form CH2, CH2-CH2, or CH2OCH2, R 6 The molecule is hydrogen, halo, C1-C5 alkyl, CN, 3-6 member cycloalkyl, 4-6 member heterocycloalkyl, 5-6 member aryl, or 5-6 member heteroaryl, and the 3-6 member cycloalkyl, 4-6 member heterocycloalkyl, 5-6 member aryl, and 5-6 member heteroaryl are optionally substituted with one or more substituents independently selected from halo, methyl, halomethyl, OH, or OCH3, and the C1-C5 alkyl is optionally substituted with one or more substituents independently selected from halo, OH, and OCH3. R 7is either hydrogen, F, OH, OCH3, C1-C3 alkyl, or one R 3 It condenses with to form CH2, CH2-CH2, or CH2OCH2, R 8 However, R 8A A 3-6 member cycloalkyl, 4-6 member heterocycloalkyl, 5-6 member aryl, or 5-6 member heteroaryl, which is optionally condensed with or substituted with such a cycloalkyl, R 8A However, these are 3-6 member cycloalkyls, 4-6 member heterocycloalkyls, 5-6 member aryls, or 5-6 member heteroaryls. R 9 However, it is hydrogen, C1-C3 alkyl, or R 9A It condenses with to form CH2 or CH2-CH2, R 10 However, R 8A A 3-6 member cycloalkyl, 4-6 member heterocycloalkyl, 5-6 member aryl, or 5-6 member heteroaryl, which is optionally condensed with or substituted with such a cycloalkyl, R 11 However, the molecule is C1-C4 alkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-C3 alkyl)2, and the C1-C4 alkyl, C1-C3 alkyl and C3-C5 cycloalkyl molecules are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN. R 12 However, the molecule is C1-C4 alkyl, C3-C5 cycloalkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl, or N(C1-C3 alkyl)2, and the C1-C4 alkyl, C1-C3 alkyl, and C3-C5 cycloalkyl molecules are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN. R 13 However, it is hydrogen, halo, or C1-C3 alkyl. R 14 However, it is hydrogen, halo, or C1-C3 alkyl. R 8 , R10 and R 8A is / are optionally substituted with one or more substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z4-R 12 , a compound wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, or a pharmaceutically acceptable salt thereof.

[0022] In formulas (II) and (IIA), A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Y5, Y6, R 2 and R 6 are as defined above for formula (I), X4 is N or C-R 9 and R 9 is hydrogen or C1-C3 alkyl, Z' is a bond, 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, azetidine, pyrrolidine or piperidine.

[0023] In formula (III), A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Y5, Y6, Z2, R 2 and R 6 are as defined above for formula (I), X4 is N or C-R 9 and R 9 is hydrogen or C1-C3 alkyl.

[0024] In formula (IIIA), A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Y5, Y6, R 2 and R 6This is as defined above for equation (I).

[0025] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), X1 may be C and X2 may be N, or X1 may be N and X2 may be C.

[0026] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), X1 may be C, X2 may be N, and the following are formed:

[0027] [ka] During the ceremony, * indicates the connection point to A in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0028] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), X1 may be N, X2 may be C, and the following are formed:

[0029] [ka] During the ceremony, * indicates the connection point to A in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0030] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), X1 may be C, X2 may be N, and X3 may be CH, forming the following:

[0031] [ka] During the ceremony, * indicates the connection point to A in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0032] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), X1 may be N, X2 may be C, and X3 may be CH, forming the following:

[0033] [ka] During the ceremony, * indicates the connection point to A in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0034] The specific chemical nomenclature rules used herein are intended to be familiar to those skilled in the chemical art. Some terms are defined specifically for further clarity.

[0035] As used herein, the term “alkyl” refers to a hydrocarbon chain that may be linear or branched and contains the indicated number of carbon atoms. For example, as used herein, the term “C1-C5 alkyl” refers to a saturated linear or branched monovalent hydrocarbon radical with 1, 2, 3, 4, or 5 carbon atoms. Examples of C1-C5 alkyls include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, and hexyl. Examples of C1-C4 alkyls include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, and hexyl. Examples of C1-C3 alkyls include, but are not limited to, methyl, ethyl, 1-propyl, or isopropyl.

[0036] As used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon group containing the indicated number of carbon atoms. For example, as used herein, the term "3- to 6-membered cycloalkyl" refers to a saturated cyclic hydrocarbon group having 3, 4, 5, or 6 carbon atoms. Examples of 3- to 6-membered cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of 3- to 5-membered cycloalkyls include cyclopropyl, cyclobutyl, and cyclopentyl.

[0037] As used herein, the term "heterocycloalkyl" means C(O) 0-1 , N, O and S(O) 0-2 This refers to a saturated cyclic group containing the indicated number of atoms, selected from the above. For example, as used herein, the term “5-6 membered heterocycloalkyl” means having 5 or 6 ring atoms, of which 1, 2, or 3 are N, O, and S(O). 0-2 Selected from, the remainder is C(O) 0-1 This refers to a saturated cyclic ring system. Examples of 4-6 member heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidine-2-onyl, dioxanyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, and isothiazolid-2-onyl. Examples of 5-6 member heterocycloalkyl groups include, but are not limited to, piperidyl, piperazinyl, pyrrolidinyl, pyrrolidine-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, and isothiazolid-2-onyl.

[0038] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group having the indicated number of carbon atoms. For example, as used herein, the term "5-6 membered aryl" refers to an aromatic cyclic hydrocarbon group having five or six carbon atoms. Examples of 5-6 membered aryls include cyclopentadienyl and phenyl.

[0039] As used herein, the term “heteroaryl” refers to an aromatic cyclic group having the indicated cousin atoms, selected from C, N, O, and S. For example, the term “5-6 membered heteroaryl” refers to an aromatic cyclic group having 5 or 6 ring atoms, of which 1, 2, or 3 are selected from N, O, and S, and the rest are C. Examples of 5-6 membered heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiozolyl, oxadiazolyl, and thiadiazolyl. Examples of 6 membered heteroaryls include, but are not limited to, pyridinyl and pyrazinyl, pyrimidinyl and pyridadinyl.

[0040] As used herein, the terms "halogen" or "halo" refer to F (fluoro), Cl (chloro), Br (bromo), and I (iodine).

[0041] As used herein, the term "haloalkyl" refers to a -CH3 molecule in which one or more hydrogen atoms are replaced by independently selected halos.

[0042] As used herein, the term "oxo" refers to the substitution of CH2 at O ​​to form C(O).

[0043] As used herein, the term "N(C1-C3 alkyl)2" allows for the independent selection of each C1-C3 alkyl substituent, for example, N may be substituted with methyl and ethyl.

[0044] When used herein, substituent-NR 4 C(O) is R via N 2 It is connected.

[0045] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a 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 substituted with .

[0046] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole, or 1,2,4-triazole substituted with [the specified compound].

[0047] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole, or 1,2,4-triazole substituted with R, where R 1A is hydrogen, and R 1 It is a C1-C3 alkyl group.

[0048] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole, or 1,2,4-triazole substituted with R 1A is hydrogen, and R 1 This is CH3.

[0049] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0050] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 1 It can be a C1-C3 alkyl group.

[0051] In the compound of formula (IIIA), A is,

[0052] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 1 It can be a C1-C3 alkyl group.

[0053] In the compound of formula (I), Z is CHR 9A It may be cyclobutyl, azetidine, pyrrolidine, or piperidine.

[0054] In compounds of formula (I) or (IA), Z is a bond,

[0055] [ka] It could be, During the ceremony, * This indicates the connection point to Z1 in equation (I) or (IA), ** indicates the connection point to A in equation (I) or (IA).

[0056] In compounds of formula (I) or (IA), Z is a bond,

[0057] [ka] It could be, During the ceremony, * This indicates the connection point to Z1 in equation (I) or (IA), ** This indicates the connection point to A.

[0058] In compounds of formula (I) or (IA), Z is CHR 9A Z1 may be selected from CH2 or CH2-CH2, R 9 is, R 9A It can condense with other molecules to form CH2 or CH2-CH2.

[0059] In compounds of formula (I) or (IA), Z is CHR 9A Z1 could be CH2, R 9 is, R 9A It can condense with other molecules to form CH2 or CH2-CH2.

[0060] In compounds of formula (I) or (IA), Z is CHR 9A It could be, and Z1 could be CH2-CH2, R 9 is, R 9A It can condense with other molecules to form CH2 or CH2-CH2.

[0061] In compounds of formula (I) or (IA), Z is CHR 9A Z1 may be selected from CH2 or CH2-CH2, R 9 is, R 9A It can condense with other molecules to form CH2.

[0062] In compounds of formula (I) or (IA), Z is CHR 9A Z1 may be selected from CH2 or CH2-CH2, R 9 is, R 9A It can condense with other molecules to form a CH2-CH2 structure.

[0063] In compounds of formula (I) or (IA), Z is CHR9A Z1 could be CH2, R 9 is, R 9A It can condense with other molecules to form CH2.

[0064] In compounds of formula (I) or (IA), Z is CHR 9A It could be, and Z1 could be CH2-CH2, R 9 is, R 9A It can condense with other molecules to form a CH2-CH2 structure.

[0065] In the compound of formula (II) or (IIA), Z' is,

[0066] [ka] It could be, During the ceremony, ** This indicates the connection point to A in equation (II) or (IIA), * indicates the other connection point from Z' in equation (II) or (IIA).

[0067] In the compound of formula (II) or (IIA), Z' is,

[0068] [ka] It could be, During the ceremony, ** This indicates the connection point to A in equation (II) or (IIA), * indicates the other connection point from Z' in equation (II) or (IIA).

[0069] In compounds of formula (I) or (IA), Z can be a bond.

[0070] In the compounds of formula (II) or (IIA), Z' can be a bond.

[0071] In compounds of formula (I), (II), (IA), or (IIA), Z1 can be a bond.

[0072] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y may be NH or O.

[0073] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y may be O.

[0074] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y1 is a bond, CHR 7 CH2-CHR 7 or CHR 7 -CH2 is possible, R 7 Y2 is selected from hydrogen, F, OH and CH3, and Y2 is bonded, CHR 3 CH2-CHR 3 or CHR 3 -CH2 is possible, R 3 The element is selected from hydrogen, F, OH, and CH3.

[0075] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y1 is a bond or CHR 7 It could be, R 7 is hydrogen, F, OH or CH3, and Y2 is a bond or CHR 3 It could be, R 3 These are hydrogen, F, OH, or CH3.

[0076] In compounds of formula (I), (II), (III), (IA), or (IIA), Y1 is a bond, CHR 7 CH2-CHR 7 or CHR 7 -CH2 is possible, R 7 is hydrogen, F, OH or CH3, and Y2 is a bond, CHR 3 CH2-CHR 3 or CHR 3 -CH2 is possible, R 3 is hydrogen, F, OH, or CH 3. And,

[0077] [ka] Forming, During the ceremony, * This indicates a connection point to Z1 in equation (I) or (IA), Z' in equation (II) or (IIA), or A in equation (III).

[0078] In compounds of formula (I), (II), (III), (IA), or (IIA), Y1 is a bond or CHR 7 It could be, R 7 is hydrogen, F, OH or CH3, and Y2 is a bond or CHR 3 It could be, R 3 is hydrogen, F, OH, or CH3,

[0079] [ka] Forming, * This indicates a connection point to Z1 in equation (I) or (IA), Z' in equation (II) or (IIA), or A in equation (III).

[0080] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y1 is a bond, CHR 7 CH2-CHR 7 or CHR 7 -CH2 is possible, R 7 is hydrogen, F, OH or CH3, and Y2 is a bond, CHR 3 CH2-CHR 3 or CHR 3 -CH2 is possible, R 3 is hydrogen, F, OH, or CH 3. And,

[0081] [ka] Forming, During the ceremony, *indicates the connection point to A in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0082] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y1 is a bond or CHR 7 It could be, R 7 is water, element, F, OH or CH3, and Y2 is a bond or CHR 3 It could be, R 3 is hydrogen, F, OH, or CH3,

[0083] [ka] Forming, During the ceremony, * This indicates a connection point to A in equations (I), (II), (III), (IA), (IIA), or (IIIA), or * This indicates a connection point to Z1 in equation (I) or (IA), Z' in equation (II) or (IIA), or A in equation (III) or (IIIA).

[0084] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1A This can be a C1-C3 alkyl group optionally substituted with hydrogen, or one or more substituents independently selected from halo, OH, and OCH3.

[0085] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1A This can be hydrogen or CH3.

[0086] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1A It could be hydrogen.

[0087] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1This can be methyl, ethyl, or propyl.

[0088] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1 It can be methyl.

[0089] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 The C1-C3 alkyls may be optionally substituted with one, two, three, or four substituents independently selected from the above, and the C1-C4 alkyls and C3-C5 cycloalkyls may be substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN.

[0090] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It can be a C1-C3 alkyl group optionally substituted with one or more substituents independently selected from the given group.

[0091] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 teeth,

[0092] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0093] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 teeth,

[0094] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0095] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 teeth,

[0096] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the formula, *indicates the connection point to Y in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0097] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 teeth,

[0098] [ka] It could be, These are F, OH, CN, oxo, -OCH3 and -OC3 cycloalkyl and R 10 It is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0099] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y1 is a bond, CHR 7 CH2-CHR 7 or CHR 7 -CH2 is possible, R 7 This can be selected from hydrogen, F, OH, and CH3.

[0100] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y2 is a bond, CHR 3 CH2-CHR 3 or CHR 3 -CH2 is possible, R 3 This can be selected from hydrogen, F, OH, and CH3.

[0101] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y3 is CR 4 R 5 Alternatively, it could be CF2, R 4 is hydrogen or CH3, and R 5 is hydrogen, F, OH or CH3, and Y4 is CR 3 R4 Or CF2, R 4 is hydrogen or CH3, and R 3 These are hydrogen, F, OH, or CH3.

[0102] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y3 is CR 4 R 5 It could be, R 4 is hydrogen, and R 5 is one R 3 It condenses with to form CH2, CH2-CH2, or CH2OCH2, and Y4 is CR 3 R 4 And R 4 is hydrogen, and R 3 is, R 5 It condenses with other substances to form CH2, CH2-CH2, or CH2OCH2.

[0103] In compounds of formula (I), (II), (III), (IA), or (IIA), Y3 is CR 4 R 5 It could be, R 4 is hydrogen, and R 5 is one R 3 It condenses with to form CH2, CH2-CH2, or CH2OCH2, and Y4 is CR 3 R 4 And R 4 is hydrogen, and R 3 is, R 5 It condenses with to form CH2, CH2-CH2, or CH2OCH2,

[0104] [ka] Forming, During the ceremony, * This indicates a connection point to Z1 in equation (I) or (IA), Z' in equation (II) or (IIA), or A in equation (III).

[0105] In the compound of formula (IIIA), Y3 is CR 4 R 5It could be, R 4 is hydrogen, and R 5 is one R 3 It condenses with to form CH2, CH2-CH2, or CH2OCH2, and Y4 is CR 3 R 4 And R 4 is hydrogen, and R 3 is, R 5 It condenses with to form CH2, CH2-CH2, or CH2OCH2,

[0106] [ka] Forming, During the ceremony, * This indicates the connection point A in equation (IIIA), or * This indicates a connection point to Z1 in equation (I) or (IA), Z' in equation (II) or (IIA), or A in equation (III) or (IIIA).

[0107] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 It could be, R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 It could be, R 13 and R 14 It is selected independently from H and CH3.

[0108] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y5 may be CH2 or CH2-CH2, and Y6 may be CH2 or CH2-CH2.

[0109] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y5 and Y6 may be CH2.

[0110] In compounds of formula (I), (II), (III), (IA), or (IIA), X4 is N or CR. 9 It could be, R 9 It is either hydrogen or CH3.

[0111] In compounds of formula (I) or (IA), X4 is CR 9 It could be, R 9 is, R 9A It condenses with to form CH2 or CH2-CH2, and Z1 is CH2 or CH2-CH2.

[0112] In compounds of formula (I), (II), (III), (IA), or (IIA), X4 may be N or CH.

[0113] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 This can be CN, F, Cl, CH3, CF3, or cyclopropyl.

[0114] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 This can be CN, F, or Cl.

[0115] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 This can be CN or Cl.

[0116] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 It could be CN.

[0117] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6It can be Cl.

[0118] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 8 is, R 8A They may be 5-6 member cycloalkyl, 5-6 member heterocycloalkyl, 5-6 member aryl, or 5-6 member heteroaryl molecules, which are optionally condensed with or substituted with such molecules.

[0119] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 8 is, R 8A It may be a 5-6 member cycloalkyl or 5-6 member heterocycloalkyl, which is arbitrarily condensed with it.

[0120] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 8 is, R 8A It may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranil, tetrahydropyranil, phenyl, or pyridinyl, which are optionally condensed with these.

[0121] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 8 is, R 8A It may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranil, or tetrahydropyranil, which are optionally condensed with the above.

[0122] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 8 is, R 8A It may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranil, or tetrahydropyranil, which are arbitrarily condensed with R 8A It may be phenyl or a 6-membered heteroaryl.

[0123] In compounds of formula (I), (II), (III), (IA), or (IIA), R 9 It could be hydrogen.

[0124] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be a 3-6 member cycloalkyl, 5-6 member heterocycloalkyl, 5-6 member aryl, or 5-6 member heteroaryl molecule, which are arbitrarily condensed with the above.

[0125] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A They may be 3-6 member cycloalkyl, 5-6 member heterocycloalkyl, phenyl, or 5-6 member heteroaryl molecules, optionally condensed with or substituted with.

[0126] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidine-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, which are optionally condensed with or substituted with.

[0127] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8AIt may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, which are optionally condensed with or substituted with the above.

[0128] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, which are optionally condensed with or substituted with the above.

[0129] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, which are optionally condensed with or substituted with the above.

[0130] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10This can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidine-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0131] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 This can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0132] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 This can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0133] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 This can be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl.

[0134] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, condensed with or substituted with.

[0135] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, or pyridinyl, either condensed with or substituted with.

[0136] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, or pyridinyl, either condensed with or substituted with.

[0137] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, or pyridinyl, either condensed with or substituted with.

[0138] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be cyclopentyl, cyclohexyl, phenyl, or pyridinyl, either condensed with or substituted with.

[0139] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be a phenyl or pyridinyl compound condensed with R 8A This can be a 5-6 member heterocycloalkyl or a 5-6 member heteroaryl.

[0140] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be a phenyl or pyridinyl compound condensed with R 8A This can be pyrrolidinil, pyrrolidine-2-onyl, dioxanil, tetrahydrofuranil, tetrahydrothiophenyl, tetrahydropyranil, oxazolidinil, isothiazolidinil, oxozolid-2-onyl, isothiazolid-2-onylfuranil, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0141] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be a phenyl or pyridinyl compound condensed with R 8A This may be tetrahydrofuranil, tetrahydrothiophenyl, tetrahydropyranil, oxazolidinil, isothiazolidinil, oxozolid-2-onyl, isothiazolid-2-onyl, furanil, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0142] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is, R 8A It may be a phenyl or pyridinyl compound condensed with R 8AThis can be tetrahydrofuranil, tetrahydrothiophenyl, tetrahydropyranil, oxazolidinil, isothiazolidinil, oxozolid-2-onyl, or isothiazolid-2-onyl.

[0143] In compounds of formula (I) or (IA), if both Z and Z1 are bonds, they combine to form a single bond.

[0144] In compounds of formula (I) or (IA), Z is CHR 9A Z1 could be CH2, X4 is CR 9 It could be, R 9 is, R 9A It condenses with it to form CH2,

[0145] [ka] Forming, During the ceremony, * This indicates the connection point to A.

[0146] In compounds of formula (I), (II), (III), (IA), or (IIA), R 5 is one R 3 It can condense with it to form CH2-CH2, for example,

[0147] [ka] Forming, During the ceremony, * This indicates a connection point to Z1 in equation (I) or (IA), or to Z' in equation (II) or (IIA), or to A in equation (III).

[0148] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 5 is one R 3 It can condense with it to form CH2-CH2, for example,

[0149] [ka] Forming, During the ceremony, * This indicates a connection point to Z1 in equation (I) or (IA), or to Z' in equation (II) or (IIA), or to A in equation (III) or (IIIA).

[0150] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 8 is, R 8A It can be a condensed cyclopentyl, R 8A It could be pyridinyl, for example,

[0151] [ka] Forming, During the ceremony, * This indicates the connection point to Y.

[0152] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole, or 1,2,4-triazole substituted with, where Y may be NH or O.

[0153] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole, or 1,2,4-triazole substituted with R 1A is hydrogen, and R 1 is a C1-C3 alkyl group, and Y can be NH or O.

[0154] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0155] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 1 can be a C1-C3 alkyl group, and Y can be NH or O.

[0156] In the compound of formula (IIIA), A is,

[0157] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 1 can be a C1-C3 alkyl group, and Y can be NH or O.

[0158] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole, or 1,2,4-triazole substituted with, where Y may be O.

[0159] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 1A is hydrogen, and R 1 is a C1-C3 alkyl group, and Y can be O.

[0160] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0161] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 1 can be a C1-C3 alkyl group, and Y can be O.

[0162] In the compound of formula (IIIA), A is,

[0163] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 1 can be a C1-C3 alkyl group, and Y can be O.

[0164] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 6 This can be CN, F, Cl, CH3, CF3, or cyclopropyl.

[0165] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 1A is hydrogen, and R 1 It is a C1-C3 alkyl group, and R 6 This can be CN, F, Cl, or CF3.

[0166] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0167] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 This can be CN, F, Cl, CH3, CF3, or cyclopropyl.

[0168] In the compound of formula (IIIA), A is,

[0169] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 This can be CN, F, Cl, CH3, CF3, or cyclopropyl.

[0170] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0171] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6This can be CN, F, Cl, or CF3.

[0172] In the compound of formula (IIIA), A is,

[0173] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 CN, F, Cl, CH 3又は It could be CF3.

[0174] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0175] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 1 It can be a C1-C3 alkyl, R 6 This can be CN or Cl.

[0176] In the compound of formula (IIIA), A is,

[0177] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 1 It can be a C1-C3 alkyl, R 6This can be CN or Cl.

[0178] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 6 can be CN, F, Cl, CH3, CF3, or cyclopropyl, and Y can be NH or O.

[0179] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 1A is hydrogen, and R 1 It is a C1-C3 alkyl group, and R 6 can be CN, F, Cl, or CF3, and Y can be NH or O.

[0180] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0181] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl, CH3, CF3, or cyclopropyl, and Y can be NH or O.

[0182] In the compound of formula (IIIA), A is,

[0183] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl, CH3, CF3, or cyclopropyl, and Y can be NH or O.

[0184] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0185] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl, or CF3, and Y can be NH or O.

[0186] In the compound of formula (IIIA), A is,

[0187] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl, or CF3, and Y can be NH or O.

[0188] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R6 can be CN, F, Cl, CH3, CF3, or cyclopropyl, and Y can be O.

[0189] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 1A is hydrogen, and R 1 It is a C1-C3 alkyl group, and R 6 can be CN, F, Cl, or CF3, and Y can be O.

[0190] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0191] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl, CH3, CF3, or cyclopropyl, and Y can be O.

[0192] In the compound of formula (IIIA), A is,

[0193] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl, CH3, CF3, or cyclopropyl, and Y can be O.

[0194] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0195] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl, or CF3, and Y can be O.

[0196] In the compound of formula (IIIA), A is,

[0197] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl, or CF3, and Y can be O.

[0198] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0199] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 1 It can be a C1-C3 alkyl, R 6can be CN or Cl, and Y can be O.

[0200] In the compound of formula (IIIA), A is,

[0201] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl, or CF3, and Y can be O.

[0202] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, Y can be NH or O, and R 2 These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 The C1-C3 alkyls may be optionally substituted with one, two, three, or four substituents independently selected from the above, and the C1-C4 alkyls and C3-C5 cycloalkyls may be optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN.

[0203] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 6 can be CN, F, Cl, CH3, CF3, or cyclopropyl, Y can be NH or O, R 2These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It can be a C1-C4 alkyl group optionally substituted with one or more substituents independently selected from the given group.

[0204] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0205] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0206] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0207] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0208] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0209] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0210] In the compound of formula (I), A is R 1 and R 1A It may be a pyrazole, 1,2,3-triazole or 1,2,4-triazole substituted with R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0211] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), (IIA), or (IIIA).

[0212] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0213] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, Y can be NH or O, and R 2 These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 The C1-C3 alkyls may be optionally substituted with one, two, three, or four substituents independently selected from the above, and the C1-C4 alkyls and C3-C5 cycloalkyls may be optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN.

[0214] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0215] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl, CH3, CF3, or cyclopropyl, Y can be NH or O, R 2 These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It can be a C1-C4 alkyl group optionally substituted with one or more substituents independently selected from the given group.

[0216] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0217] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0218] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), or (IIA).

[0219] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0220] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0221] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), or (IIA).

[0222] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0223] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0224] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), or (IIA).

[0225] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0226] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0227] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), or (IIA).

[0228] In the compound of formula (IIIA), A is,

[0229] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0230] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * This indicates the connection point to Y in equation (IIIA).

[0231] In the compound of formula (IIIA), A is,

[0232] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), **R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0233] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * This indicates the connection point to Y in equation (IIIA).

[0234] In the compound of formula (IIIA), A is,

[0235] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0236] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * This indicates the connection point to Y in equation (IIIA).

[0237] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0238] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, Y can be NH or O, and R 2 These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 Y5 may be a C1-C3 alkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from , and the C1-C4 alkyl and C3-C5 cycloalkyl groups may be optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN. 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0239] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0240] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, Y can be NH or O, and R 2 These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 Y5 may be a C1-C4 alkyl group optionally substituted with one or more substituents independently selected from CR. 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0241] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0242] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), **R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0243] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10 The C1-C4 and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), or (IIA). Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0244] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0245] [ka] It could be, During the ceremony,* This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0246] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), or (IIA), where Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0247] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0248] [ka] It could be, During the ceremony, *This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0249] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10 The C1-C4 and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), or (IIA). Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0250] In compounds of formula (I), (II), (III), (IA), or (IIA), A is,

[0251] [ka] It could be, During the ceremony, * This indicates the connection point to Z, Z', or Z2 in equations (I), (II), (III), (IA), or (IIA), ** R indicates the other connection point from A in equations (I), (II), (III), (IA), or (IIA), where R 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0252] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equations (I), (II), (III), (IA), or (IIA), where Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0253] In the compound of formula (IIIA), A is,

[0254] [ka] It could be, During the ceremony,* This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6 can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0255] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equation (IIIA), and Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0256] In the compound of formula (IIIA), A is,

[0257] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0258] [ka] It could be, These are halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, and -Z3-R 11 and R 10 The C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one, two, three, or four substituents independently selected from the following: the C1-C4 alkyl and C3-C5 cycloalkyl groups are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN, in the formula, * indicates the connection point to Y in equation (IIIA), and Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0259] In the compound of formula (IIIA), A is,

[0260] [ka] It could be, During the ceremony, * This indicates the connection point to the substituent containing Y1 in formula (IIIA), ** R indicates the other connection point from A in equation (IIIA), and 6can be CN, F, Cl or CF3, Y can be NH or O, and R 2 teeth,

[0261] [ka] It could be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 It is substituted with 1, 2, 3, or 4 substituents independently selected from the formula, * indicates the connection point to Y in equation (IIIA), and Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 It is selected independently from H and CH3, and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 And R 13 and R 14 H and CH 3. It is selected independently of others.

[0262] In one embodiment, the compound of formula (I) is

[0263] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof, During the ceremony, * The joining of positions is

[0264] [ka] It is represented as follows.

[0265] For example, for the compound of the following formula,

[0266] [ka] During the ceremony, * The joining of positions is

[0267] [ka] Represented by the following compounds:

[0268] [ka] It forms.

[0269] In further embodiments, the compound of formula (I) is

[0270] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof, in the formula, * The joining of positions is

[0271] [ka] It is represented as follows.

[0272] In further embodiments, the compound of formula (I) is

[0273] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof, in the formula, * The joining of positions is

[0274] [ka] It is represented as follows.

[0275] In further embodiments, the compound of formula (I) is

[0276] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof, in the formula, * The joining of positions is

[0277] [ka] It is represented as follows.

[0278] In further embodiments, the compound of formula (I) is

[0279] [ka]

[0280] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof, in the formula, * The joining of positions is

[0281] [ka] It is represented as follows.

[0282] In further embodiments, the compound of formula (I) is

[0283] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0284] In further embodiments, the compound of formula (I) is

[0285] [ka]

[0286] [ka]

[0287] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0288] In further embodiments, the compound of formula (I) is

[0289] [ka]

[0290] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0291] In further embodiments, the compound of formula (I) is

[0292] [ka]

[0293] [ka]

[0294] [ka]

[0295] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0296] In further embodiments, the compound of formula (I) is

[0297] [ka]

[0298] [ka]

[0299] [ka]

[0300] [ka]

[0301] [ka]

[0302] [ka] Selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

[0303] Compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or their pharmaceutically acceptable salts, any or all hydrogens present in the compound, or in any particular group or part within the compound, may be replaced with deuterium or tritium. Therefore, the list of alkyls includes deuterated alkyls where one to the maximum number of hydrogens present can be replaced with deuterium. For example, C2D x H 5-xWhen 1 to 5 hydrogen atoms in such compounds are replaced by deuterium, ethyl refers to either C2H5 or both C2H5.

[0304] Compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) provided herein may form pharmaceutically acceptable salts. The examples provided herein may form pharmaceutically acceptable salts. It is intended that such pharmaceutically acceptable salts be included. Pharmaceutically acceptable salts and general methods for preparing them are well known in the art (e.g., P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2 nd See Revised Edition (Wiley-VCH, 2011), SMBerge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0305] The compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or their pharmaceutically acceptable salts, may be mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. More specifically, the compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or their pharmaceutically acceptable salts, may be formulated as pharmaceutical compositions. Such pharmaceutical compositions and processes for preparing them are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy (A. Gennaro, et al., eds., 21st ed., Mack Publishing Co., 2005)).

[0306] The compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or their pharmaceutically acceptable salts, and their pharmaceutically acceptable compositions, may be administered by various routes. Such routes of administration include oral and intravenous administration.

[0307] Compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) described herein, or pharmaceutically acceptable salts thereof, may be combined with one or more other therapeutic agents.

[0308] Compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) described herein, or pharmaceutically acceptable salts thereof, may be components of a pharmaceutical composition for the treatment of cancer, comprising one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally one or more additional therapeutic agents.

[0309] Compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) described herein, or pharmaceutically acceptable salts thereof, may be components of a pharmaceutical composition for the treatment of cancer, comprising one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally one or more additional therapeutic agents.

[0310] The compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or their pharmaceutically acceptable salts, may be combined with one or more other therapeutic agents for simultaneous, individual, or sequential administration.

[0311] Compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or pharmaceutically acceptable salts thereof, and their pharmaceutically acceptable compositions may be used in the methods described herein.

[0312] The compounds of formulas (I), (II), (III), (IA), (IIA), or (IIIA) described herein, or their pharmaceutically acceptable salts, are generally effective over a wide range of doses. For example, the daily dose is typically within the range of about 0.5 to about 100 mg / kg body weight. In some cases, dose levels lower than the lower limit of the aforementioned range may be sufficient, and in other cases, higher doses may be used without any adverse side effects; therefore, the aforementioned dose range is not intended to limit the scope of the invention in any way. It is understood that the actual amount of compound administered will be determined by a physician taking into account the condition being treated, the chosen route of administration, the actual compound(s) administered, the individual patient's age, weight, and response, and relevant circumstances including the severity of the patient's symptoms.

[0313] Certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or their pharmaceutically acceptable salts, selectively target FGFR2. For example, certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or their pharmaceutically acceptable salts, selectively target FGFR2 rather than other FGFRs. For example, certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or their pharmaceutically acceptable salts, selectively target FGFR2 rather than FGFR1. For example, certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, are at least approximately three times more selective than FGFR1 for FGFR2 (e.g., at least approximately four times, five times, six times, seven times, eight times, nine times, ten times, fifteen times, twenty times, thirty times, forty times, fifty times, or more).

[0314] As used herein, the term “selectivity” of a compound refers to a compound that exhibits stronger activity at the first target than at the second target. Multiple selectivity can be calculated by any method known in the art. For example, multiple selectivity is calculated by the IC of a compound against a second target (e.g., FGFR1). 50 The IC value of the same compound against the first target (e.g., FGFR2) 50 It can be calculated by dividing by the value. IC 50 The value can be determined by any method known in the relevant art. For example, IC 50 The values ​​may be determined as described in the following assay.

[0315] As used herein, the term “cancer” refers to or describes a physiological condition in a patient typically characterized by uncontrolled cell proliferation. This definition includes benign and malignant cancers, and primary and metastatic cancers.

[0316] As used herein, the term “FGFR2-related cancer” refers to cancers associated with, or having, dysregulation of the expression, activity, or level of the FGFR2 gene, FGFR2 kinase, or any of them. Non-exclusive examples of FGFR2-related cancers are described herein. As used herein, "FGFR2-related cancer" includes stomach cancer, hepatobiliary tract cancer, cancer of unknown primary origin, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), sarcoma, esophagogastric cancer (e.g., esophagogastric junction adenocarcinoma, remnant gastric adenocarcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma), glioma (e.g., astrocytoma, oligodendroglioma, ependymoma), non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma), gastrointestinal stromal tumor, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, and small cell lung cancer), urothelial carcinoma, bladder cancer (e.g., urothelial bladder cancer, nonmuscle-invasive bladder cancer, muscle-invasive bladder cancer), and gastric cancer. Examples of cancers include, but are not limited to, gastric adenocarcinoma, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, squamous cell carcinoma, melanoma, head and neck cancer, glioblastoma, endometrial cancer, endometrioid adenocarcinoma, cervical cancer, and ovarian cancer.

[0317] As used herein, the term “to treat” (“treatment”) means to suppress, slow, stop or reverse the progression or severity of an existing symptom, condition, or disorder.

[0318] As used herein, the term “patient” refers to a mammal, in particular a human.

[0319] Provided herein are compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in therapeutic applications.

[0320] Provided herein are compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in the treatment of cancer.

[0321] Provided herein is the use of compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, in the manufacture of drugs for the treatment of cancer.

[0322] Provided herein are methods for treating cancer, comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof.

[0323] The cancers provided in the methods and uses of this specification include stomach cancer, hepatobiliary tract cancer, cancer of unknown primary origin, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), sarcoma, esophagogastric cancer (e.g., esophagogastric junction adenocarcinoma, remnant gastric adenocarcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma), glioma (e.g., astrocytoma, oligodendroglioma, ependymoma), non-Hodgkin lymphoma (e.g., B-cell non-Hodgkin lymphoma), gastrointestinal stromal tumors, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, and small cell lung cancer), urothelial carcinoma, bladder cancer (e.g., urothelial bladder cancer, nonmuscle-invasive bladder cancer, muscle-invasive bladder cancer), and gastric cancer. The cancers selected are those consisting of (e.g., gastric adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), prostate cancer (e.g., prostate adenocarcinoma), colorectal cancer (e.g., colorectal adenocarcinoma, colon adenocarcinoma), multiple myeloma, liver cancer (e.g., hepatocellular carcinoma, fibrous hepatocellular carcinoma), skin cancer (e.g., squamous cell carcinoma), melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., head and neck squamous cell carcinoma, hypopharyngeal cancer, laryngeal cancer, lip and oral cancer, salivary gland cancer), glioblastoma, endometrial cancer (e.g., endometrioid adenocarcinoma), cervical cancer, and ovarian cancer (e.g., epithelial ovarian cancer).In particular, cancers include stomach cancer, hepatobiliary tract cancer, cancer of unknown primary origin, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), esophagogastric cancer (e.g., esophagogastric junction adenocarcinoma, remnant gastric adenocarcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma), glioma (e.g., astrocytoma, oligodendroglioma, ependymoma), breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma and small cell lung cancer), and gastric cancer. The cancers selected are those consisting of (e.g., gastric adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), colorectal cancer (e.g., colorectal adenocarcinoma, colon adenocarcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrous hepatocellular carcinoma), skin cancer (e.g., squamous cell carcinoma), melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., head and neck squamous cell carcinoma, hypopharyngeal cancer, laryngeal cancer, lip and oral cancer, salivary gland cancer), glioblastoma, endometrial cancer (e.g., endometrioid adenocarcinoma), and ovarian cancer (e.g., epithelial ovarian cancer). More specifically, cancer is selected from the group consisting of hepatobiliary cancer, cancer of unknown primary origin, gallbladder cancer (e.g., adenocarcinoma of the gallbladder), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrous hepatocellular carcinoma), skin cancer (e.g., squamous cell carcinoma), melanoma (e.g., cutaneous melanoma), and endometrial cancer (e.g., endometrioid adenocarcinoma). Most specifically, cancer is selected from the group consisting of hepatobiliary cancer, gallbladder cancer (e.g., adenocarcinoma of the gallbladder), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrous hepatocellular carcinoma), and endometrial cancer (e.g., endometrioid adenocarcinoma).

[0324] The compounds provided herein can be prepared as described in the following preparations and examples.

[0325] Scheme A

[0326] [ka] Scheme A shows the preparation of compound (A8), defined as R1' being a C1-C3 alkyl group, by multiple synthetic routes resulting in compound (A11), from which compound (A8) is further synthesized to formula 1. Alcohol (A1) can be reacted with mesyl chloride or tosyl chloride to obtain compound (A2a) or (A2b), which can then be reacted with (A3a) to obtain (A4). Compound (A8) can be obtained by treating compound (A4) with LDA and a suitable alkylating agent. Alternatively, compound A8 can be synthesized directly by alkylating compound A3b with mesylate A2a or tosylate A2b to obtain compound A8.

[0327] Compound (A8) can also be synthesized via an alternative route as shown in Scheme 1. The alcohol (A1) can be reacted under Mitsunobu conditions to obtain the azide (A5). The azide (A5) can be condensed with a beta-ketoester to obtain the triazole ester (A6), which can be saponified to obtain the carboxylate (7). Treatment of the carboxylate (A7) with bromine in the presence of a base yields compound (A8).

[0328] Scheme 1 further illustrates the preparation of compound (A11). Compound (A8) can be deprotected to obtain (A9). When compound (A9) is reacted with a suitable ketone (A10) under reductive amination conditions, compound (A11) is obtained. 1’ It is defined as a C1-C3 alkyl group.

[0329] Scheme A1

[0330] [ka] Scheme A1 shows an alternative route for obtaining compound (A8). A trimethylsilyl analog of (A5a) can be obtained by reacting (A5) under microwave conditions in the presence of trimethyl(propa-1-in-1-yl)silane. Compound (A8) can be obtained by treating (A5a) with NBS in the presence of SiO2.

[0331] Scheme A2

[0332] [ka] Scheme A2 shows the preparation of compound (A2i') where R1' is defined as a C1-C3 alkyl, which is further synthesized to formula 1. The O-protected cyclobutan-1-one (A2a') can be reacted in the presence of NaBH4 to obtain the alcohol (A2b'). The formation of the azide (A2c') can be achieved by reacting the alcohol (A2b') with PPh3 and DIAD, followed by DPPA. The azide (A2c') can be reacted with ethyl acetoethyl to obtain the ester (A2d'). Hydrolysis of (A2d') under basic conditions can yield the acid (A2e'), which can then be brominated under basic conditions to obtain the bromide (A2f'). Removal of the protecting group from (A2f') can yield the alcohol (A2g'). The alcohol (A2g') can be oxidized to obtain the ketone (A2h'), which can then be reacted under reductive amination conditions to obtain (A2i').

[0333] Scheme A3

[0334] [ka] Scheme A3 shows the preparation of compound (A3h'), which is further synthesized to formula 1. A solution of (A3a') is reacted with N-diazo-1,1,1-trifluoromethanesulfonamide in the presence of copper sulfate and NaHCO3 to obtain the azide (A3b'). (A3c') can be obtained by treating the azide under microwave conditions in the presence of trimethyl(propa-1-in-1-yl)silane. The formation of the bromide (A3d') can be achieved by treating (A3c') with NBS in the presence of SiO2. (A3d') can be subjected to Mitsunobu conditions with p-nitrobenzoic acid to obtain the ester (A3f'). The alcohol (A3f') can be obtained by hydrolysis of the ester (A3e') under basic conditions. When the alcohol (A3f') is treated with (trifluoromethane)sulfonyltrifluoromethanesulfonate in the presence of a base, a triflate (A3g') may be formed. By substituting the triflate (A3g') with a suitable amine, (A3h') can be obtained.

[0335] Scheme B

[0336] [ka] Scheme B shows the preparation of compounds B6, B8, B9, and B10, which are further synthesized into formula 1. Compounds (B10) and (B10a) can be further synthesized into formulas 2, 3, 4, or 4a.

[0337] Compound (B2) can be synthesized by starting with either halide (B1a) or (B1b) and reacting one of these halides with tributyl(1-ethoxyethenyl) stannane under palladium-catalyzed conditions. Hydrolysis of ethoxyvinyl (B2) yields ketone (B5). Ketone (B5) can be reduced to alcohol (B6), which is then reacted with MsCl to obtain mesylate (B8) or chloride (B9).

[0338] Alternatively, the compound (B6) can be synthesized by reacting the aldehyde (B7) with a suitable Grignard reagent to obtain the alcohol (B6). A third alternative route to the compound (B6) can be achieved by treating the halide (B1b) with lithium dibutyl (methyl) magnesite, followed by the addition of acetaldehyde to obtain the alcohol (B6).

[0339] Alpha-bromoketone (B10) can be obtained by treating ketone (B5) with phenyltrimethylammonium bromide. Alternatively, alpha-bromoketone (B10) can be formed by the reaction of ethoxyvinyl (B2) in aqueous THF in the presence of NBS.

[0340] Scheme B1

[0341] [ka] Scheme B1 shows an alternative route for (B10a) to an alpha-haloketone, which can then be synthesized to formula 1. (B10a) can be obtained by treating (B1b) with i-PrMgCl, followed by its addition to chloro-N-methoxy-N-methylacetamide, which can then be synthesized to the compound of formula (I).

[0342] Scheme C

[0343] [ka] Scheme C shows the preparation of compound (C5), which is further synthesized to formula 1. By treating compound (C1) with i-PrMgCl and subsequently adding the aldehyde (C2), alcohol (C3) can be obtained. By reacting alcohol (C3) with potassium t-butoxide in the presence of methyl iodide, compound (C4) can be obtained, which is then deprotected to obtain alcohol (C5).

[0344] Scheme C1

[0345] [ka] Scheme C1 shows the preparation of compound (C1e), which is further synthesized to formula 1. Reaction of ethenyl (C1a) in the presence of K2OsO4 and NMO yields bisalcohol (C1b). The primary alcohol (C1a) can be protected by SEM-Cl treatment in the presence of a base, thereby yielding (C1b). The secondary alcohol (C1b) is alkylated with methyl iodide under silver catalytic conditions to yield ether (C1d). Removal of the protecting group of (C1d) under acidic conditions yields the primary alcohol (C1e).

[0346] Scheme D

[0347] [ka] Scheme D shows the preparation of compound (D7), which is further synthesized to formula 1. Ester (D2) can be obtained by treatment of methyl 3,3-difluorocyclobutane-1-carboxylate with KHMDS in the presence of fluoro(D1) where X=Br. Reduction of ester (D2) to alcohol (D4) is achieved by treatment with LiBH4. Tetrahydropyran (D5) can be obtained by protecting alcohol (D4) with DHP and a catalytic amount of TsOH. (D6) can be obtained by reaction of tetrahydropyran (D5) with n-BuLi, followed by the addition of NFSI. Alcohol (D7) can be obtained by removing the protecting group under acidic conditions.

[0348] Scheme E

[0349] [ka] Scheme E shows the preparation of compounds (E1) and (E6), which are further synthesized into formula 1. Compound (E6) can be synthesized by reacting (E2) with POCl3 to obtain halogenated compound (E3). Treatment of (E3) with tributyl(1-ethoxyethenyl) stannane under palladium catalytic conditions yields ethoxyvinyl (E4). Reaction of (E4) with benzylamine yields N-benzyl protection (E5). Deprotection of (E5) yields amine (F6).

[0350] Compound (E1) can be synthesized by treating (B5) with NH4OAc.

[0351] Scheme F

[0352] [ka] Scheme F shows the preparation of compound (F5), which is further synthesized to formula 1. (F2) can be obtained by the reaction of (F1) with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of CuI. The boronic acid ester (F3) can be obtained by treatment of (F2) with bis(pinacolato)diborone under palladium-catalyzed conditions. (F4) can be obtained by palladium-catalyzed coupling of the boronic acid ester (F3) with a suitable bromide, which is then demethylated with NDM to obtain (F5).

[0353] Scheme G

[0354] [ka] Scheme G shows the preparation of compound (G5), which is further synthesized to formula 1. Reaction of (G1) with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) yields (G2), where R6 is defined as R6=F. Treatment of (G2) with bis(pinacolato)diborone under palladium-catalyzed conditions yields the boronic acid ester (F3). Coupling of the boronic acid ester (F3) with a suitable bromide in the presence of a palladium catalyst yields (G4). Demethylation of (G4) with NDM yields (G5).

[0355] Scheme H

[0356] [ka] Scheme H shows several methods for preparing compounds (H4) and (H6), which are further synthesized in Formula 1. Boronic acid ester (H1) can be obtained by reacting compound (G1), where Hal is defined as Hal=halogen, with bis(pinacolato)diborone under palladium-catalyzed conditions. Boronic acid ester (H1) can be coupled with a suitable bromide in the presence of a palladium catalyst to obtain (H2). By chlorinating (H2) with NSC, (H3) can be obtained, where R6 is defined as R6=Cl, and this can then be demethylated with NDM to obtain (H4). By deprotecting (H4) under acidic conditions, (H5) can be obtained, and this can then be subjected to reductive amination conditions using a suitable ketone to obtain (H6). Alternatively, (H7) can be obtained by coupling boronic acid ester (H1), where R6 is defined as R6=H, with a suitable bromide. Chlorination of (H7) can be achieved by treating it with NCS to obtain (H8), where R6 is defined as R6=Cl. (H6) can be obtained by demethylating (H8) with NDM.

[0357] Scheme H also shows several methods for preparing compounds (H4) and (H6) where R6 is defined as R6=CN and Hal is defined as Hal=Br, which can be further synthesized to formula (I). Compound (G1) can be reacted with bis(pinacolato)diborone under palladium-catalyzed conditions to obtain the boronic acid ester (H1). The boronic acid ester (H1) can be coupled with a suitable bromide in the presence of a palladium catalyst to obtain (H2). Demethylation of (H2) by NDM can yield (H4). Deprotection of (H4) under acidic conditions can yield (H5), which can then be subjected to reductive amination conditions using a suitable ketone to obtain (H6). Alternatively, the boronic acid ester (H1) can be coupled with a suitable bromide to obtain (H7). Demethylation of (H7) by NDM can yield (H6).

[0358] Scheme J

[0359] [ka] Scheme J shows the preparation of the compound of formula 1. (J1) can be alkylated with the halogens (B8), (B10), (B10a), or (B9) mesylate to obtain (K2). Alternatively, (J2) can also be obtained by the reaction of the alcohol (C1e), (C5), or (D7) under Mitsunobu conditions. Deprotection of (J2) under acidic conditions can yield (J3), which can then be subjected to reductive amination conditions using a suitable ketone to obtain the compound of formula 1. Alternatively, the compound of formula 1 can be synthesized by alkylating (J4) with the halogens (B8), (B10), (B10a), or (B9) mesylate, or alternatively by reacting it with the alcohol (C1e), (C5), or (D7) under Mitsunobu conditions. Those skilled in the art will recognize that compound (J1) can be replaced with the compound (G5) or (H4). Furthermore, a person skilled in the art can recognize that compound (J4) can be substituted for compound (F5) or (H6).

[0360] Scheme K

[0361] [ka] Scheme K shows the preparation of the compound of formula 1. (K1) can be reacted with Hal, defined as Hal=Br, and alkylated with the halides (B8), (B10), (B10a) or the mesylate (B9) to obtain (L2). Treatment of (K2) with bis(pinacolato)diborone under palladium-catalyzed conditions can yield the boronic acid ester (K3). Palladium-catalyzed coupling of (K3) with a suitable bromide, (A2i') or (A3h') can yield the compound of formula (I). Alternatively, the compound of formula (I) can be synthesized by palladium-catalyzed coupling of (K3) with a suitable bromide to obtain (K4). Deprotection of (K4) under acidic conditions can yield (K5), which can then be subjected to reductive amination conditions with a suitable ketone to obtain the compound of formula 1.

[0362] Scheme K1

[0363] [ka] Scheme K1 shows the preparation of an alternative compound (K3) that can be used in Formula 1. Reaction of (K1) under Mitsunobu conditions yields the ketone (K1a). Reduction of the ketone (K1a) yields the alcohol (K1b), which can be alkylated with a suitable alkylating agent to obtain the ether (K1c). Treatment of (K1b) or (K1c) with bis(pinacolato)diborone under palladium-catalyzed conditions yields (K3). Alternatively, (K1a) can be reacted with a suitable Grignard reagent to obtain (K1d). Treatment of (K1d) with bis(pinacolato)diborone under palladium-catalyzed conditions yields (K3).

[0364] Scheme L

[0365] [ka] Scheme L shows two methods for preparing the compound of formula 1. In the first method, (L2) can be obtained by treating (L1) with NIS, and then reacting this with CuCN to obtain (L3). (L4) can be obtained by reacting (L3) with an amine (F4) in the presence of an organic base. A boronic acid ester (L5) can be obtained by treating (L4) with bis(pinacolato)diborone under palladium-catalyzed conditions. The compound of formula 1 can be obtained by palladium-catalyzed coupling of (L5) with a suitable bromide. Alternatively, in the second method, the compound of formula 1 can be synthesized by palladium-catalyzed coupling of (L5) with a suitable bromide to obtain (L7). (L8) can be obtained by deprotection of (L7) under acidic conditions, and this can be subjected to reductive amination conditions with a suitable ketone to obtain the compound of formula 1. For the compound of formula 1, the enantiomers can be separated by chiral chromatography.

[0366] Scheme L shows the preparation of the compound of formula 1. By treating (L3) with an amine (F4) or (F5) under palladium-catalyzed conditions, (L4) can be obtained. By reacting (L4) with bis(pinacolato)diborone under palladium-catalyzed conditions, a boronic acid ester (L5) can be obtained. By palladium-catalyzed coupling of (L5) with a suitable bromide, the compound of formula 1 can be obtained. For the compound of formula 1, the enantiomers can be separated by chiral chromatography.

[0367] Scheme M

[0368] [ka] Scheme M shows the preparation of the compound of formula 1, where R6 is defined as R6=Cl and X1, X2, and X3 are defined as X2=N and X1, and X3=C. By treatment of (M1), where Hal is defined as Cl and Y is defined as O, with chloroacetaldehyde in the presence of a base, (M2) can be obtained. By reaction of (M2) with bis(pinacolato)diborone under palladium-catalyzed conditions, a boronic acid (M3) can be obtained. By palladium-catalyzed coupling of (M3) with a suitable bromide, (M4) can be obtained. By demethylation of (M4) with NDM, (M5) can be obtained, which can then be reacted with the alcohol (C1e) or (C5) under Mitsunobu conditions to obtain (M6). By deprotection of (M6) under acidic conditions, (M7) can be obtained, which can then be subjected to reductive amination conditions with a suitable ketone to obtain the compound of formula 1. For the compound of formula 1, the enantiomer can be separated by chiral chromatography.

[0369] Scheme N

[0370] [ka] Scheme N shows two methods for preparing the compound of formula 2. In the first method, (N1) can be alkylated with alpha-bromoketone (B10) or (B10a) to obtain (N2). Subsequent deprotection of (N2) under acidic conditions can yield (N3), which can then be reacted with a suitable ketone to obtain the compound of formula 2. In the second method, (N6) can be alkylated with alpha-bromoketone (B10) or (B10a). Enantiomers of the compound of formula 2 can be separated by chiral chromatography.

[0371] The compound of formula 3 can be synthesized by treating the compound of formula 2 with a suitable Grignard reagent to obtain the compound of formula 3. The enantiomers of the compound of formula 3 can be separated by chiral chromatography.

[0372] The compound of formula 4 can be synthesized by two routes. In the first route, the reduction of the ketone of the compound of formula 2 can be achieved by treating it with NaBH4 to obtain the compound of formula 4. In the second route, the ketone (N2) can be reduced with NaBH4 to obtain (N4), which can then be deprotected under acidic conditions to obtain (N5). By treating (N5) with a suitable ketone under reductive amination conditions, the compound of formula 4 can be obtained. The enantiomers of the compound of formula 4 can be separated by chiral chromatography.

[0373] A person skilled in the art can recognize that compound (N1) can be substituted for compound (G5) or (H4). Furthermore, a person skilled in the art can also recognize that compound (N6) can be substituted for compound (F5).

[0374] The compound of formula (4a) can be synthesized by reacting trimethylsulfoxonium iodide in the presence of a base, followed by the addition of the compound of formula 4.

[0375] Scheme N1

[0376] [ka] Scheme N1 shows the asymmetric synthesis of the compounds of formulas 4b and 4c. The asymmetric reduction of the ketone (N2) can be achieved by treatment with chloro(n-[(1R,2R)-2-[(S)-[2-[[1,2,3,4,5,6-η]-4-methylphenyl]methoxy]ethyl]amino]-1,2-diphenylethylmethanesulfoneamidate)ruthenium(II) to obtain the alcohol (N4a). Deprotection of (N4a) under acidic conditions can yield the amine (N5a). Reductive amination of (N5a) with a suitable ketone can yield the compound of formula 4b.

[0377] Alkylation of the alcohol (N4a) with a suitable alkylating agent can yield the alkyl ether (N4b). Subsequent deprotection of (N4b) under acidic conditions can yield the amine (N4c). Reductive amination of (N4c) with a suitable ketone can yield the compound of formula 4c.

[0378] Scheme N2

[0379] [ka] Scheme N2 shows an alternative preparation for the compound of formula 3. The ketone (N2) can be reacted with a Grignard reagent to obtain the tertiary alcohol (N2a). By removing the protecting group of (N2a) under acidic conditions, the amine (N2b) can be obtained. By reacting (N2b) with a suitable ketone under reductive amination conditions, the compound of formula 3 can be obtained.

[0380] If R6=H for (N2a), treatment with NCS can yield a compound where R6=Cl for (N2b'). Subsequent treatment of (N2b') under acidic conditions can yield the amine (N2b).

[0381] Scheme N3

[0382] [ka] Scheme N3 shows an alternative route for the synthesis of the compound of formula 4c. Alkylation of the alcohol (N4) with a suitable alkylating agent can yield the alkyl ether (N4a'). Deprotection of (N4a') under acidic conditions can yield the amine (N4b'), which can then be reacted with a suitable ketone under reductive amination conditions to obtain the compound of formula 4c.

[0383] Scheme P

[0384] [ka] Scheme P shows the preparation of compounds of formula 6 or formula 7. To prepare the compound of formula 6, the compound of formula 4 is reacted with NaH and subsequently treated with a suitable alkylating agent to obtain the compound of formula 6. To prepare the compound of formula 6, the compound of formula 4 is reacted with MsCl to obtain (P1). Subsequent treatment of (P1) with a suitable amine yields the compound of formula 7.

[0385] Scheme P1

[0386] [ka] Scheme P1 shows an alternative preparation for the compound of formula 7. Mesylate (P1a) can be prepared by the reaction of (N4) with methanesulfonyl chloride. By substitution of mesylate (P1a) with an amine, alkylamino (P1b) can be obtained. By deprotection of (P1b) under acidic conditions, amine (P1c) can be obtained, which can then be reacted with a suitable ketone under reductive amination conditions to obtain the compound of formula 7.

[0387] For clarity, certain stereochemical centers are left unspecified and certain substituents are excluded in the following schemes, but this is not intended to limit the teaching of these schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers can be separated or decomposed by those skilled in the art at any convenient point in the synthesis of the compounds of the present invention by methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981 and ELEliel and SHWilen, "Stereochemistry of Organic Compounds," Wiley-Interscience, 1994). The designations "Isomer 1" and "Isomer 2" refer to the compounds that elute first and second from chiral chromatography, respectively, under the conditions described herein, and if chiral chromatography is initiated early in the synthesis, the same designations apply to subsequent intermediates and examples. Furthermore, the intermediates described in the following scheme may contain several nitrogen-protecting groups or oxygen-protecting groups. The variable protecting groups may be the same or different each time they appear, depending on the specific reaction conditions and transformations performed. The conditions for protection and deprotection 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," Fourth Edition, by Peter GMWuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0388] The designation "Isomer 1" was also used when the ketone was subjected to asymmetric reduction using the ruthenium catalyst described herein. The same designation was applied to subsequent intermediates and examples unless the examples were subjected to chiral chromatography. Asymmetric reduction of ketones to secondary alcohols using a ruthenium catalyst is publicly known in the literature (see, for example, J.Am.Chem.Soc.2011,133,14960-14963).

[0389] "AcOH" refers to acetic acid, "AcCN" refers to acetonitrile, "NH4OAc" refers to ammonium acetate, "NH4OH" refers to ammonium hydroxide, "aq." refers to aqueous solution, "BPR" refers to back pressure regulator, "NBS" refers to N-bromosuccinimide, "nBuOH" refers to 1-butanol, "n-BuLi" refers to n-butyllithium, "DCDMH" refers to 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione, "NCS" refers to N-chlorosuccinimide, "conc." indicates that it is concentrated, "cHex" refers to cyclohexane, "DE" refers to diatomaceous earth, "DHP" refers to 3,4-dihydropyran, "DIAD" refers to diisopropyl azodicarboxylate, and "DDQ" refers to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. "DCE" refers to 1,2-dichloroethane, "DCM" refers to dichloromethane, "DEA" refers to diethylamine, "Et2O" refers to diethyl ether, "DIPEA" refers to diisopropylethylamine, "DIEA" refers to diisopropylethylamine, "ex" refers to examples, "DMA" refers to dimethylacetamide, "DME" refers to 1,2-dimethoxyethane, "HA "TU" refers to N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethaneaminium hexafluorophosphate N-oxide, "NDM" refers to 1-dodecaneethiol, "DMEA" refers to dimethylethylamine, "NMO" refers to N-methylmorpholine N-oxide, "Et2O" refers to diethyl ether, and "DMF" refers to N,N-dimethylformamide is the term used in the Japanese abbreviations for methylmagnesium bromide. "DMSO" refers to dimethyl sulfoxide, "dppf" refers to 1'-bis(diphenylphosphino)ferrocene, "DPPA" refers to diphenylphosphoryl azide, "EtOH" refers to ethanol, "EA" refers to ethyl acetate, "EtMgBr" refers to ethylmagnesium bromide, "NFSI" refers to N-fluorobenzenesulfonimide, "FA" refers to formic acid, "h" refers to time, "hal" refers to halogen, "NIS" refers to N-iodosuccinimide, "IPA" refers to isopropyl alcohol, "IPAm" refers to isopropylamine, "i-PrMgCl" refers to isopropylmagnesium chloride, "L" refers to liter, "LDA" refers to lithium diisopropylamide, "MsCl" refers to methanesulfonyl chloride, "MeMgBr" refers to methylmagnesium bromide, and "MTBE" refers to methyl tert-br "MeTHF" refers to 2-methyltetrahydrofuran, "ml" refers to milliliters, "min" refers to minutes, "M" refers to moles, "PdCl2(DtBPF)" refers to [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), "KHMDS" refers to potassium bis(trimethylsilyl)amide, and "Pd(PPh3)4" refers to tetetrakis(triphenyl "Pd(dppf)Cl2" refers to palladium(0) phosphine, "Pd(dppf)Cl2" refers to (1,1'-bis(diphenylphosphino)ferrocene) palladium(II) dichloride, "Pd2(dba)3" refers to tris(dibenzylideneacetone) dipalladium(0) PE refers to petroleum ether, "POCl3" refers to phosphorus oxychloride, "KOAc" refers to potassium acetate, "t-BuOK" refers to potassium t-butoxide, "RT" refers to room temperature, "t, R" refers to retention time, "sat" refers to saturation, "NaOMe" refers to sodium methoxide, "Na(OAc)3BH" refers to sodium triacetoxyborohydride, "sat." refers to saturation, "soln" refers to solution, "SFC" refers to supercritical fluid chromatography, "THF" refers to tetrahydrofuran, "SOCl2" refers to thionyl chloride, "TsOH" refers to p-toluenesulfonic acid, "NEt3" and "E "t3N" refers to triethylamine, "Et3Si" refers to triethylsilane, "TFA" refers to trifluoroacetic acid, "SEM-Cl" refers to 2-(trimethylsilyl)ethoxymethyl chloride, "PPh3" refers to triphenylphosphine, "Dess-Martin" refers to 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, and "Xphos "Palladacycle Gen 4" refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II), "XPhos Pd G4" refers to dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphanium, methanesulfonic acid, N-methyl-2-phenylaniline, palladium, "ACN" refers to acetonitrile, "CAN" refers to acetonitrile, and "NSC" refers to N-chlorosuccinimide.

[0390] [Table 1]

[0391] Preparation 1 tert-butyl6-hydroxy-2-azaspiro[3,3]heptane-2-carboxylate

[0392] [ka] A 50 ml MeOH solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (3.6 g, 17 mmol) was cooled to 0°C and treated in several portions with NaBH4 (1.0 g, 26 mmol). The reaction mixture was stirred overnight and slowly warmed to room temperature. The reaction mixture was diluted with EA (100 ml) and washed with NaHCO3 aqueous solution (2 × 100 ml) and brine (100 ml). The organic layer was collected, dried over MgSO4, filtered, and concentrated to obtain the title compound (3.1 g, 85%) as a white solid. MS ES+m / z 158[MH- t AD] + .

[0393] The following compounds were prepared in a manner essentially similar to that of Preparation 1, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0394] [Table 2]

[0395] Preparation 4 tert-butyl6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate

[0396] [ka] A solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (3.1 g, 15 mmol) in DCM (35 ml) cooled to 0°C was treated with Et3N (3.6 ml, 26 mmol), followed by dropwise addition of methanesulfonyl chloride (1.5 ml, 19 mmol). The reaction mixture was stirred at 0°C and slowly warmed to room temperature. After stirring for 1 hour, the reaction mixture was diluted with EA (75 ml), washed with 50% brine (100 mL), collected, dried over MgSO4, filtered, and concentrated to obtain the title compound (4.3 g, 87%) as a white solid, which was used without purification. MS ES+m / z 236[MH- t AD]+ .

[0397] The following compounds were prepared in a manner essentially similar to that of Preparation 4, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0398] [Table 3]

[0399] Preparation 8 Benzyloxycyclobutanol

[0400] [ka] A mixture of 3-(benzyloxy)cyclobutan-1-one (20 g, 113.5 mmol) and NaBH4 (4.29 g, 113.5 mmol) in MeOH (50 ml) was stirred under N2 at room temperature for 2 hours. The reaction mixture was quenched with H2O at 0°C, extracted with EA (3 × 100 ml), washed with brine (2 × 100 ml), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (20 g, 99%) as a pale yellow oil. 1 H NMR(400MHz,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).

[0401] Preparation 9 tert-butyl(1R,5S)-3-azido-8-diazabicyclo[3.2.1]octane-8-carboxylate

[0402] [ka] A mixture of tert-butyl(1R,5S)-3-(p-tolylsulfonyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (4.5 g, 12 mmol) in DMSO (79 ml) was sonicated to aid in solubilization of the solid, and then treated with NaN3 (4 M in H2O, 4.1 ml, 17 mmol). 80 ml of this solution was then passed through a Uniqsis Flowsyn system consisting of a 14 ml Teflon reactor (1 / 16 inch) at a residence time of 40 minutes, temperature of 135 °C, and BPR of 10 bar. The reaction mixture was diluted with H2O (200 ml) and extracted with EA (2 × 100 ml). The combined organic matter was dried over MgSO4, filtered, and concentrated to obtain the title compound as a solution in DMSO, which was used in the next synthetic step without purification, assuming 100% conversion.

[0403] Preparation 10 tert-butyl(4R)-4-azide-3,3-difluoropiperidine-1-carboxylate

[0404] [ka] A solution of tert-butyl(4R)-4-amino-3,3-difluoropiperidine-1-carboxylate (2 g, 8.47 mmol) and K2CO3 (1.99 g, 14.39 mmol) in MeOH (20 ml) was treated with CuSO4·5H2O (0.21 g, 0.85 mmol) and 1H-imidazole-1-sulfonyl azide hydrochloride (2.13 g, 10.16 mmol) under N2 at room temperature and stirred overnight. The reaction mixture was diluted with H2O (50 ml) and extracted with EA (2 × 100 ml). The combined organic layers were washed with brine (2 × 50 ml), dried over Na2SO4, filtered, and concentrated to obtain the title compound (3.4 g, crude) as a yellow oil. 1 H NMR(300MHz,CDCl3)δ(ppm):4.25-4.14(m,1H),4.08-3.90(m,1H),3.76-3.71(m,1H) ,3.59-3.37(m,1H),3.20(d,1H),2.04-1.91(m,1H),1.69-1.54(m,1H),1.41(s,9H).

[0405] The following compounds were prepared in a manner essentially similar to that of Preparation 10, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0406] [Table 4]

[0407] Preparation 12 N-diazo-1,1,1-trifluoromethanesulfonamide

[0408] [ka] A solution of NaN3 (9.22 g, 142 mmol) and ammonium hydrogen tetra(buta-1-yl) sulfate (0.48 g, 1.42 mmol) in distilled H2O (30 mL) cooled to 0°C was slowly added to a solution of (CF3SO2)2O (8.00 g, 28.4 mmol) in heptane (25 mL). 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 × 10 mL). The combined organic layers were dried on a NaOH pellet. The organic layers were decanted, and the solution was immediately used in the next reaction.

[0409] Preparation 13 (1r,3r)-3-azidocyclobutanol

[0410] [ka] (1r,3r)-3-aminocyclobutan-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) were treated with a freshly prepared stock solution of N-diazo-1,1,1-trifluoromethanesulfonamide in heptane (4.96 g, 28.3 mmol). Additional MeOH was added to the reaction mixture in 5 mL increments until a homogeneous mixture was obtained (a total of 20 mL was added). The reaction mixture was stirred overnight at room temperature. EA was added and the layers were separated. The aqueous layer was extracted with EA (3x). The combined organic layers were concentrated under vacuum to obtain a dark green solution (1.60 g, 100%, estimated quantitative yield). 1 H NMR(400MHz,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).

[0411] Preparation 14 tert-butyl(3R,4R)-4-azido-3-fluoropiperidine-1-carboxylate

[0412] [ka] To tert-butyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (4 g, 18.24 mmol) and PPh3 (6.22 g, 23.72 mmol) in THF (40 ml), DIAD (5.53 g, 27.37 mmol) was added dropwise under N2 at 0°C, followed by dropwise addition of DPPA (5.52 g, 20.07 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with PE / EA (10:1) to obtain the title compound (1.7 g, 38%) as a pale yellow solid. 1H NMR(300MHz,DMSO-d6)δ 4.63-4.24(m,1H),4.09-3.83(m,2H),3.80-3.55(m,1H),3.20-2.84(m,2H),2.06-1.78(m,1H),1.42-1.36(m,10H).

[0413] The following compounds were prepared in a manner essentially similar to that of Preparation 14, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0414] [Table 5] 1 Purified by reverse-phase chromatography using a C18 column, eluting with 40%-50% ACN in H2O. 2 1 1H NMR (300MHz, DMSOd6). 3 Purification was performed by silica gel chromatography using PE / EA (20:1) elution. 4 Purification was performed by silica gel chromatography using PE / EA (15:1) elution. 5 1 1H NMR (400MHz, DMSOd6).

[0415] Preparation 19 tert-butyl 4-methyl-4-(5-methyl-4-trimethylsilyl-triazole-1-yl)piperidine-1-carboxylate

[0416] [ka] A mixture of tert-butyl 4-azido-4-methylpiperidine-1-carboxylate (4 g, crude) and trimethyl(propa-1-in-1-yl)silane (5.61 g, 49.94 mmol) was irradiated with microwave radiation at 150°C for 1 hour. After cooling to room temperature, the resulting mixture was concentrated in vacuum to obtain the title compound as a yellow solid (4.1 g, crude). MS ES+m / z 353[M+H] + .

[0417] The following compounds were prepared in a manner essentially similar to that of Preparation 19, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0418] [Table 6] 1 Toluene was used as the solvent for this conversion. 2 Purification was performed by silica gel chromatography using PE / EA (5:1~3:1) elution. 3 The solution was purified by silica gel chromatography using elution in heptane with 0% to 100% EA. 4 The reaction was carried out in toluene. a 1 H NMR(400MHz,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=8.38,8.38,5.14,5.14,0.73Hz,1 H)5.31(d,J=4.89Hz,1 H).

[0419] Preparation 26 tert-butyl 4-(4-bromo-5-methyl-triazole-1-yl)-4-methyl-piperidine-1-carboxylate

[0420] [ka] A mixture of tert-butyl 4-methyl-4-(5-methyl-4-trimethylsilyl-triazole-1-yl)piperidine-1-carboxylate (2.3 g, crude) and SiO2 (0.78 g, 13.05 mmol) in ACN (15 ml) was treated with NBS (1.74 g, 9.79 mmol) under N2 at room temperature. The resulting mixture was stirred under N2 at 80°C for 2 hours. After cooling to room temperature, the reaction was quenched with H2O and extracted with EA (2 × 200 ml). The combined organic layer was washed with brine (2 × 100 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to obtain the title compound as a yellow solid (2 g, 85%). MS ES+m / z( 79 Br / 81 Br)359 / 361[M+H] + .

[0421] The following compounds were prepared in a manner essentially similar to that of Preparation 26, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0422] [Table 7] 1 Purification was performed by silica gel chromatography using PE / EA (3:1) elution. 2 Purification was performed by silica gel chromatography using PE / EA (4:1) elution. 3 The solution was purified by silica gel chromatography using elution in heptane with 0% to 100% EA. a 1 H NMR(400MHz,DMSO-d6)δ 2.20(s,3H)2.37-2.47(m,2H)2.69-2.77(m,2H)4.41-4.49(m,1H)4.99-5.09(m,1H)5.09-5.67(m,1H).

[0423] Preparation 33 tert-butyl 4-(4-ethoxycarbonyl-5-methyl-triazole-1-yl)azepan-1-carboxylate

[0424] [ka] A solution of tert-butyl 4-(p-tolylsulfonyloxy)azepan-1-carboxylate (15 g, 38.57 mmol) in DMSO (120 ml) was stirred under N2. A solution of NaN3 (2.8 g, 42 mmol) in H2O (16.8 ml) was added. After stirring at room temperature for 30 minutes, a solution was obtained. The solution was subjected to the following flow chemistry conditions: reactor size 20 ml (Teflon type mas T: 150 °C), flow rate: 0.666 ml / mi, BPR 1.2 bar, temperature: 100 °C, residence time: 30 minutes. The intermediate azide was isolated as a solution in DMSO / H2O (8:1) (0.28 M, total 130 ml). The azide intermediate solution was used in the next step.

[0425] To the solution of the above azide intermediate, ethyl acetoethyl (5 ml, 39.30 mmol) and K2CO3 (12 g, 86.83 mmol) were added. The reaction mixture was stirred at room temperature for 15 minutes, then heated overnight at 80°C. The reaction mixture was cooled to room temperature and then diluted with H2O (100 ml). After stirring for 15 minutes, all solids dissolved. MTBE (100 ml) was added, and the mixture was stirred at room temperature for 15 minutes. The organic layer was separated, and the aqueous layer was extracted twice with MTBE (2 × 50 ml). The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the title compound (3.9 g, 25%, purity 75%). MS ES+m / z 353[M+H] + .

[0426] Preparation 34 tert-butyl(1R,5S)-3-(4-ethoxycarbonyl-5-methyl-triazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0427] [ka] To a stirred solution of tert-butyl(3-endo)-3-azido-8-azabicyclo[3.2.1]octane-8-carboxylate (3.63 g, 14.4 mmol) and ethyl 3-oxobutanoic acid (2.25 g, 17.3 mmol) in DMSO (29 ml), K2CO3 (5.97 g, 43.2 mmol) was added under N2 at room temperature. The reaction mixture was stirred at 85 °C for 6 hours. After cooling to room temperature, the reaction mixture was poured into ice / H2O (200 ml) while stirring. The resulting creamy precipitate was collected by filtration, washed with H2O (100 ml), and dried overnight at 40 °C to obtain the title compound (3.10 g, 59%). MS ES+m / z 365[MH- t AD] + .

[0428] Preparation 35 Ethyl 1-(3-benzyloxycyclobutyl)-5-methyltriazole-4-carboxylate

[0429] [ka] A stirred mixture of 3-(azidocyclobutoxy)methylbenzene (21 g, 103.32 mmol) and ethyl acetoethyl (14.79 g, 113.66 mmol) in DMF (100 ml) was mixed with K2CO3 (42.84 g, 309.97 mmol) under N2 at room temperature. The resulting mixture was stirred under N2 at 80°C for 2 hours. After cooling to room temperature, the reaction product was concentrated under vacuum. The mixture was diluted with H2O (300 ml) and extracted with EA (3 × 200 ml). The combined organic layers were washed with brine (3 × 200 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with 50% EA in PE to obtain the title compound (29 g, 93%) as a yellowish-brown oil. ES+m / z 316[M+H] + .

[0430] Preparation 36 1-[(1R,5S)-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octan-3-yl]-5-methyl-triazole-4-carboxylic acid

[0431] [ka] A solution of tert-butyl(1R,5S)-3-(4-ethoxycarbonyl-5-methyl-triazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 4.1 mmol) in H2O (8 ml) was treated with KOH (0.28 g, 5 mmol), stirred at room temperature for 1 hour, then at 55°C for 2 hours, and then at 40°C overnight. The reaction mixture was cooled to room temperature, quenched with 2 M aqueous HCl until the pH was approximately 2, and extracted with EA (2 × 30 ml). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound (1.16 g, 84%), which was used in the next synthetic step without purification or analysis.

[0432] The following compounds were prepared in a manner essentially similar to that of Preparation 36, using appropriate reagents and adjusting the reaction time to determine the completion of the reaction. MeOH can be used as a co-solvent.

[0433] [Table 8]

[0434] Preparation 38a tert-butyl6-(4-bromo-5-methylpyrazole-1-yl)-2-azaspiro[3.3]heptan-2-carboxylate

[0435] [ka] and Preparation 38b tert-butyl6-(4-bromo-3-methylpyrazole-1-yl)-2-azaspiro[3.3]heptan-2-carboxylate

[0436] [ka] A DMSO suspension (10 ml) of tert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g, 8.6 mmol) and 4-bromo-5-methyl-1H-pyrazole (1.2 g, 7.5 mmol) was treated with Cs2CO3 (5.7 g, 17 mmol), and the reaction mixture was stirred at 50°C for 12 hours, then placed in a refrigerator. After 4 days, the reaction mixture was poured over ice and H2O, which resulted in the formation of a precipitate. Insoluble material was removed by filtration and washed with H2O to obtain the title compound (2.7 g, 44%) as a mixture. MS ES+m / z 300 / 302[M+H-tBu] + .

[0437] Preparation 39a tert-butyl2-(4-bromo-5-methylpyrazole-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0438] [ka] and Preparation 39b tert-butyl 2-(4-bromo-3-methylpyrazole-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0439] [ka] 10 ml of DMF contained tert-butyl 2-methylsulfonyloxy-7-azaspiro[3.5]nonane-7-carboxylate (1.41 g, 4.41 mmol) and 4-bromo-5-methyl-1H-pyrazole (0.67 g, 4.14 mmol), which were treated with Cs2CO3 (2.02 g, 6.2 mmol) at room temperature. After stirring at 90°C for 3.5 hours, the reaction mixture was stirred at room temperature over the weekend. Another portion of 4-bromo-5-methyl-1H-pyrazole (0.67 g, 4.14 mmol) and another portion of Cs2CO3 (2.02 g, 6.2 mmol) were added, and the reaction mixture was stirred at 90°C for 2 hours. Another portion of 4-bromo-5-methyl-1H-pyrazole (0.67 g, 4.14 mmol) was added, and the mixture was stirred at 90°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with H2O (50 ml) and extracted with EA (twice). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The resulting oily substance was purified by silica gel chromatography eluting with 33% EA in hexane to obtain the title compound (1.68 g) as a mixture. MS ES+m / z 328 / 330[M+H-tBu] + .

[0440] The following compounds were prepared in a manner essentially similar to that of preparations 39a and 39b, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0441] [Table 9]

[0442] Preparation 42 1-(1-tert-butoxycarbonylazetidine-3-yl)-5-methyl-triazole-4-carboxylic acid

[0443] [ka] To a solution of 1-(1-tert-butoxycarbonylazetidine-3-yl)-5-methyl-triazole-4-carboxylate (12.15 g, 39.14 mmol) in THF (75 ml), aqueous LiOH (75 ml, 75 mmol, 1 M) was added, and the reaction mixture was stirred overnight at room temperature. After stirring for 18 hours, aqueous HCl (1 N) was added until the pH reached 5-6. The mixture was extracted with EA and DCM / MeOH (9:1) (5 times). The combined organic layer was dried over MgSO4, and the filtrate was concentrated to obtain the title compound (10.3 g, 93%) as a light brown solid. MS ES+m / z 283[M+H] + .

[0444] Preparation 43 1-(1-tert-butoxycarbonylazepan-4-yl)-5-methyltriazole-4-carboxylic acid

[0445] [ka] To a stirred solution of tert-butyl 4-(4-ethoxycarbonyl-5-methyl-triazole-1-yl)azepan-1-carboxylate (3.1 g, 8.8 mmol) in THF (15 ml), aqueous LiOH (15 ml, 15 mmol, 1 M) was added, and the reaction mixture was stirred at room temperature for 210 minutes. Aqueous HCl (1 N) was added until the pH reached approximately 5-6. The reaction mixture was extracted twice with EA and twice with 10% MeOH in DCM. The organic layers were combined, dried over MgSO4, filtered, and the filtrate was concentrated under vacuum to obtain the title compound (2.89 g, 96%, 95% by mass). MS ES+m / z 296[M+H] + .

[0446] Preparation 44 tert-butyl(3S)-3-(4-bromo-5-methylpyrazole-1-yl)piperidine-1-carboxylate

[0447] [ka] To tert-butyl(3S)-3-(4-bromopyrazole-1-yl)piperidine-1-carboxylate (500 mg, 1.51 mmol) in THF (5 ml), LDA in hexane (2.3 ml, 4.6 mmol, 2 M) was added at -70°C and stirred for 0.5 hours. Next, CH3I (0.19 mL, 3.1 mmol) was added and stirring continued for 30 minutes. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 ml) and concentrated. The mixture was extracted with EA (3 × 20 ml). The combined organic layers were washed with brine (3 × 20 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether / EA (1:0~10:1) to obtain the title compound (0.4 g, yield 70%) as a yellow oil. MS ES+m / z( 79 Br / 81 Br)344 / 346[M+H] + .

[0448] The following compounds were prepared in a manner essentially similar to that of Preparation 44, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0449] [Table 10]

[0450] Preparation 46 tert-butyl 4-(4-bromo-5-methyl-triazole-1-yl)piperidine-1-carboxylate

[0451] [ka] A solution of 1-(1-tert-butoxycarbonyl-4-piperidyl)-5-methyl-triazole-4-carboxylic acid (17 g, 55 mmol) and KOH (3.7 g, 66 mmol) in H2O (60 ml) was treated in several portions with Br2 (10.4 g, 66 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction product was extracted with EA (3 × 30 ml). The combined organic layer was washed with brine (2 × 150 mL), dried over Na2SO4, filtered, and concentrated to obtain the title compound (13 g, 68%) as a yellow solid. MS ES+m / z 345[M+H] + .

[0452] The following compounds were prepared in a manner essentially similar to that of Preparation 46, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0453] [Table 11] 1 Before workup, the reactants were diluted with a 2N NaOH aqueous solution. a 1 H NMR(400MHz,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).

[0454] Preparation 51 (1s,3s)-[3-(4-bromo-5-methyltriazole-1-yl)cyclobutyl]4-nitrobenzoate

[0455] [ka] To a solution of DIAD (4.18 g, 20.68 mmol) in THF (40 ml), PPh3 (5.88 g, 22.41 mmol) was added dropwise under N2 at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Next, under N2 at room temperature, (1r,3r)-3-(4,5-dimethyl-1H-1,2,3-triazole-1-yl)cyclobutan-1-ol (4.0 g, 17.24 mmol) and p-nitrobenzoic acid (3.46 g, 20.68 mmol) were added in several portions. The mixture was stirred at room temperature for 2 hours, and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to obtain the title compound (8 g, crude) as a white solid. MS ES+m / z( 79 Br / 81 Br)381 / 383[M+H] + .

[0456] Preparation 52 (1s,3s)-3-(4-bromo-5-methyl-1H-1,2,3-triazole-1-yl)cyclobutan-1-ol

[0457] [ka] To a stirred solution of (1s,3s)-[3-(4-bromo-5-methyl-triazole-1-yl)cyclobutyl]4-nitrobenzoate (8.0 g, crude) in THF (50 ml), LiOH·H2O (0.79 g, 18.89 mmol) was added in several portions under N2 at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, C18; mobile phase, 10%~50% ACN (0.1% FA) in H2O to obtain the title compound (2.5 g, 51%) as a yellow oily substance. MS ES+m / z( 79 Br / 81 Br)232 / 234[M+H] + . 1H NMR(300MHz,DMSO-d6)δ 5.46-5.28(m,1H),4.55-4.40(m,1H),4.14-3.90(m,1H),2.87-2.76(m,2H),2.49-2.41(m,2H),2.25-2.19(m,3H).

[0458] Preparation 53 3-(4-bromo-5-methyl-triazole-1-yl)cyclobutanol

[0459] [ka] A mixture of 1-(3-benzyloxycyclobutyl)-4-bromo-5-methyl-triazole (8.5 g, 26.4 mmol) and FeCl3 (8.56 g, 52.8 mmol) in DCM (100 ml) was stirred under N2 at 50°C for 2 hours. After cooling to room temperature, the mixture was diluted with H2O (50 ml) and extracted with EA (3 × 100 ml). The combined organic layer was washed with brine (2 × 100 ml), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain the title compound (8 g, crude) as a brown solid. 1 H NMR(400MHz,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).

[0460] Preparation 54 4-(4-bromo-5-methyltriazole-1-yl)piperidine hydrochloride

[0461] [ka] A solution of tert-butyl 4-(4-bromo-5-methyl-triazole-1-yl)piperidine-1-carboxylate (58 g, 159.6 mmol) in 2-propanol (60 ml) was treated with HCl in 2-propanol (250 ml, 1250 mmol, 4.99 M) and stirred overnight. The reaction mixture was diluted with MTBE (250 ml), and the resulting suspension was stirred at room temperature for 1 hour. The suspension was filtered to obtain the title compound (41.5 g, 91%) as a white solid. MS ES+m / z( 79 Br / 81 Br)245 / 247[M+H] + .

[0462] Preparation 55 4-(4-bromo-3,5-dimethylpyrazole-1-yl)piperidine

[0463] [ka] A DCM solution (15 ml) of tert-butyl 4-(4-bromo-3,5-dimethylpyrazole-1-yl)piperidine-1-carboxylate (0.97 g, 2.70 mmol) was treated with TFA (4 ml), and the reaction mixture was stirred at room temperature. After stirring for 45 minutes, the reaction mixture was loaded onto an SCX column pre-treated with MeOH. The column was washed with MeOH. The title compound was eluted with 2 M NH3 in MeOH, and concentrated to obtain the title compound (557 mg, 80%) as a colorless oil. MS ES+m / z( 79 Br / 81 Br)258 / 260[M+H] + .

[0464] The following compounds were prepared in a manner essentially similar to that of Preparation 55, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0465] [Table 12] 1The crude product was loaded into an SCX cartridge. Non-basic impurities were washed away from the cartridge with MeOH, and then the title compound was eluted with methanolic ammonia (2N).

[0466] Preparation 57 3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanone

[0467] [ka] A mixture of 3-(4-bromo-5-methyl-triazole-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 EA (3 × 100 mL), washed with brine (2 × 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by reverse-phase chromatography under the following conditions: column, C18; mobile phase, 20%~40% ACN (0.1% FA) in H2O to obtain the title compound (2.10 g, 52.96%) as a white solid. ES / MS m / z( 79 Br / 81 Br)230 / 232[M+H] + .

[0468] Preparation 58 (1s,3s)-[3-(4-bromo-5-methyltriazole-1-yl)cyclobutyl]trifluoromethanesulfonate

[0469] [ka] (1.1 g, 4.74 mmol) and DIEA (3.06 g, 23.70 mmol) in DCM (10 ml) were mixed with trifluoromethanesulfonate (2.01 g, 7.11 mmol) dropwise at -70°C under N2. The reaction mixture was stirred at -70°C for 1 hour. The mixture was used in the next step assuming 100% conversion without further purification. ES / MS m / z( 79 Br / 81 Br)364 / 366[M+H] + .

[0470] Preparation 59 tert-butyl 4-((1r,3r)-3-(4-bromo-5-methyl-1H-1,2,3-triazole-1-yl)cyclobutyl)piperazine-1-carboxylate

[0471] [ka] (1.7 g, 4.67 mmol) of (1s,3s)-[3-(4-bromo-5-methyl-triazole-1-yl)cyclobutyl]trifluoromethanesulfonate and DIEA (1.81 g, 14.01 mmol) in DCM (10 ml) were mixed with tert-butylpiperazine-1-carboxylate (1.74 g, 9.34 mmol) in several portions under N2 at -70°C. The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to obtain the title compound (1.1 g, 59%) as a white solid. ES / MS m / z( 79 Br / 81 Br)400 / 402[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 5.02-4.90(m,1H),3.38-3.35(m,4H),3.08-2.96(m,1H),2.65-2.52(m,4H),2.32-2.23(m,4H),2.23-2.20(m,3H),1.40(s,9H).

[0472] Preparation 60 tert-butyl 4-[3-(4-bromo-5-methyl-triazole-1-yl)cyclobutyl]piperazine-1-carboxylate

[0473] [ka] 3-(4-bromo-5-methyl-triazole-1-yl)cyclobutanone (1.67 g, 7.25 mmol) and tert-butylpiperazine-1-carboxylate (0.90 g, 4.83 mmol) were added to MeOH (5 ml) in several portions at room temperature. The resulting mixture was stirred under N2 at 50°C for 30 minutes. Next, NaBH3CN (0.61 g, 9.66 mmol) was added under N2 at room temperature in several portions. The reaction mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with H2O (100 ml) and the pH was adjusted to approximately 7 with saturated NaHCO3 aqueous solution. The mixture was extracted with EA (3 × 100 ml). The organic layers were combined, washed with brine (2 × 100 ml), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 1% to 50% EA in PE to obtain the title compound (1.4 g, 72%) as an oil. ES / MS m / z( 79 Br / 81 Br)400 / 402[M+H] + .

[0474] Preparation 61 4-(4-bromo-5-methyl-triazol-1-yl)-1-(oxetan-3-yl)piperidine

[0475] [ka] A 700 ml solution of 4-(4-bromo-5-methyl-triazole-1-yl)piperidine hydrochloride (41 g, 142.69 mmol) in MeOH (700 ml) was treated with oxetan-3-one (35 g, 485.7 mmol) under N2 conditions and stirred at room temperature for 5 minutes. The reaction mixture was treated with AcOH (11.53 g, 192 mmol) and stirred for 5 minutes, then treated with NaBH3CN (35 g, 556.95 mmol) in several portions over 1 hour. The reaction mixture was stirred at room temperature for 30 minutes, then stirred overnight at 30°C. After cooling to room temperature, the reaction mixture was quenched with H2O (50 ml) and the pH was adjusted to 9 with 2 M K3PO4 aqueous solution (75 ml). The organic solvent was removed under vacuum. The resulting suspension was diluted with H2O (30 ml), stirred for 30 minutes, and filtered to obtain the title compound (30 g, 62%) as a pale white solid. MS ES+m / z 301 / 303[M+H] + .

[0476] Preparation 62 4-(4-bromo-3,5-dimethylpyrazole-1-yl)-1-(oxetan-3-yl)piperidine

[0477] [ka] NaBH3CN (0.51 g) was added to a solution of 4-(4-bromo-3,5-dimethylpyrazole-1-yl)piperidine (0.56 g, 2.18 mmol), oxetane-3-one (292 mg, 4.05 mmol), and AcOH (0.15 ml, 2.62 mmol) in MeOH (10 ml). The resulting mixture was stirred at room temperature for 15 minutes, then at 50°C for 18 hours. After cooling to room temperature, the reaction product was concentrated under vacuum. The residue was suspended in DCM and washed with a saturated solution of NaHCO3. The organic phase was separated, and the aqueous phase was extracted with DCM (twice). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of elution in cHex with 0% to 100% EA followed by 0% to 20% MeOH in DCM, and the title compound (510 mg, 60%) was obtained as a white solid. MS ES+m / z( 79 Br / 81 Br)314 / 316[M+H] + .

[0478] The following compounds were prepared in a manner essentially similar to that of Preparation 62, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0479] [Table 13] 1 Purification was performed by silica gel chromatography, which elutes with 0% to 10% MeOH in DCM.

[0480] Preparation 64 (1R,5S)-3-(4-bromo-5-methyl-triazol-1-yl)-8-(oxetane-3-yl)-8-azabicyclo[3.2.1]octane

[0481] [ka] To a solution of tert-butyl(1R,5S)-3-(4-bromo-5-methyl-triazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.03 g, 2.77 mmol) in 1,4-dioxane (5 ml, 58.57 mmol), HCl (3 ml, 12 mmol, 4 mol / L) in 1,4-dioxane was added, and the mixture was stirred at room temperature for 1 hour, then heated at 50°C for 1 hour, and stirred overnight at room temperature. The reaction product was concentrated under vacuum to obtain the intermediate (1R,5S)-3-(4-bromo-5-methyl-triazole-1-yl)-8-azoniabicyclo[3.2.1]octane hydrochloride as a solid. This substance was used in the next step without further purification or characterization.

[0482] To a solution of (1R,5S)-3-(4-bromo-5-methyl-triazol-1-yl)-8-azoniabicyclo[3.2.1]octane hydrochloride (0.75 g, 2.44 mmol) in MeOH (10 ml), 3-oxetanone (0.7 mL, 10 mmol) was added. The mixture was stirred at room temperature for 5 minutes, then NaBH3CN (0.7 g, 10 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was heated at 50 °C for 9 hours. Additional 3-oxetanone (170 μl, 2.79 mmol) and NaBH3CN (170 mg, 2.70 mmol) were added, and the reaction mixture was stirred overnight at 50 °C. The reaction mixture was quenched with H2O and extracted with EA (3 × 25 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%-20% EA in DCM, followed by 0-5% MeOH in DCM. The title compound (630 mg, 69%) was obtained as an orange solid. ES+m / z( 79 Br / 81 Br)327 / 329[M+H] + .

[0483] Preparation 65 2-Chloro-4-cyclopropyl-5-fluoropyridine

[0484] [ka] A solution of 2-chloro-5-fluoro-4-iodopyridine (1.50 g, 5.827 mmol) and Pd(PPh3)4 (674 mg, 0.583 mmol) in THF (5 ml) was degassed by three freeze-pump-thaw cycles. A solution of cyclopropyl zinc bromide (30 ml, 15.150 mmol, 0.5 M in THF) was added dropwise at 0°C. The reaction mixture was stirred overnight and slowly warmed to room temperature. The reaction mixture was quenched with H2O and extracted with EA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EA in heptane to obtain the title compound as a colorless oil (758 mg, 76%). ES+m / z 172.1[M+H] + .

[0485] Preparation 66 3-Chloro-5-(trifluoromethyl)pyridazine

[0486] [ka] A solution of 4-(trifluoromethyl)-1H-pyridazin-6-one (10 g, 60.94 mmol) and POCl3 (46.72 g, 304.72 mmol) in ACN (80 ml) was stirred overnight at 80°C under N2. The mixture was cooled to room temperature, poured into H2O / ice (300 ml), and basicized to pH 8 with NaHCO3. The resulting mixture was extracted with EA (3 × 100 ml). The combined organic layers were washed with brine (1 × 100 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (40:1~10:1) to obtain the title compound (5 g, 45%) as a yellow oil. MS ES+m / z 183[M+H] + .

[0487] Preparation 67 5-Fluoro-2-[1-(trifluoromethyl)vinyl]pyridine

[0488] [ka] Solutions of 2-bromo-5-fluoropyridine (8 g, 45.46 mmol) and 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (11.10 g, 50.00 mmol) in DME (40 ml) and H2O (10 ml) were treated with K2CO3 (18.85 g, 136.37 mmol) and Pd(PPh3)4 (1.05 g, 0.91 mmol) under N2. After stirring at 100°C for 2 hours, the mixture was diluted with H2O (100 ml) and extracted with EA (3 × 100 ml). The combined organic layers were washed with brine (3 × 100 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (20-10:1) to obtain the title compound (3.4 g, 39%) as an off-white oil. MS ES+m / z 192[M+H] + .

[0489] Preparation 68 3-(1-ethoxyvinyl)-5-(trifluoromethyl)pyridazine

[0490] [ka] To a mixture of tributyl(1-ethoxyethenyl) stannane (11.87 g, 32.87 mmol) and 3-chloro-5-(trifluoromethyl)pyridazine (5.00 g, 27.39 mmol) in 1,4-dioxane (40 ml), Pd(PPh3)4 (0.95 g, 0.82 mmol) was added under N2 at room temperature. The reaction mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was purified by silica gel column chromatography eluting with PE / EA (30:1~12:1) to obtain the title compound (4.6 g, 77%) as a yellow oily substance. MS ES+m / z 219[M+H] + .

[0491] The following compounds were prepared in a manner essentially similar to that of Preparation 68, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0492] [Table 14] 1 Purification was performed by silica gel chromatography using PE / EA (10:1~5:1) elution. 2 The reactants were quenched with a saturated KF aqueous solution. 3 EA was purified by silica gel chromatography that elutes it in heptane.

[0493] Preparation 72 N-methoxy-N-methyl-1-(trifluoromethyl)pyrazole-3-carboxamide

[0494] [ka] 1-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (780 mg, 4.33 mmol) was dissolved in SOCl2 (10 ml) and stirred under reflux for 2 hours. The reaction mixture was concentrated in vacuum, then redissolved in DCM (8.5 ml) at 0°C, and DIPEA (2.2 ml, 12.84 mmol) was added, followed by N,O-dimethylhydroxylamine hydrochloride (840 mg, 8.56 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted in DCM, washed with saturated NaHCO3 solution, the combined organic phase was dried over MgSO4, filtered, and the filtrate was concentrated in vacuum to obtain the title compound as a pale yellow oil (809 mg, 85%). MS ES+m / z 224.1[M+H] + .

[0495] Preparation 73 N-methoxy-N-methyl-5-(trifluoromethyl)pyridine-3-carboxamide

[0496] [ka] A DCM suspension (60 ml) of 5-(trifluoromethyl)pyridine-3-carboxylic acid (4 g, 20.93 mmol) was treated with 1,1'-carbonyldiimidazole (3.73 g, 23 mmol) and Et3N (5.8 mL, 42 mmol). The reaction mixture was stirred at room temperature for 3 hours, diluted with H2O, the organic phase was collected, and the aqueous phase was re-extracted with DCM. The combined organic layers were washed with saturated NaHCO3 aqueous solution, collected, dried over MgSO4, filtered, and concentrated to obtain the title compound (3.75 g) as a yellow oil, which was used without purification. MS ES+m / z 235[M+H] + .

[0497] Preparation 74 N-methoxy-N,2,5-trimethylthiazole-4-carboxamide

[0498] [ka] 2,5-dimethylthiazole-4-carboxylic acid (1.25 g, 7.95 mmol) and ammonium methoxy(methyl) chloride (1.95 g, 20.0 mmol) were dissolved in ice-cold solution in DMF (10 ml), to which NEt3 (2.85 g, 28 mmol) was added. The mixture was stirred at room temperature for 5 minutes, then HATU (3.6 g, 9.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into H2O, the aqueous solution was extracted with DCM (twice), the combined organic layer was washed with 10% LiCl aqueous solution, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 30% EA in cHex to obtain the title compound. The title compound was used in the next step.

[0499] Preparation 75 1-[5-(trifluoromethyl)pyridazin-3-yl]ethanone

[0500] [ka] A solution of 3-(1-ethoxyethenyl)-5-(trifluoromethyl)pyridazine (1.0 g, 4.58 mmol) and concentrated HCl (2.26 g, 22.92 mmol) in THF (10 ml) was stirred at room temperature under N2 for 1 hour. The resulting mixture was diluted with H2O (10 ml), basicized to pH 8 with NaHCO3, and extracted with MTBE (3 × 20 ml). The combined organic layers were washed with brine (1 × 10 ml), dried over anhydrous Na2SO4, collected, and filtered. The filtrate was concentrated to obtain the title compound (810 mg, 93%) as a yellow solid. MS ES+m / z 191[M+H] + .

[0501] The following compounds were prepared in a manner essentially similar to that of Preparation 75, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0502] [Table 15]

[0503] Preparation 77 1-(4-cyclopropyl-5-fluoro-2-pyridyl)ethanone

[0504] [ka] A solution of 2-chloro-4-cyclopropyl-5-fluoropyridine (617 mg, 3.60 mmol) and Pd(PPh3)4 (416 mg, 0.36 mmol) in toluene (10 ml) was degassed by vacuum / N2 cycles (3 times). Tributyl(1-ethoxyvinyl)tin (1.56 mL, 4.32 mmol) was added, and the mixture was stirred under N2 at 100°C for 6 hours. The reaction product was treated with saturated KF aqueous solution (2.5 mL), filtered through a DE pad, and the cake was washed with EA (30 ml). The phase was separated from the filtrate. The organic phase was washed with saturated NaHCO3 aqueous solution (3 × 20 ml) and brine (20 ml), dried over MgSO4, filtered, and concentrated under vacuum to obtain the intermediate vinyl ether as a brown oily substance.

[0505] The intermediate vinyl ether was dissolved in THF (10 ml), then aqueous HCl (2 M, 5 ml) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was treated with saturated aqueous NaHCO3 (30 ml), and the mixture was vigorously stirred for 10 minutes. The aqueous phase was extracted with EA (3 × 25 ml), the combined organic layers were washed with brine (25 ml), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EA in heptane to obtain the title compound as a colorless oil (226 mg, 35%). ES+m / z 180.1[M+H] + .

[0506] The following compounds were prepared in a manner essentially similar to that of Preparation 77, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0507] [Table 16]

[0508] Preparation 79 1-[5-(trifluoromethyl)-3-pyridyl]ethanone

[0509] [ka] A solution of N-methoxy-N-methyl-5-(trifluoromethyl)pyridine-3-carboxamide (2 g, 6.41 mmol, 75% by mass) in 30 ml of THF at 0°C was treated dropwise with MeMgBr (10 mL, 14 mmol, 1.4 M in toluene / THF[3:1]) and stirred for 1 hour. The reaction mixture was quenched with saturated NH4Cl aqueous solution at 0°C, diluted with H2O, and extracted with EA (twice). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The resulting oily substance was purified by silica gel chromatography with elution at a gradient of 0% to 80% EA in cHex to obtain the title compound (1.0 g, 83%) as a white solid. 1H NMR (400MHz, CDCl3): δ 9.35(d,J=1.9Hz,1H),9.07(d,J=1.5Hz,1H),8.48-8.47(m,1H),2.72(s,3H).

[0510] The following compounds were prepared in a manner essentially similar to that of Preparation 79, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0511] [Table 17] a The material was used in subsequent processes without further characterization. 1 Purification was performed by silica gel chromatography, which elutes with 0% to 30% EA in cHex.

[0512] Preparation 83 Methyl 1-(5-bromo-2-pyridyl)-3,3-difluorocyclobutanecarboxylate

[0513] [ka] A toluene (50 mL) solution of 5-bromo-2-fluoropyridine (7.0 g, 39.78 mmol) and methyl 3,3-difluorocyclobutane-1-carboxylate (6.57 g, 43.75 mmol) was added dropwise with KHMDS (51.7 ml, 51.71 mmol, 1.0 M in THF) under a nitrogen atmosphere at -70°C. After stirring at -70°C for 30 minutes, the reaction mixture was quenched with saturated NH4Cl aqueous solution at room temperature, acidified to pH 1-2 with HCl aqueous solution (1.2 M), and extracted with EA (3 × 100 ml). The combined organic layer was washed with brine (2 × 100 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (11 g, crude) as a yellow solid. The crude was used directly without further purification. MS ES+m / z( 79 Br / 81 Br)306 / 308[M+H] + .

[0514] Preparation 84 1-Methyl-2-(2-pyridyl)pyrrolidine-3-ol

[0515] [ka] To a solution of 2-(2-pyridyl)pyrrolidine-3-ol (450 mg, 2.74 mmol) in DCM (40 ml), H2CO (13.31 mol / L) in H2O (0.65 ml) was added. After stirring for 10 minutes, Na(OAc)3BH (0.9 g, 4 mmol) was added. The mixture was stirred overnight at room temperature. The reaction product was quenched with saturated NaHCO3 aqueous solution. The aqueous phase was acidified to pH 2 with HCl and then directly loaded onto an SCX column. The title compound was eluted with 2N NH3 in MeOH to obtain the title compound (200 mg, 9%). MS ES+m / z 179[M+H] + .

[0516] Preparation 85 1-[1-(trifluoromethyl)pyrazole-3-yl]ethanol

[0517] [ka] MeMgBr (0.21 ml, 1.80 mmol, 3M) was added to a solution of N-methoxy-N-methyl-1-(trifluoromethyl)pyrazole-3-carboxamide (329 mg, 2.00 mmol) in THF (2.7 ml) under N2 conditions at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was carefully quenched with AcOH (0.13 ml, 2.25 mmol) and diluted with MeOH (2 ml). Next, NaBH4 (102 mg, 2.70 mmol) was added all at once, and the reaction mixture was stirred at 0°C for 40 minutes. The reaction mixture was diluted with saturated NH4Cl aqueous solution (4 ml), extracted with Et2O (2 × 5 ml) and DCM (2 × 5 ml), the combined organic phase was dried over MgSO4, filtered, and the solvent was concentrated under vacuum to obtain the title compound as a pale yellow oily substance (174 mg, quantitative). ES+m / z 180.9[M+H] + .

[0518] Preparation 86 1-(1-methylpyrrolo[2,3-c]pyridine-4-yl)ethanol

[0519] [ka] A 0.5 M solution of lithium dibutyl(methyl)magnesium oxide was prepared by adding MeMgBr (5 ml, 15 mmol) and n-BuLi (18.75 mL, 30 mmol) to THF (6.25 ml) in a round-bottom flask at 0°C.

[0520] A stock solution of lithium dibutyl(methyl)magnesate (10 ml, 5 mmol) was added dropwise to a solution of 4-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridine (979 mg, 4.64 mmol) in THF (25 ml) at -40°C. After 1 hour, acetaldehyde (2.6 ml, 46.40 mmol) was added at -40°C. The reaction mixture was stirred for 1 hour and the temperature was raised to -20°C. The reaction mixture was quenched with saturated NH4Cl and then extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with MeOH in DCM to obtain the title compound as a solid (548 mg, 67%). MS ES+m / z 177.1[M+H] + .

[0521] Preparation 87 1-(1-methylpyrazolo[3,4-c]pyridine-4-yl)ethanol

[0522] [ka] To a solution of MeMgBr (1.67 ml, 3.0 M solution, 5.0 mmol) in THF (10 ml), n-BuLi (6.25 ml, 1.6 M solution in hexane, 10.0 mmol) was added under N2 at 0°C. The reaction mixture was stirred for 30 minutes and then cooled to -40°C. Next, 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (1.01 g, 4.76 mmol) was added to the reaction mixture. The resulting suspension was stirred briefly (about 2 minutes) at 0°C to completely dissolve the solid. The solution was cooled again to -40°C and stirred for 1 hour. Next, acetaldehyde (2.65 ml, 8.9 mmol) was added dropwise. The solution was stirred at -40°C for 90 minutes, and then the reaction mixture was treated with saturated NH4Cl solution and diluted with EA. The phases were separated, and the aqueous layer was extracted with EA (4 times). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with MeOH in DCM to obtain the title compound as a beige solid (372 mg, 44%). MS ES+m / z 178.2[M+H] + .

[0523] Preparation 88 1-(1-isopropyltriazole-4-yl)ethanol

[0524] [ka] MeMgBr in Et2O (2.5 M, 2.2 ml, 5.47 mmol) was added dropwise to a solution of 1-isopropyl-1H-1,2,3-triazole-4-carbaldehyde (508 mg, 3.65 mmol) in THF (5 ml) under N2 at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. The solution was then cooled to 0°C, quenched with saturated NH4Cl (aqueous solution, 25 ml), and extracted with DCM (3 × 25 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to obtain the title compound as a pale yellow oil (558 mg, 99%). MS ES+m / z 156.2[M+H] + .

[0525] The following compounds were prepared in a manner essentially similar to that of Preparation 88, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0526] [Table 18]

[0527] Preparation 92 1-(2-isopropylthiazole-4-yl)ethanol

[0528] [ka] 4-bromo-2-isopropyl-2H-1,2,3-triazole (1.00 g, 5.26 mmol) was dissolved in 10 ml of THF under N2 and cooled to -78°C. A solution of n-BuLi (3.62 ml, 5.79 mmol, 1.6 M in hexane) was added dropwise. The solution was stirred at -78°C for 45 minutes, then acetaldehyde (1.63 ml, 26.31 mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with H2O (30 mL), extracted with EA (3 × 15 ml), and the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography eluting with MeOH in DCM to obtain the title compound as a pale yellow oil (299 mg, 37%). 1 H NMR(400MHz,CDCl3)δ(ppm):7.51(s,1H),5.04(q,J=6.5Hz,1H),4.79(hept,J=6.7Hz,1H),1.57(t,J=6.5Hz,3H),1.56(d,J=6.7Hz,6H).

[0529] The following compounds were prepared in a manner essentially similar to that of Preparation 92, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0530] [Table 19] 1 Purification was performed by silica gel chromatography, which elutes with 10% to 50% EA in cHex.

[0531] Preparation 94 1-[5-difluoromethyl)-3-pyridyl]ethanol

[0532] [ka] In a separate flask, a degassed (by sonication) solution of 1-[5-(difluoromethyl)-3-pyridyl]ethanone (856 mg, 5.00 mmol) in aqueous FA solution (2.1 g, 1.7 ml, 45 mmol) and NEt3 (6.0 g, 60 mmol) was added to [[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-(p-trisulfonyl)amino]-chlororuthenium;1-isopropyl-4-methylbenzene (29 mg, 0.05 mmol) at room temperature. The mixture was stirred overnight under N2 at room temperature. H2O and EtOH were added to the mixture and partially evaporated. Saturated aqueous NaHCO3 solution was added to ensure a high pH, ​​and the mixture was extracted with EA (4 times). The combined organic layers were dried over Na2SO4 and filtered. DE was added, and the suspension was evaporated. The residue was purified by silica gel chromatography with elution in cHex under a gradient of 30% to 90% EA to obtain the title compound (815 mg, 94%) as a green oily substance. MS ES+m / z 174[M+H] + .

[0533] The following compounds were prepared in a manner essentially similar to that of Preparation 94, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0534] [Table 20] 1Purification was performed by silica gel chromatography, which elutes at 5% EA (2 CV) in cHex, 5%–50% EA (15 CV) in cHex, and 50%–100% EA (5 CV) in cHex. 2 Purification was performed by silica gel chromatography, which elutes with 0% to 50% EA in cHex.

[0535] Preparation 97 1-(2-methoxythiazole-4-yl)ethanol

[0536] [ka] In a glass pressure flask, 1-(2-bromothiazole-4-yl)ethanol (2.14 g, 9.25 mmol) in MeOH (23 ml) was added to a solution of NaOMe (30% by mass) in MeOH (23 ml). The headspace was purged with N2 and the flask was sealed. The reaction mixture was stirred at 50°C. After 6 hours, the reaction mixture was stirred overnight at room temperature. The next day, heating was resumed for 4 hours. Once cooled to room temperature, the reaction mixture was poured into saturated NH4Cl aqueous solution (150 ml) and DCM (30 ml) was added. The organic layer was separated, and the aqueous layer was extracted with DCM (3 × 20 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DCM, dried and loaded onto DE, and purified by silica gel column chromatography under the following conditions: elution with 100% cHex (1 CV), 0% to 35% EA in cHex (16 CV), and 35% to 50% EA in cHex (14 CV). 1 H NMR (400.21MHz, CDCl3): δ 6.50(d,J=1.0Hz,1H),4.82-4.77(m,1H),4.08(s,3H),2.37(d,J=4.4Hz,1H,OH),1.53(d,J=6.4Hz,3H).

[0537] Preparation 98 1-[5-(trifluoromethyl)pyridazin-3-yl]ethanol

[0538] [ka] To a stirred solution of 1-[5-(trifluoromethyl)pyridazin-3-yl]ethanone (810 mg, 4.26 mmol) in MeOH (10 ml), NaBH4 (48.35 mg, 1.28 mmol) was added under N2 at 0°C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction product was quenched with H2O (10 ml) at 0°C. The mixture was extracted with EA (3 × 20 ml). The combined organic layers were washed with brine (2 × 10 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (800 mg, 98%). 1 H NMR(400MHz,DMSO-d6)δ 9.61(d,1H),8.10(d,1H),5.88(d,1H),5.14-5.08(m,1H),1.50(d,3H).

[0539] The following compounds were prepared in a manner essentially similar to that of Preparation 98, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0540] [Table 21] a The material was used in subsequent processes without further characterization.

[0541] Preparation 104 [1-(5-bromo-2-pyridyl)-3,3-difluorocyclobutyl]methanol

[0542] [ka] A solution of methyl 1-(5-bromo-2-pyridyl)-3,3-difluorocyclobutanecarboxylate (11.0 g, crude) in THF (100 ml) was treated in several portions with LiBH4 (0.78 g, 35.94 mmol) under N2 at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was quenched with saturated NH4Cl and concentrated. The residue was purified with silica gel eluted with PE:EA (5:1) to obtain the title compound (1.8 g, 16% across two steps) as a yellow solid. MS ES+m / z 278 / 280[M+H] + .

[0543] Preparation 105 2-Benzyloxy-1-(3,5-difluoro-2-pyridyl)ethanol

[0544] [ka] 2-bromo-3,5-difluoropyridine (5 g, 25.78 mmol) in toluene (50 ml) was treated with i-PrMgCl (19.33 ml, 38.66 mmol, 2 M in THF) under N2 at 0°C. After stirring at room temperature for 3 hours, the reaction mixture was cooled to 0°C and treated with 2-(benzyloxy)acetaldehyde (3.10 g, 20.62 mmol). The reaction mixture was stirred at room temperature for 2 hours and then quenched with saturated NH4Cl aqueous solution (200 mL). The reaction mixture was extracted with EA (3 × 300 ml). The combined organic layers were washed with brine (2 × 200 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to obtain the title compound (1.6 g, 23%) as a pale yellow oil. MS ES+m / z 266[M+H] + .

[0545] Preparation 106 1-(5-fluoropyrimidine-2-yl)ethane-1,2-diol

[0546] [ka] To a mixture of 2-ethenyl-5-fluoropyrimidine (15.0 g, crude) and K2OsO4·2H2O (1.38 g, 3.75 mmol) in ACN:H2O (6:1, 140 ml), NMO (17.56 g, 149.86 mmol) was added under N2 at 0°C. The resulting mixture was stirred under N2 at room temperature for 2 hours. The reaction product was diluted with H2O (20 ml) and extracted with MTBE (3 × 200 ml). The aqueous layer was extracted with CHCl3:IPA (3:1) (3 × 250 ml). The combined organic layers were washed with brine (3 × 50 ml), dried over Na2SO4, filtered, and concentrated to obtain the title compound (6.0 g, 51%) as a black oil. MS ES+m / z 159[M+H] + .

[0547] Preparation 107 1-(5-fluoropyrimidine-2-yl)-2-(2-trimethylsilylethoxymethoxy)ethanol

[0548] [ka] A mixture of 1-(5-fluoropyrimidine-2-yl)ethane-1,2-diol (6.0 g, 37.94 mmol) and DIEA (14.71 g, 113.83 mmol) in DCM (60 ml) was met with dropwise addition of SEM-Cl (4.43 g, 26.56 mmol) under N2 at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched at room temperature by adding MeOH (20 ml). The mixture was stirred for 30 minutes and then concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (6:1~4:1) to obtain the title compound (3.0 g, 27%) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 8.93(d,2H),4.93-4.86(m,1H),4.78-4.71(m,2H),4.66-4.60(m,1H),3.8 3-3.74(m,2H),3.59-3.41(m,2H),0.84-0.59(m,2H),0.03-0.03(s,9H).MS ES+m / z 289[M+H] + .

[0549] 2-(5-Fluoropyrimidin-2-yl)-2-(2-trimethylsilylethoxymethoxy)ethanol was also isolated after chromatography (600 mg, 5%). 1 1H NMR (300 MHz, DMSO-d6) δ 8.91 (d, 2H), 5.56 (d, 1H), 4.89-4.75 (m, 1H), 4.61-4.53 (m, 2H), 3.98-3.71 (m, 2H), 3.47-3.38 (m, 2H), 0.88-0.78 (m, 2H), 0.03-0.03 (s, 9H). MS ES+ m / z 289 [M+H] + .

[0550] Preparation 108 2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethanol

[0551]

Chem.

[0552] Preparation 109 2-(2-Benzyloxy-1-methoxy-ethyl)-3,5-difluoro-pyridine

[0553] [ka] A solution of 2-benzyloxy-1-(3,5-difluoro-2-pyridyl)ethanol (1.5 g, 5.66 mmol) and CH3I (1.20 g, 8.48 mmol) in THF (20 ml) was treated with t-BuOK (6.79 ml, 6.79 mmol, 1 M in THF) under N2 at 0°C. The resulting mixture was stirred at room temperature for 1 hour, quenched with saturated NH4Cl aqueous solution (100 ml), and extracted with EA (3 × 200 ml). The combined organic layer was washed with brine (2 × 200 ml), dried over Na2SO4, filtered, and concentrated to obtain the title compound (1.52 g, 96%) as a pale yellow oil. MS ES+m / z 280[M+H] + .

[0554] Preparation 110 tert-butyl-[2-(5-fluoro-2-pyridyl)-2-methoxyethoxy]-dimethylsilane

[0555] [ka] A solution (30 ml) of 2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethanol (3.0 g, 11.05 mmol) and CH3I (7.84 g, 55.27 mmol) in 0°C THF (30 ml) was treated in several portions with NaH (0.53 g, 22.11 mmol, 60 wt%) under N2. After stirring at room temperature for 2 hours, the reaction mixture was quenched with H2O (50 ml) and extracted with EA (2 × 50 ml). The combined organic layer was washed with brine (2 × 80 ml), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (2.9 g, 92%) as a yellow solid. MS ES+m / z 286[M+H] + .

[0556] Preparation 111 2-[[2-(5-fluoropyrimidine-2-yl)-2-methoxy-ethoxy]methoxy]ethyl-trimethyl-silane

[0557] [ka] To a stirred mixture of 1-(5-fluoropyrimidine-2-yl)-2-(2-trimethylsilylethoxymethoxy)ethanol (1.01 g, 3.50 mmol) in THF (10 ml), CH3I (746 mg, 5.25 mmol) and Ag2O (2.43 g, 10.51 mmol) were added in several portions under N2 at room temperature. The reaction mixture was stirred under N2 at 60°C for approximately 4 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with DCM / EA (2:1~3:1) to obtain the title compound (948 mg, 90%) as a yellow oil. MS ES+m / z 303[M+H] + .

[0558] Preparation 112 5-Bromo-2-[3,3-difluoro-1-(tetrahydropyran-2-yloxymethyl)cyclobutyl]pyridine

[0559] [ka] A solution of [1-(5-bromo-2-pyridyl)-3,3-difluorocyclobutyl]methanol (1.7 g, 6.113 mmol) and DHP (2.57 g, 30.565 mmol) in DCM (10 ml) was treated with TsOH (10.5 mg, 0.06 mmol) under N2. After stirring at 50°C for 2 hours, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA (20:1) to obtain the title compound (2.1 g, 94.8%) as a yellow oil. MS ES+m / z 362 / 364[M+H] + .

[0560] Preparation 113 2-[3,3-difluoro-1-(tetrahydropyran-2-yloxymethyl)cyclobutyl]-5-fluoropyridine

[0561]

Chem.

[0562] Preparation 114 [3,3-difluoro-1-(5-fluoro-2-pyridyl)cyclobutyl]methanol

[0563]

Chem.

[0564] Preparation 115 2-(3,5-difluoro-2-pyridyl)-2-methoxyethanol

[0565] [ka] A solution of 2-benzyloxy-1-(3,5-difluoro-2-pyridyl)ethanol (1.5 g, 5.37 mmol) in TFA (15 ml) was stirred under N2 at 80°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with H2O (50 ml), basicized to pH 9 with K2CO3, and extracted with EA (3 × 100 ml). The combined organic layers were washed with brine (2 × 100 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1~4:1) to obtain the title compound (545 mg, 54%) as a pale yellow oil. MS ES+m / z 190[M+H] + .

[0566] Preparation 116 2-(5-fluoro-2-pyridyl)-2-methoxyethanol

[0567] [ka] A solution of tert-butyl-[2-(5-fluoro-2-pyridyl)-2-methoxyethoxy]dimethylsilane (2.9 g, 10.16 mmol) in DCM (5 ml) was treated dropwise with 4 M HCl in 1,4-dioxane (30 ml) under N2 conditions at room temperature. After completion, the reaction mixture was concentrated, the residue was dissolved in 50 ml of H2O, basicized to pH 9 with saturated Na2CO3 aqueous solution, and extracted with EA (2 × 60 ml). The combined organic layers were washed with brine (2 × 40 ml), dried over Na2SO4, and concentrated to obtain the title compound (1.6 g, crude) as a yellow oil. MS ES+m / z 172[M+H] + .

[0568] Preparation 117 2-(5-fluoropyrimidine-2-yl)-2-methoxyethanol

[0569] [ka] 925 mg, 3.06 mmol of 2-[[2-(5-fluoropyrimidine-2-yl)-2-methoxy-ethoxy]methoxy]ethyl-trimethyl-silane (925 mg, 3.06 mmol) was added to 3 ml of concentrated HCl under N2 conditions at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then quenched with 100 ml of H2O. The mixture was basicized to pH 8 with NaHCO3. The aqueous layer was extracted with EA (3 × 100 ml). The combined organic layers were concentrated under vacuum to obtain the title compound as a white solid (450 mg, 85%). MS ES+m / z 173[M+H] + .

[0570] Preparation 118 1-[5-(trifluoromethyl)-3-pyridyl]ethaneamine

[0571] [ka] A solution of 1-[5-(trifluoromethyl)-3-pyridyl]ethanone (0.77 g, 4.06 mmol) in EtOH (30 ml) was treated with NH4OAc (4.7 g, 61 mmol) and stirred at room temperature for 20 minutes. The reaction mixture was treated with NaBH3CN (0.54 g, 8.12 mmol) and stirred at room temperature for 1 hour, then at 85°C for 1.25 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting oily substance was loaded into an SCX cartridge. Non-basic impurities were washed from the cartridge with MeOH, and the title compound was then eluted with methanolic ammonia (2 M). The resulting oily substance was purified by reverse-phase (Claricep C) chromatography eluting with 20%-50% NH4CO3 aqueous solution in ACN to obtain the title compound (1.9 g, 77%) as a yellow oily substance. MS ES+m / z 191[M+H] + .

[0572] Preparation 119 N-benzyl-3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propan-1-amine

[0573] [ka] 5-Fluoro-2-[1-(trifluoromethyl)vinyl]pyridine A 30 ml solution of (3.4 g, 17.79 mmol) of benzylamine in THF was treated with benzylamine (3.81 g, 35.58 mmol) under N2. After stirring at 50°C for 2 hours, the reaction mixture was cooled to room temperature, diluted with H2O (100 ml), and extracted with EA (3 × 100 ml). The combined organic layer was washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluted with PE / EA (20:1~10:1) to obtain the title compound (4.0 g, 75%) as a colorless oil. MS ES+m / z 299[M+H] + .

[0574] Preparation 120 3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propan-1-amine

[0575] [ka] To a solution of N-benzyl-3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propan-1-amine (3.50 g, 11.73 mmol) in IPA (50 ml), Pd / C (2.50 g, 23.47 mmol) and Pd(OH)2 / C (2.82 g, 20.11 mmol) were added under N2 conditions. The resulting mixture was stirred under H2 conditions at room temperature for 2 hours. The mixture was filtered and washed with MeOH (3 × 10 ml). The filtrate was concentrated to obtain the title compound (2.0 g, crude). MS ES+m / z 209[M+H] + .

[0576] Preparation 121 3-(1-chloroethyl)-5-(trifluoromethyl)pyridine

[0577] [ka] To a stirred mixture of 1-[5-(trifluoromethyl)pyridine-3-yl]ethanol (36.00 g, 188 mmol) in DCM (400 ml), SOCl2 (44.81 g, 376 mmol) was added under N2 at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H2O (500 ml). The mixture was extracted with DCM (3 × 500 ml). The combined organic layers were washed with brine (1 × 500 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (40 g, crude) as a yellow oil. ES+m / z 210[M+H] + .

[0578] Preparation 122 4-(1-chloroethyl)-2-isopropyl-triazole

[0579] [ka] 1-(2-isopropylthiazole-4-yl)ethanol (344 mg, 2.22 mmol) was dissolved in SOCl2 (3 mL) and toluene (3 mL), and then refluxed for 1 hour. The reaction mixture was concentrated under vacuum to obtain the title compound as a brown oily substance (365 mg, quantitative). This substance was immediately used in the next step.

[0580] The following compounds were prepared in a manner essentially similar to that of Preparation 122, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0581] [Table 22] 1 The reactants were refluxed in a 1:1 mixture of SOCl2:toluene. 2 The reaction was carried out at room temperature in a 1:1 mixture of SOCl2:DCM. 3 The reactants were evaporated and co-evaporated with toluene. 4 The reaction was carried out at room temperature in a 1:5 mixture of SOCl2:DCM.

[0582] Preparation 127 4-[1-chloroethyl]-2-cyclopropyl-thiazole

[0583] [ka] MsCl (0.16 ml, 2.1 mmol) was added dropwise to a solution of 1-(2-cyclopropylthiazole-4-yl)ethanol (320.5 mg, 1.76 mmol) and NEt3 (0.49 ml, 3.5 mmol) in DCM (7 ml) cooled to 0°C under N2. The reaction mixture was stirred at 0°C for 1 hour, and then the cooling bath was removed. After 3.5 hours, the reaction mixture was recooled to 0°C and quenched by slowly adding H2O (5 ml). The layers were separated, and the aqueous layer was extracted with DCM (3 ml). The combined organic layers were washed with brine (5 ml), dried over Na2SO4, filtered, and concentrated to obtain the title compound (316 mg, 95%) as a brown oil. 1 HNMR (400MHz, CDCl3): δ 7.03(s,1H),5.18(qd,J=6.8,0.6Hz,1H),2.38-2.33(m,1H),1.90(d,J=6.8Hz,3H),1.18-1.15(m,4H).

[0584] The following compounds were prepared in a manner essentially similar to that of Preparation 127, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0585] [Table 23]

[0586] Preparation 130 1-(3,6-dimethylpyrazine-2-yl)ethylmethanesulfonate

[0587] [ka] MsCl (903.09 mg, 7.88 mmol) was added dropwise to a stirred mixture of 1-(3,6-dimethylpyrazine-2-yl)ethanol (1 g, 6.57 mmol) and DIEA (127.38 mg, 0.99 mmol) in DCM (10 ml) under N2 at 0°C and stirred for 2 hours. The reaction mixture was removed from the cooling bath, quenched with H2O (10 ml), and extracted with DCM (3 × 10 ml). The combined organic layer was washed with brine (3 × 10 ml), dried over Na2SO4, filtered, and concentrated to obtain the title compound (1.1 g, 73%) as a brown oil. MS ES+m / z 231[M+H] + .

[0588] The following compounds were prepared in a manner essentially similar to that of Preparation 130, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and adjusting the purification system as necessary.

[0589] [Table 24]

[0590] [Table 25] a The material was used in subsequent processes without further characterization.

[0591] Preparation 141 2-Bromo-1-[(5-Fluoro-2-pyridyl)pyridine

[0592] [ka] NBS (1.14 g, 6.38 mmol) was added in small amounts over 5-10 minutes to a solution of 3-chloro-2-(1-ethoxyvinyl)-5-fluoropyridine (1.22 g, 6.06 mmol) in a mixture of THF (12 ml) and H2O (3 ml) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then diluted with EA (50 ml), washed with H2O (50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with EA in heptane to obtain the title compound as a pale yellow oil (1.394 g, 91%). 1 H NMR(400MHz,CDCl3)δ(ppm):8.44(d,J=2.3Hz,1H),7.61(dd,J=7.9,2.4Hz,1H),4.69(s,2H).

[0593] The following compounds were prepared in a manner essentially similar to that of Preparation 141, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0594] [Table 26] 1 Purification was performed by silica gel chromatography using elution with EA in heptane.

[0595] Preparation 143 2-Bromo-1-(3,5-difluoro-2-pyridyl)ethanone

[0596] [ka] A solution of phenyltrimethylammonium bromide (51.36 g, 133 mmol) in THF (423 ml) was treated with a THF solution (181 mL) of 1-(3,5-difluoro-2-pyridyl)ethanone (20 g, 120.93 mmol) under N2 at room temperature. After stirring at 60°C for 1.5 hours, the mixture was cooled to room temperature and stirred for 1 hour. The resulting suspension was filtered, and the solid was washed with THF (2 × 100 ml). The combined filtrate was concentrated to obtain a brown oily substance, which was purified by silica gel chromatography eluting under a gradient of 10% to 50% DCM in cHex to obtain the title compound (15 g, 42%) as a yellow oily substance. MS ES+m / z( 79 Br / 81 Br)237[M+H] + .

[0597] The following compounds were prepared in a manner essentially similar to that of Preparation 143, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0598] [Table 27] 1 The residue was purified by silica gel chromatography using a gradient of 5% to 30% DCM in cHex.

[0599] Preparation 145 2-Chloro-1-(5-fluoropyrimidine-2-yl)ethanone

[0600] [ka] To a stirred solution of 2-bromo-5-fluoropyrimidine (3.0 g, 16.95 mmol) in toluene (30 ml), i-PrMgCl (1 M in THF) (10.17 mL, 20.340 mmol) was added dropwise under N2 at 0°C. The reaction mixture was stirred at room temperature for 2 hours. To the above mixture, 2-chloro-N-methoxy-N-methylacetamide (2.33 g, 16.95 mmol) was added dropwise over 20 minutes under N2 at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then quenched with saturated NH4Cl aqueous solution (200 ml). The mixture was extracted with EA (2 × 300 ml). The combined organic layers were washed with brine (2 × 300 ml), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (2.3 g, 78%) as a yellow oil. MS ES+m / z 175[M+H] + .

[0601] Preparation 146 6-Bromo-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine

[0602] [ka] 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 with elution in heptane with a linear gradient from 0% to 100% EA. The fraction containing the title compound was concentrated under vacuum and combined with the filtered solid to obtain the title compound (0.60 g, 94.1%). ES / MS m / z( 79 Br / 81 Br)352.6 / 354.6[M+H] + .

[0603] Preparation 147 6-Bromo-4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine

[0604] [ka] 6-Bromo-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine (2 g, 5.67 mmol) was dissolved in DMF (28 ml) and treated with CuI (3.8 g, 20 mmol). N2 was bubbling over the mixture for 5 minutes, then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.9 g, 20 mmol) was added, and the reaction mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EA, filtered, and the solid was washed with EA. The filtrate was diluted with H2O, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated to obtain the title compound (582 mg, 29%) as a yellow solid. MS ES+m / z 295 / 297[M+H] + .

[0605] Preparation 148 6-Bromo-3-fluoro-4-methoxy-pyrazolo[1,5-a]pyridine

[0606] [ka] A solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5 g, 22.021 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (7.04 g, 22.02 mmol) in ACN (50 ml) was stirred overnight at room temperature under N2. The resulting mixture was diluted with H2O (50 ml) and extracted with EA (3 × 100 ml). The combined organic layer was washed with brine (2 × 100 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase C18 flash chromatography at 254 nm under the following conditions: column, C18; mobile phase, elution with a gradient of 30%-40% ACN (0.1% FA) in H2O; to obtain the title compound (810 mg, 15%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 8.56(t,1H),8.04(d,1H),6.77(d,1H),3.97(s,3H).

[0607] Preparation 149 6-Bromo-4-methoxy-3-methylpyrazolo[1,5-a]pyridine

[0608] [ka] Et3Si (8.0 ml, 50.20 mmol) was added dropwise at 0°C to a solution of (6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-yl)methanol (6.45 ml, 25.10 mmol) in TFA (50 ml). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under vacuum, the residue was dissolved in DCM, washed twice with saturated Na2CO3 aqueous solution, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with EA in heptane to obtain the title compound as a white solid (3.81 g, 63%). MS ES+m / z( 35 Cl / 37 Cl)241 / 243[M+H] + .

[0609] Preparation 150 7-Chloro-5-methoxyimidazo[1,2-a]pyridine

[0610] [ka] 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-BuOH (140 ml) was divided into 14 batches and stirred overnight in a sealed tube at 65°C. The solution was cooled to room temperature, diluted with H2O (200 ml), and extracted with EA (3 × 200 mL). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50% EA in PE to obtain the title compound as a light brown solid (6.1 g, 76%). ES / MS m / z 183[M+H]+.

[0611] Preparation 151 6-Bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile

[0612] [ka] A suspension of 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (100 g, 396.72 mmol) in 1 L of DMA was treated in one step at 40°C with a solution of NaOH (31.7 g, 793 mmol) in H2O (100 ml), followed by treatment with NDM (161 g, 793 mmol). After stirring at 50°C for 1 hour, the reaction mixture was cooled to 0°C and quenched with 37% aqueous HCl (100 ml) to a final pH of 5. The reaction mixture was diluted with H2O (4 L), and the resulting solid was collected by filtration. It was washed with H2O (1 L) and heptane (500 ml) to obtain the title compound (85.5 g, 82%) as a beige solid. MS ES+m / z 238[M+H] + .

[0613] Preparation 152 5,7-Dichloro-3-iodoimidazo[1,2-a]pyridine

[0614] [ka] A solution of 5,7-dichloroimidazo[1,2-a]pyridine (5.00 g, 26.74 mmol) in DCM (50 ml) was treated in several portions with NIS (12.03 g, 53.47 mmol) under N2 at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was diluted with H2O (100 ml) and extracted with DCM (3 × 50 ml). The combined organic layers were washed with brine (3 × 50 ml), dried over Na2SO4, filtered, and concentrated to obtain the title compound (12.0 g, crude) as a dark yellow solid. MS ES+m / z 313[M+H] + .

[0615] Preparation 153 5,7-Dichloroimidazo[1,2-a]pyridine-3-carbonitrile

[0616] [ka] A DMF solution of 5,7-dichloro-3-iodoimidazo[1,2-a]pyridine (11.00 g, 35.15 mmol) was treated in several portions with CuCN (6.30 g, 70.31 mmol) under N2 at room temperature. After stirring at 100°C for 2 hours, the reaction mixture was cooled to room temperature, and NH4OH (100 ml) was added dropwise over 5 minutes. The mixture was diluted with H2O (300 ml) and stirred at room temperature for 2 hours. The reaction mixture was extracted with DCM (3 × 400 mL), the combined organic layer was washed with brine (3 × 300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1~1:2) to obtain the title compound (3.5 g, 47%) as a yellow solid. MS ES+m / z( 35 Cl / 37 Cl)212 / 214[M+H] + .

[0617] Preparation 154 7-Chloro-5-[2-(3,5-difluoro-2-pyridyl)-2-methoxyethoxy]imidazo[1,2-a]pyridine

[0618] [ka] A stirred mixture of 2-(3,5-difluoro-2-pyridyl)-2-methoxyethanol (6.57 g, 34.76 mmol) and 5,7-dichloroimidazo[1,2-a]pyridine (6.5 g, 34.76 mmol) in THF (120 ml) was treated dropwise with t-BuOK (48.66 ml, 48.66 mmol, 1 M in THF) under N2 at 0°C. After stirring at room temperature for 2 hours, the reaction was quenched with saturated NH4Cl aqueous solution, extracted with EA (2 × 500 ml), washed with brine (2 × 200 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase C18 flash chromatography eluting under a gradient of 40% to 50% ACN in H2O to obtain the title compound as a bright yellow solid (1.75 g, 15%). MS ES+m / z 340[M+H] + .

[0619] Preparation 155 6-Bromo-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0620] [ka] 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (45.43 g, 190.84 mmol) in DMF (350 ml) was mixed with K2CO3 (79.13 g, 572.52 mmol) and 3-(1-chloroethyl)-5-(trifluoromethyl)pyridine (40 g, crude) in several additions over 2 minutes at 80°C. The reaction mixture was stirred under N2 at room temperature for 2 hours. The resulting mixture was diluted with H2O (1 L) and extracted with EA (3 × 1.5 L). The combined organic layers were washed with brine (5 × 1 L), dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1~2:1) to obtain the title compound (32 g, 40.78%) as a yellow solid. MS ES+m / z( 79 Br / 81 Br)411 / 413[M+H] + .

[0621] A racemic mixture (32g) of the title compound was subjected to the following chromatography conditions: SFC, column: NB_CHIRAL ART Cellulose-SB; 5×25cm, 5μm, elution with 15% IPA (0.2% DEA) in CO2 to obtain the title compound and isomer 2 (13.5g, 42.19%). R It was 6.58 minutes, 99% ee. MS ES+m / z( 79 Br / 81 Br)411 / 413[M+H] + .

[0622] Preparation 156 6-Bromo-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrilate

[0623] [ka] A 300 ml THF solution of PPh3 (34.1 g, 130 mmol) was added dropwise with DIAD (23.2 g, 115 mmol) over 4 minutes at room temperature. After stirring at room temperature for 30 minutes, a 100 ml THF solution of 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (20 g, 76.5 mmol) and (1S)-1-(2-pyridyl)ethanol (11.3 g, 91.8 mmol) was added dropwise over 6 minutes. After stirring at room temperature for 45 minutes, the reaction mixture was concentrated under vacuum. The residue was slurryed in hexane / MTBE (4:1; 250 ml) and allowed to stand overnight at room temperature. The resulting solid was collected by filtration, washed with hexane (2 × 100 ml), and purified by silica gel chromatography eluting with a gradient of 0% to 15% acetone in hexane. The resulting solid was dissolved in MTBE (100 mL) and treated with 4-methylbenznesulfonic acid hydrate (8.85 g, 46.5 mmol). The resulting suspension was stirred overnight at room temperature. The solid was recovered by filtration and washed with MTBE (3 × 50 mL) to obtain the title compound (43.4 g, 87%) as a white solid. MS ES+( 79 Br / 81 Br)m / z 343 / 345[M+H] + .

[0624] Preparation 157 6-Bromo-3-chloro-4-[2-(5-fluoropyrimidine-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine

[0625] [ka] DIAD (2.52 g, 12.45 mmol) was added dropwise to PPh3 (3.50 g, 13.34 mmol) in THF (10 ml) under N2 at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. Next, 6-bromo-3-chloropyrazolo[1,5-a]pyridine-4-ol (1.1 g, 4.45 mmol) and 2-(5-fluoropyrimidine-2-yl)-2-methoxyethanol (918.26 mg, 5.334 mmol, 1.2 equivalents) were added to THF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, C18; mobile phase, eluting with 50%-55% ACN in H2O to obtain the title compound (700 mg, 39%) as a yellow solid. MS ES+m / z 402 / 403[M+H] + .

[0626] Preparation 158 6-Bromo-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0627] [ka] A mixture of 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (4 g, 16.80 mmol) and Cs2CO3 (8.21 g, 25.2 mmol) in ACN (20 ml) was stirred at room temperature under N2 for 0.5 hours. A solution of 2-bromo-1-(5-fluoro-2-pyridyl)ethanone (4.6 g, 20 mmol) in ACN (20 ml) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O (100 ml) to obtain a suspension. The solid was recovered by filtration and washed with H2O to obtain the title compound (5.86 g, 93%) as a white solid. MS ES+m / z 375 / 377[M+H] + .

[0628] The following compounds were prepared in a manner essentially similar to that of Preparation 158, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0629] [Table 28] 1 DIPEA was used as the base for this conversion. 2 Workup: The reaction products were concentrated under vacuum. The residue was dissolved in MeOH and ground with H2O. The precipitated product was recovered by filtration. 3 The reaction mixture was heated to 80°C. 4 Workup: The reaction mixture was concentrated in a vacuum. The residue was ground in H2O. The precipitated product was recovered by filtration. 5 Workup: The reaction mixture was diluted with H2O, extracted with EA, dried with Na2SO4, filtered, and concentrated under vacuum. 6 Purification was performed by silica gel chromatography, which elutes EA (1:30~1:15) in DCM.

[0630] Preparation 162 1-(6-bromopyrazolo[1,5-a]pyridine-4-yl)oxy-2-(5-fluoro-2-pyridyl)propan-2-ol

[0631] [ka] A solution of 2-(6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy-1-(5-fluoro-2-pyridyl)ethenone (3g, 8.57 mmol) in THF (10 ml) was added to a stirred solution of MeMgBr (3M in Et2O, 14.3 ml, 42.84 mmol) in THF (30 ml) at room temperature under N2, and the reaction mixture was stirred for 2 hours. The solution was quenched with H2O (50 ml) and extracted with EA (3 × 50 ml). The combined organic layers were washed with brine (3 × 50 ml), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (3g, crude) as a brown oily substance. MS ES+m / z( 79 Br / 81Br)366 / 368[M+H] + .

[0632] The following compounds were prepared in a manner essentially similar to that of Preparation 162, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0633] [Table 29] 1 The reactants were quenched with a saturated NH4Cl aqueous solution (30 ml) at 0°C. 2 Purification was performed by silica gel chromatography using DCM / PE (1:2~2:1) elution. 3 Purified by preparative TLC PE / EA (8:1).

[0634] Preparation 165 6-Bromo-4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0635] [ka] A suspension of 6-bromo-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (2.18 g, 5.82 mmol) in MeOH (50 ml) was cooled in an ice bath and then treated with NaBH4 (0.85 g, 22.47 mmol) in one step. The reaction mixture was stirred at 0°C for 5 minutes, then at room temperature for 1 hour. The reaction mixture was concentrated, the residue was dissolved in DCM, and washed with H2O and brine. The organic layer was recovered, dried over MgSO4, filtered, and concentrated to obtain the title compound (1.98 g, 83%) as a beige solid. MS ES+m / z 377 / 379[M+H] + .

[0636] The following compounds were prepared in a manner essentially similar to the method for Preparation 165, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and adjusting the purification system as necessary.

[0637]

Table 30

[0638] Preparation 168 6-bromo-3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine

[0639]

Chemical Formula

[0640] Preparation 169 6-bromo-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0641] [ka] To a stirred solution of 6-bromo-4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (3 g, 7.95 mmol) and CH3I (2.26 g, 15.91 mmol) in THF (30 mL), NaH (60%) (636 mg, 15.91 mmol) was added in several portions under N2 at 0°C. The mixture was stirred at room temperature for 2 hours, then quenched with H2O (20 mL). The mixture was extracted with EA (3 × 40 mL). The combined organic layer was washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1~1:1) to obtain the title compound (2.9 g, 93%) as a yellow solid. MS ES+m / z( 79 Br / 81 Br)391.0 / 393.0[M+H] + .

[0642] Preparation 170 7-Chloro-5-[[3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propyl]amino]imidazo[1,2-a]pyridine-3-carbonitrile

[0643] [ka] A stirred solution of 3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propan-1-amine (2.0 g, 9.6 mmol) and 5,7-dichloroimidazo[1,2-a]pyridine-3-carbonitrile (2.64 g, 12.5 mmol) in DMF (5 ml) was treated with DIEA (3.72 g, 28.8 mmol) under N2. After stirring at 100°C for 24 hours, the reaction product was purified by reverse-flash C18 chromatography using the following conditions: column, C18; elution with a gradient of 50% to 70% ACN in H2O to obtain the title compound (1.2 g, 34%). MS ES+m / z 384[M+H] + .

[0644] Preparation 171 6-Bromo-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethylamino]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0645] [ka] Pd2(dba)3 (0.05 g, 0.05 mmol), dppf (0.06 g, 0.1 mmol), K3PO4 (1.3 g, 6 mmol), and DME (5 ml) were placed in a pressure flask. The suspension was degassed by blowing N2 into the mixture for several minutes, and then 1-[5-(trifluoromethyl)-3-pyridyl]ethanamine (0.40 g, 1.89 mmol) and 4,6-dibromopyrazolo[1,5-a]pyridine-3-carbonitrile (0.52 g, 1.7 mmol) were added, and N2 was blown into the mixture for several more minutes. The tube was capped, and the reaction mixture was heated at 207°C for 15 minutes. After stirring overnight at room temperature, DME (5 mL), Pd2(dba)3 (0.05 g, 0.05 mmol), and dppf (0.06 g, 0.1 mmol) were added back to the reaction mixture. After degassing the mixture, the reaction mixture was capped and heated at 100°C for 8 hours. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EA (3 times). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography with elution at a gradient of 0% to 50% EA in cHex to obtain the title compound (393 mg), which was used in the next synthesis reaction without further purification. MS ES+m / z 410 / 412[M+H] + .

[0646] The following compounds were prepared in a manner essentially similar to that of Preparation 171, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0647] [Table 31] 1The solution was eluted in cHex with 0% to 100% EA and purified by silica gel chromatography. 2 Purification was performed by silica gel chromatography, which elutes with 0% to 50% EA in cHex.

[0648] Preparation 174 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethylamino]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0649] [ka] 6-bromo-4-[[2-(5-fluoro-2-pyridyl)-2-methoxy-ethyl]amino]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.39 g, 0.55 mmol), bis(pinacolato)diborone (0.21 g, 0.82 mmol), KOAc (0.21 g, 2.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.01 g, 0.01 mmol), and 1,4-dioxane (4 ml) were placed in a high-pressure flask. N2 was blown into the mixture for several minutes, then the flask was closed and the reaction mixture was heated at 90°C for 5.5 hours. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with EA (3 times). The combined organic layers were dried over MgSO4, filtered, concentrated, and the residue purified by silica gel chromatography eluting with 0% to 80% EA in cHex to obtain the title compound (0.39 g, 82%) as a concentrated brown oil. MS ES+m / z 376[M+H] as boronic acid. + .

[0650] The following compounds were prepared in a manner essentially similar to that of Preparation 174, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0651] [Table 32]

[0652] Preparation 177 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[0653] [ka] A solution of 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine (50.0 g, 220.2 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (61.0 g, 240.3 mmol) in 1,4-dioxane (500 ml) was degassed with N2 at room temperature for 15 minutes. KOAc (64.0 g, 652.1 mmol) was added, followed by Pd(dppf)Cl2 (6.0 g, 8.2 mmol) being added in several portions under N2 at 25°C. The mixture was degassed with N2 for 15 minutes. The reaction mixture was stirred under N2 at 80°C for 12 hours. The reaction mixture was cooled to 25°C and filtered through DE. The filtration cake was washed with 1,4-dioxane (3 × 100 ml). The filtrate was concentrated under vacuum at 45°C to obtain an oily black residue. The residue was purified by silica gel plug filtration (300 g, column diameter 12 cm). The plug was eluted with c-Hex:EA in a 20:1 to 3:1 ratio to obtain the title compound (62.7 g, 206 mmol) as a pale yellow solid. MS ES+m / z 275[M+H] + .

[0654] Preparation 178 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0655] [ka] A 200 ml stirred solution of 1,4-dioxane (20.0 g, 79.34 mmol) containing 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile was treated at room temperature under N2 with bis(pinacorato)diborone (30.22 g, 119.01 mmol), KOAc (23.36 g, 238.03 mmol), and Pd(dppf)Cl2 (2.90 g, 3.97 mmol). After stirring the reaction mixture at 80°C for 1 hour, the crude reaction product was used in the next synthesis step without purification. MS ES+m / z 300[M+H] + .

[0656] The following compounds were prepared in a manner essentially similar to that of Preparation 178, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0657] [Table 33]

[0658] [Table 34] 1 Purification was performed by silica gel chromatography, which elutes with 0% to 50% EA in cHex. 2 Purification was performed by silica gel chromatography, which elutes with 0% to 80% EA in cHex. 3 The compound is degraded by MS. The MS data shows a mixture of boronic acid ester and boronic acid. 4 The compound is broken down by MS. The MS data is consistent with boronic acid. 5 Xphos Palladacycle Gen 4 was used as a catalyst for this conversion. 6 Pd(dppf)Cl2.CH2Cl2 was used as a catalyst for this conversion. 7 The reaction mixture was heated to 100°C. aThe material was used in subsequent processes without further characterization. 8 Purification was performed by silica gel chromatography using elution with EA in heptane.

[0659] Preparation 189 tert-butyl(3S,4R)-4-[4-[3-chloro-4-[2-(5-fluoropyrimidine-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazole-1-yl]-3-fluoro-piperidine-1-carboxylate

[0660] [ka] 6-bromo-3-chloro-4-[2-(5-fluoropyrimidine-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine (626 mg, 1.56 mmol) and bis(pinacorato)diborone (475 mg, 1.87 mmol) were added in several portions to dioxane (7 ml) at room temperature under N2 conditions, along with Pd(dppf)Cl2·CH2Cl2 (64 mg, 0.08 mmol) and KOAc (459 mg, 4.68 mmol). The reaction mixture was stirred at 100°C under N2 conditions for 2 hours and then cooled to room temperature. Next, tert-butyl(3S,4R)-4-(4-bromo-5-methyl-triazole-1-yl)-3-fluoropiperidine-1-carboxylate (534 mg, 1.47 mmol), K2CO3 (554 mg, 4.01 mmol), PdCl2(DtBPF) (44 mg, 0.07 mmol), and H2O (2 ml) were added under N2 at room temperature. The mixture was stirred overnight at 100°C. After cooling to room temperature, the reaction was quenched by adding H2O (100 ml). The mixture was extracted with EA (3 × 100 ml), the organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1~100% EA). The title compound (585 mg, 72%) was obtained as a brown solid. MS ES+m / z 605[M+H] + .

[0661] The following compounds were prepared in a manner essentially similar to that of Preparation 189, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0662] [Table 35] 1 The solution was eluted using PE / EA (2:3~1:4) and purified by silica gel chromatography. 2 The solution was eluted using PE / EA (1:3~1:4) and purified by silica gel chromatography. 3 The solution was eluted using PE / EA (1:2~1:3) and purified by silica gel chromatography. 4 The solution was eluted using PE / EA (1:2~1:3) and purified by silica gel chromatography.

[0663] Preparation 194 tert-butyl4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0664] [ka] The mixture obtained from the synthesis of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20.0 g, 79.34 mmol) was treated under N2 at room temperature with tert-butyl 4-(4-bromo-5-methyl-triazole-1-yl)piperidine-1-carboxylate (27.70 g, 80.23 mmol), K2CO3 (27.72 g, 200.57 mmol), PdCl2(DtBPF) (2.18 g, 3.34 mmol) and H2O (50 mL). The reaction mixture was stirred at 80°C for 1 hour and cooled to room temperature. The reaction mixture was diluted with H2O (300 ml) and extracted with EA (3 × 300 ml). The combined organic layers were washed with brine (3 × 300 ml), dried over Na₂SO₄, filtered, and concentrated to obtain the title compound (15.31 g, two-step yield 44%) as a yellow solid. MS ES+m / z 438[M+H] + .

[0665] Preparation 195 tert-butyl4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazole-1-yl)piperidine-1-carboxylate

[0666] [ka] 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (5.160 g, 18.83 mmol) and K2CO3 (5.0 g, 36.18 mmol) were mixed with a solution of tert-butyl 4-(4-bromo-5-methyl-triazole-1-yl)piperidine-1-carboxylate (7.0 g, 20.28 mmol) in toluene (50 ml), followed by the addition of H2O (12.5 ml). The mixture was degassed with N2 for 10 minutes, and then PdCl2(DtBPF) (1.0 g, 1.54 mmol) was added. Degassing with N2 was continued for another 5 minutes. The reaction mixture was heated at 90°C for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum to remove most of the toluene. The residue was diluted with H2O to obtain a brown solid. The solid was decanted from H2O. EA (50 ml) was added to the solid and then evaporated. This process was repeated three times. EA (25 ml) was added, the mixture was heated to 50°C, and then cooled to room temperature. The yellow solid was recovered by filtration to obtain the title compound (4.6 g, 53%). MS ES+m / z 413.2[M+H] + The filtrate was concentrated, and the residue was purified by silica gel chromatography eluting with 10% to 100% EA in c-Hex to obtain the title compound (2.0 g, 24%) as an oily yellow solid. MS ES+m / z 413.2[M+H] + .

[0667] Preparation 196 tert-butyl4-[4-[3-cyano-4[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methylpyrazole-1-yl]piperidine-1-carboxylate

[0668] [ka] A mixture of 4-[(1R)-1-(2-pyridyl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitride (5.0 g, 12.81 mmol) and tert-butyl 4-(4-bromo-5-methylpyrazole-1-yl)piperidine-1-carboxylate (5.0 g, 14.53 mmol) in toluene (50 ml) was degassed by blowing N2 for 5 minutes. Next, a solution of K3CO2 (4.0 g, 28.94 mmol) in H2O (12.5 ml) was added, and the mixture was degassed for another 5 minutes. PdCl2(DtBPF) (500 mg, 0.77 mmol) was added, and the mixture was degassed with N2 while the reaction mixture was heated to 60°C. At this point, the blowing of N2 was stopped. Next, the reactants were heated to 100°C under N2 conditions.

[0669] After 2 hours, the reaction mixture was cooled to room temperature, and DE was added while stirring (6 g). After 30 minutes, the mixture was filtered over a DE plug, and the solid was washed with H2O (50 ml) and toluene (150 ml). The layers were separated from the filtrate, the organic layer was dried over MgSO4, filtered, and concentrated to obtain the title compound (7.0 g, 98%) as an oily brown substance. MS ES+m / z 528[M+H] + .

[0670] The following compounds were prepared in a manner essentially similar to that of Preparation 196, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary. K3PO4 can be used instead of K3CO2.

[0671] [Table 36]

[0672] [Table 37]

[0673] [Table 38] 1 Silica gel column chromatography eluting with PE / EA (2:1 to 1:1). 2 Pd(PPh3)4 was used as a catalyst for this conversion. 3 Purification was performed by silica gel chromatography, which elutes with 10% to 100% EA in cHex. 4 The solution was purified by silica gel chromatography, which involved elution with 0% to 100% EA in hexane, followed by elution with 0% to 20% MeOH in EA. 5 Purification was performed by silica gel chromatography, which elutes with 0% to 100% EA in cHex. 6 Purification was performed by silica gel chromatography using EA / EtOH (30:1) elution. 7 Dioxane was used as the solvent. 8 The reaction mixture was heated to 80°C. 9 Workup: The reaction products were extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. 10 Purification was performed by silica gel column chromatography using PE / EA (10:1~3:1) elution. 11 Purification was performed by silica gel column chromatography, which elutes with 50% EA in PE. 12 Workup: The reaction products were concentrated. The residue was slurryed in H2O, and the resulting insoluble material was recovered by filtration. 13 Purification was performed by reverse-phase C18 chromatography, which elutes with 40% to 60% ACN in H2O. 14 Workup: The reaction mixture was diluted with H2O and extracted with EA. The combined organic matter was washed with brine, dried with Na2SO4, filtered, and concentrated. 15Purification was performed by silica gel chromatography using elution with 20% EA in PE. 16 Workup: The reactants were concentrated. 17 Purification was performed by silica gel column chromatography, which elutes at 50% to 75% EA in PE. 18 Purification was performed by silica gel column chromatography eluting with 10% MeOH in DCM. 19 Pd(dppf)Cl2 was used as a catalyst for this conversion. The reactants were heated to 90°C. 20 Purification was performed by silica gel chromatography using MeOH elution in DCM. 21 The sample was purified by silica gel column chromatography using DCM / MeOH (15:1~10:1) elution. 22 The sample was purified by silica gel column chromatography using DCM / MeOH (10:1) elution.

[0674] Preparation 214a tert-butyl2-[4-[3-cyano-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazole-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate

[0675] [ka] and Preparation 214b tert-butyl2-[4-[3-cyano-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-3-methylpyrazole-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate

[0676] [ka] A mixture of tert-butyl 2-(4-bromo-5-methylpyrazole-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate, tert-butyl 2-(4-bromo-3-methylpyrazole-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.68 g, 3.11 mmol) and 4-[(1R)-1-(2-pyridyl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrilate (1.33 g, 3.41 mmol) in toluene (40 ml) and H2O (4 ml) was treated with K2CO3 (1.14 g, 8.25 mmol). N2 was blown into the reactant for 2 minutes, then PdCl2(DtBPF) (135 mg, 0.21 mmol) was added and the tube was sealed. After stirring at 90°C for 20 hours, the reactant was cooled and diluted with EA (50 ml) and H2O (20 ml). The layers were separated, and the aqueous layer was extracted with EA. The combined organic layers were concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 10% acetone in DCM to obtain the title compound (621 mg, 74%) as a concentrated yellow oil. MS ES+m / z 568[M+H] + .

[0677] The following compounds were prepared in a manner essentially similar to that of preparations 214a and 214b, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0678] [Table 39]

[0679] Preparation 216 4-Methoxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonilicate

[0680] [ka] N2 was blown into a mixture of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (39 g, 117 mmol, 90% by mass), K2CO3 (40 g, 289 mmol), and 4-(4-bromo-5-methyl-triazole-1-yl)-1-(oxetan-3-yl)piperidine (42.6 g, 135 mmol) in toluene (390 ml) and H2O (116 mL). After 10 minutes, PdCl2(DtBPF) (0.68 g, 1.04 mmol) was added, and N2 was blown into the reaction mixture for a further 5 minutes. The reaction mixture was stirred at 90°C for 8 hours, and then stirred at room temperature for approximately 60 hours. The reaction mixture was diluted with H2O (100 ml), concentrated, and toluene was removed. The resulting suspension was stirred at room temperature for 15 minutes, filtered, and the solid was washed with H2O (2 × 30 mL) to obtain the title compound (42.6 g, 83%). MS ES+m / z 394[M+H] + .

[0681] The following compounds were prepared in a manner essentially similar to that of Preparation 216, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0682] [Table 40] 1 Purification was performed by silica gel chromatography, eluting 0% to 100% EA in cHex, followed by 0% to 10% MeOH in DCM.

[0683] Preparation 219 tert-butyl4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazole-1-yl)piperidine-1-carboxylate

[0684] [ka] A solution of tert-butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazole-1-yl)piperidine-1-carboxylate (4 g, 9.12 mmol) in DCM (50 ml) was treated with NCS (700 mg, 5.24 mmol). After stirring at room temperature for 24 hours, another portion of NSC (700 mg, 5.24 mmol) was added, and stirring was continued for another 24 hours. The reaction mixture was treated with H2O (100 ml), and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 100% EA in cHex to obtain the title compound (3.4 g, 82%) as a white solid. MS ES+m / z 447 / 449[M+H] + .

[0685] Preparation 220 3-Chloro-4-methoxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl)pyrazolo[1,5-a]pyridine

[0686] [ka] 4-Methoxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine (34 g, 83.06 mmol) was dissolved in DCM (500 ml) and treated with NCS (12 g, 89.86 mmol) under N2. After stirring at room temperature for 18 hours, NCS (6.5 g, 49 mmol) was added and stirred overnight. The mixture was diluted with H2O (200 ml), the layers were separated, the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting under a gradient of 0% to 10% MeOH in DCM to obtain the title compound (16 g, 45%) as an amber-colored oil. MS ES+m / z 403 / 405[M+H] + .

[0687] The following compounds were prepared in a manner essentially similar to that of Preparation 220, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0688] [Table 41]

[0689] [Table 42] 1 Purification was performed by silica gel chromatography, which elutes with 0% to 100% EA in cHex. 2 The reaction mixture was heated to 50°C. 3 Purified by preparative TLC:PE / EA (1:1). 4 Purified by preparative TLC:DCM / MeOH(20:1). 5 The residue was used in the next process without purification. 6 Workup: The reactants were concentrated. 7 Workup: The reaction mixture was quenched with a 40% NaHSO3 aqueous solution, the layers were separated, the organic layer was dried over MgSO4, filtered, and concentrated. 8 The solution was eluted with 40%-50% MeOH in H2O and purified by reverse flushing. 9 Column: XB-phenyl, 50 × 250 mm, 10 μm; Elutes with 60-70% ACN (10 mM NH3-H2O) in H2O. 10 I used NBS instead of NCS. 11 The solution was eluted with 45% to 55% ACN in H2O and purified by reverse flushing.

[0690] Preparation 229 4-Hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0691] [ka] A mixture of 4-methoxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (20 g, 45.75 mmol) in DMA (250 ml) was mixed with NDM (21.9 ml, 91.51 mmol) and NaOH aqueous solution (7.25 ml, 137.3 mmol, 18.94 mol / L) under N2. The reaction mixture was degassed under N2 for 15 minutes and then heated at 50°C for 2 hours. After cooling to room temperature, H2O (2 L) was added. After stirring for 15 minutes, the pH was adjusted to 6.9 by adding HCl aqueous solution (10% w / w) and then K2HPO4. The reaction mixture was stirred for 15 minutes. The insoluble substance was recovered by filtration and washed with H2O (2 × 25 ml) to obtain the title compound as a light gray solid (11.0 g, yield 62%). MS ES+m / z 380[M+H] + .

[0692] Preparation 230 tert-butyl4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazole-1-yl)piperidine-1-carboxylate

[0693] [ka] To tert-butyl 4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazole-1-yl]piperidine-1-carboxylate (3.4 g, 7.5 mmol) in DMA (20 ml) under an N2 atmosphere, NDM (5.5 ml, 23 mmol) and NaOH (18.94 mol / L) in H2O (1.4 ml) were added. The reaction mixture was heated overnight at 60°C. After cooling to room temperature, the mixture was diluted with H2O (100 ml) and the pH was adjusted to pH=5 with aqueous HCl. A cream-colored solid was obtained. After stirring for 15 minutes, the insoluble material was recovered by filtration, and the solid was rinsed with H2O to obtain the title compound (1.4 g, 43%). MS ES+m / z 433[M+H] + .

[0694] Preparation 231 tert-butyl4-[4-(3-cyano-4-hydroxy-pyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0695] [ka] NaOH (50% aqueous solution) (36.57 g, 457.14 mmol) was added dropwise at 0°C to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridine-6-yl]-5-methyl-1,2,3-triazole-1-yl)piperidine-1-carboxylate (40.00 g, 91.43 mmol) and NDM (55.51 g, 274.28 mmol) in DMA (400 ml). 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, the filtered cake was washed with H2O, and dried under vacuum. The solid was pulverized in hexane (200 ml) and Et2O (200 ml), filtered, and then stirred in MeOH (400 ml) at 60°C for 2 hours. The mixture was filtered, and the filtered cake was concentrated under vacuum to obtain the title compound as a pale yellow solid (32 g, 82.6%). ES / MS m / z 424.3[M+H] + .

[0696] The following compounds were prepared in a manner essentially similar to that of Preparation 231, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0697] [Table 43] 1 Workup: The reaction mixture was cooled to room temperature, and then a 3% citrus acid solution was added until the pH reached approximately 5. The resulting insoluble material was isolated by filtration, ground in cHex, filtered, and rinsed with cHEx, followed by MTBE. 2 Workup: The reaction mixture was neutralized to pH 7-8 with NH4Cl solution and concentrated under vacuum. The residue was treated with DCM and H2O, the layers were separated, the organic layer was dried over MgSO4, filtered, and concentrated. The residue was ground in heptane, filtered, and washed with heptane. 3 Workup: The reaction mixture was cooled to room temperature, and then a 3% aqueous citrus acid solution was added. The resulting precipitate was isolated by filtration and washed with H2O, then cHex. The solid was dissolved in DCM, and then cHex was added. The solution was sonicated until a precipitate formed. The precipitate was recovered by filtration. 4 Purification was performed by silica gel chromatography, which elutes with 0% to 50% acetone in DCM.

[0698] Preparation 240 4-Hydroxy-6-[5-methyl-1-(4-piperidyl)triazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonilicate hydrochloride

[0699] [ka] A solution of tert-butyl 4-[4-(3-cyano-4-hydroxy-pyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazole-1-yl]piperidine-1-carboxylate (50 g, 118.07 mmol) in MeOH (100 ml) was treated with 4 M HCl in MeOH (300 ml) under N2 conditions at room temperature. The reaction product was concentrated to obtain the title compound (40 g, HCl salt, crude product) as a white solid. MS ES+m / z 417[M+H] + .

[0700] The following compounds were prepared in a manner essentially similar to that of Preparation 240, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0701] [Table 44] a HCl in 2-propanol was used for this conversion.

[0702] Preparation 242 4-Hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0703] [ka] A solution of 4-hydroxy-6-[5-methyl-1-(4-piperidyl)triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (40 g, HCl salt, crude product) in MeOH (300 ml) was basicized to pH 12 with NaOH (5 g), then acidified to pH 5-6 with AcOH (10 g), and then treated with 3-oxetanone (53.49 g, 742.21 mmol) under N2 at room temperature. After stirring at 50°C for 2 hours, the reaction product was treated with NaBH3CN (23.32 g, 371.10 mmol) at room temperature, and then stirred at 50°C for 2 hours. After cooling to room temperature, the reaction product was concentrated, the residue was suspended in H2O (500 ml), and basicized to pH 8 with solid NaHCO3. The suspension was filtered, the solid was washed with MTBE (3 × 100 ml), and the solid was freeze-dried to obtain the title compound (30 g, 64%) as a white solid. MS ES+m / z 380[M+H] + .

[0704] The following compounds were prepared in a manner essentially similar to that of Preparation 242, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0705] [Table 45]

[0706] Preparation 244 4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonilicate

[0707] [ka] To a suspension of 4-hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (1 g, 2.64 mmol) in ACN (10 ml), Cs2CO3 (1.12 g, 3.43 mmol) was added. The suspension was stirred at room temperature for 30 minutes. Next, a solution of 2-bromo-1-(5-fluoro-2-pyridyl)ethanone (0.747 g, 3.43 mmol) in ACN (3 ml) was added dropwise over 30 minutes at room temperature. The reaction mixture was vigorously stirred at room temperature for about 8 hours. H2O was added, the suspension was stirred for 10 minutes, and then allowed to stand overnight. The suspension was further diluted with H2O and then filtered. The solid was rinsed with EA, then c-Hex, and then dried under vacuum to obtain the title compound (1.2 g, yield 83%). MS ES+m / z 517[M+H] + .

[0708] Preparation 245 tert-butyl4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0709] [ka] A solution of tert-butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazole-1-yl]piperidine-1-carboxylate (1.5 g, 3.47 mmol) and 2-bromo-1-(5-fluoro-2-pyridyl)pyridine (1.51 g, 6.93 mmol) in ACN (30 ml) was treated with DIPEA (1.34 g, 10.40 mmol) under N2 at room temperature. After stirring at 50°C for 1 hour, the reaction mixture was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EA (1:1~1:2) to obtain the title compound (1.1 g, 56%) as a brown solid. MS ES+m / z 570[M+H] + .

[0710] The following compounds were prepared in a manner essentially similar to that of Preparation 245, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary. Cs2CO3 can be used instead of DIPEA.

[0711] [Table 46]

[0712] [Table 47]

[0713] [Table 48]

[0714] [Table 49] 1 Purification was performed by reverse-phase flash C18 chromatography using the following conditions: column, C18; elution with 75%-80% CAN in H2O. 2 The solution was purified by reverse-phase C18 chromatography using elution with 50%-60% CAN (0.1% FA) in H2O. 3 Workup: The reaction mixture was concentrated, diluted with H2O, and the insoluble material was recovered by filtration. 4 Cs2CO3 was used as the base in this synthesis. 5 Purification was performed by silica gel chromatography using MeOH elution in DCM. 6 The sample was purified by silica gel chromatography using elution with 5% (EA / EtOH 3:1) in cHex (2 CV), 5% to 50% (EA / EtOH 3:1) in cHex (20 CV), and then 100% EA / EtOH (3:1). 7Workup: The reaction mixture was concentrated, diluted with H2O, and the insoluble material was recovered by filtration. 8 Workup: EA and H2O were added, the layers were separated, and the organic layer was washed with 1N NaOH and brine. The organic layer was dried over MgSO4, filtered, and concentrated. 9 Workup: The reactants were concentrated under vacuum. The residue was dissolved in H2O and acetone. The solution was concentrated until a solid precipitated. The suspension was stirred overnight, and the solid was collected by filtration. 10 Purification was performed by silica gel chromatography using DCM (5 CV), 2% MeOH in DCM (15 CV), 5% MeOH in DCM (10 CV), and MeOH (5 CV) for elution. 11 Workup: H2O was added to the reaction mixture and then concentrated. The residue was ground in H2O, and the insoluble material was recovered by filtration. 12 Workup: The reaction mixture was diluted with H2O and ground for 30 minutes. Insoluble material was recovered by filtration and washed with H2O, MTBE, and cHex. 13 The sample was purified by silica gel chromatography using elution with 0%-50% acetone (25 CV) in DCM, 50%-100% acetone (5 CV) in DCM, and then 100% acetone. 14 Workup: H2O was added to the reactants and then concentrated. The resulting suspension was diluted with H2O and then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. 15 Workup: H2O was added to the reactants and then concentrated. The resulting suspension was diluted with H2O, ground, and the insoluble material was recovered by filtration. 16 Purification was performed by silica gel chromatography using elution with 5% MeOH in DCM. 17 The isolated substance was sonicated in a 2M Na2CO3 aqueous solution for 10 minutes, then filtered and washed with water. 18Workup: H2O was added, and the resulting precipitate was recovered by filtration.

[0715] Preparation 269 tert-butyl4-[4-[3-cyano-4-[1-(1-isopropyltriazole-4-yl)ethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0716] [ka] Cs2CO3 (1.41 g, 4.31 mmol) was added to a degassed solution of tert-butyl 4-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridine-6-yl)-5-methyl-1H-1,2,3-triazole-1-yl)piperidine-1-carboxylate (665 mg, 1.57 mmol) and 4-(1-chloroethyl)-1-isopropyl-1H-1,2,3-triazole (495 mg, 2.35 mmol) in DMF (5 ml), and the mixture was stirred at 65°C for 2 hours. The reaction product was diluted with EA (25 ml) and washed with H2O (25 ml) and brine (25 ml). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with MeOH in DCM to obtain the title compound as a pale yellow oily substance (601 mg, 68%). MS ES+m / z 561.5[M+H] + .

[0717] The following compounds were prepared in a manner essentially similar to that of Preparation 269, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0718] [Table 50]

[0719] [Table 51] 1 Purification was performed by silica gel chromatography using MeOH elution in DCM. 2 Purification was performed by silica gel chromatography, which elutes with 20% to 100% EA in cHex. 3 Purification was performed by silica gel chromatography, which elutes 20% to 40% (3:1EA:EtOH) in cHex. 4 The solution was purified by silica gel chromatography, eluting 5% EA (2 CV) in 5% cHex, 5%–50% EA (20 CV) in cHex, 50%–100% EA (10 CV) in cHex, and then 100% EA. 5 Purification was performed by silica gel chromatography, eluting at 10% 3:1 EA / EtOH (3 CV) in cHex, 10% to 20% gradient 3:1 EA / EtOH (12 CV) in cHex, 20% 3:1 EA / EtOH (2 CV) in cHex, and 20% to 50% gradient 3:1 EA / EtOH (18 CV) in cHex. 6 After cooling to room temperature, the reaction mixture was treated with H2O. The insoluble material was recovered by filtration to obtain the title compound. a The material was used in subsequent processes without further characterization.

[0720] Preparation 281 tert-butyl4-[4-[4-[2-(3,5-difluoro-2-pyridyl)-2-methoxyethoxy]-3-fluoropyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0721] [ka] A solution of PPh3 (1.04 g, 3.96 mmol) in 10 ml of THF at 0°C was treated dropwise with DIAD (0.77 g, 3.83 mmol) under N2. After stirring the reaction mixture at 0°C for 0.5 hours, it was added to a mixture of 2-(3,5-difluoro-2-pyridyl)-2-methoxyethanol (0.30 g, 1.59 mmol) and tert-butyl 4-[4-(3-fluoro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazole-1-yl]piperidine-1-carboxylate (0.55 g, 1.32 mmol) in 10 ml of THF. The resulting mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by reverse-phase flash C18 chromatography using the following conditions: column, C18; elution with a gradient of 45%-55% CAN (0.1% FA) in H2O to obtain the title compound (480 mg, 62%) as a yellow solid. MS ES+m / z 588[M+H] + .

[0722] The following compounds were prepared in a manner essentially similar to that of Preparation 281, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0723] [Table 52] 1 Purification was performed by flash reverse-phase C18 chromatography, eluting with 30%-50% CAN (0.1% NH4HCO3) in H2O. 2 Purification was performed by flash reverse-phase C18 chromatography, which elutes 60% to 70% CAN in H2O.

[0724] Preparation 284 tert-butyl4-[4-[3-chloro-5-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,2-a]pyridin-7-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0725] [ka] A solution of tert-butyl 4-[4-[5-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridine-7-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (1.4 g, 2.54 mmol) in 15 ml of DMF at 0°C was treated with DCDMH (400 mg, 2.03 mmol). After stirring at 0°C for 0.5 hours, the residue was purified by reverse-phase flash C18 chromatography using the following conditions: column, C18; elution with a gradient of 60% to 70% CAN in H2O, to obtain the title compound (700 mg, 47%) as a yellow solid. MS ES+m / z 586[M+H] + .

[0726] The following compounds were prepared in a manner essentially similar to that of Preparation 284, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0727] [Table 53] 1 Purification was performed by reverse-phase C18 chromatography, which elutes 45% to 50% AcCN in H2O. 2 Purified by preparative TLC (PE / EA1:3).

[0728] Preparation 287 tert-butyl4-[4-[3-cyano-4-[2-(3.5-difluoro-2-pyridyl)-2-hydroxyethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate, isomer 1

[0729] [ka] In a sealed tube, chloro(N-[(1R,2R)-2-[(S)-[2-[[1,2,3,4,5,6-η]-4-methylphenyl]methoxy]ethyl]amino]-1,2-diphenylethylmethanesulfoneamidate)ruthenium(II) (25 mg, 0.04 mmol, 98% by mass) was added to a stirred mixture of FA NEt3 complex (5:2 ratio) (18 ml, 42.21 mmol) and tert-butyl 4-[4-[3-cyano-4-[2-(3,5-difluoro-2-pyridyl)-2-oxoethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (3.5 g, 4.2 mmol) in DCM (14 ml, 218 mmol). The reaction mixture was heated under N2 at 45°C for 75 hours. After cooling to room temperature, the reaction mixture was diluted with DCM and washed with H2O, saturated NaHCO3 aqueous solution, H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with 20% acetone in DCM to obtain the title compound as an orange solid (3.23 g, 99%). MS ES+m / z 581[M+H] + .

[0730] The following compounds were prepared in a manner essentially similar to that of Preparation 287, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0731] [Table 54] 1 Purification was performed by silica gel flash chromatography, which elutes with MeOH in DCM. 2 The crude product was used in the next process after a water-based workup.

[0732] Preparation 291 4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0733] [ka] To a suspension of 4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (4.01 g, 6.58 mmol) in MeOH (65 ml), NaBH4 (1.0 g, 26.43 mmol) was added all at once at 0°C. The mixture was stirred at 0°C for 5 minutes, then at room temperature for 1 hour. The reaction product was diluted with H2O (100 ml). The resulting precipitate was collected by filtration and washed with H2O / MeOH (4:1) (20 ml). The resulting solid was dried under vacuum at 40°C to obtain the title compound (3.40 g, 91%). MS ES+m / z 519[M+H] + .

[0734] Preparation 292 tert-butyl4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0735] [ka] A solution of tert-butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (1 g, 1.75 mmol) in MeOH (20 ml) was treated with NaBH4 (66.37 mg, 1.75 mmol) under N2 at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was quenched with H2O (50 ml) and extracted with EA (3 × 100 ml). The combined organic layers were washed with brine (2 × 50 ml), dried over Na2SO4, filtered, and concentrated to obtain the title compound (1.0 g, 100%) as a brown solid. MS ES+m / z 572[M+H] + .

[0736] The following compounds were prepared in a manner essentially similar to that of Preparation 292, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary. DCM can be used as a co-solvent.

[0737] [Table 55]

[0738] [Table 56] 1 Purification was performed by silica gel chromatography, which elutes with 0% to 10% MeOH in DCM. 2 The solution was purified by silica gel chromatography using DCM (5 CV), 2% MeOH in DCM (10 CV), and 5% MeOH in DCM (10 CV). 3 Purification was performed by silica gel chromatography, which elutes at 0% to 40% (10% MeOH in DCM) of DCM. 4 Purification was performed by silica gel chromatography, which elutes at 0% to 40% (10% MeOH in DCM) of DCM.

[0739] Preparation 307 tert-butyl4-[4-[4-[2-(3,5-difluoro-2-pyridyl)-2-hydroxy-propoxy]-3-fluoro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0740] [ka] A solution of tert-butyl 4-[4-[4-[2-(3,5-difluoro-2-pyridyl)-2-oxo-ethoxy]-3-fluoropyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (0.61 g, 1.07 mmol) in DCM (10 ml) was slowly added to a solution of MeMgBr in THF (3 mL, 4.2 mmol, 1.4 mol / L) that had been pre-cooled to 0°C under N2. An additional 2 ml of DCM was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with aqueous NH4Cl solution, extracted with DCM, and washed with H2O and brine. The organic phase was concentrated to obtain the residue. The residue was purified by silica gel chromatography using elution with 0% to 20% acetone in DCM to obtain the title compound (175 mg, 0.25 mmol, 24%, 85% by mass) as a yellow oily substance. MS ES+m / z 588[M+H] + .

[0741] The following compounds were prepared in a manner essentially similar to that of Preparation 307, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary. DCM can be used as a co-solvent.

[0742] [Table 57] 1 Purification was performed by silica gel chromatography, which elutes at 30% DCM (10% MeOH in DCM).

[0743] Preparation 309 tert-butyl4-[4-[3-chloro-4-[2-(3.5-difluoro-2-pyridyl)-2-methylsulfonyloxyethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0744] [ka] A solution of tert-butyl 4-[4-[3-chloro-4-[2-(3.5-difluoro-2-pyridyl)-2-hydroxyethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (0.60 g, 0.74 mmol) in DCM (6 ml) was successively treated with NEt3 (0.152 g, 1.51 mmol) and MsCl (0.13 g, 1.2 mmol) at 0°C. After 15 minutes, the cooling bath was removed and the mixture was warmed to room temperature. After 1 hour, the mixture was washed with H2O (1.5 ml), dried over MgSO4, and concentrated under vacuum to obtain the title compound as a green solid. The product was used in the next step without further purification. MS ES+m / z( 35 Cl / 37 Cl)668 / 670[M+H] + .

[0745] Preparation 310 tert-butyl4-[4-[3-cyano-4-[2-(3.5-difluoro-2-pyridyl)-2-isopropoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate, isomer 1

[0746] [ka] To a mixture of tert-butyl 4-[4-[3-cyano-4-[(2S)-2-(3,5-difluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (1.0 g, 1.3 mmol, 75% by mass), Ag2O (600 mg, 2.59 mmol), and 2-iodopropane (2.6 ml, 26 mmol) in DMF (10 ml), NaH (62 mg, 1.55 mmol, 60% by mass) from mineral oil was added under N2 at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and then an additional NaH (62 mg, 1.55 mmol, 60% by mass) from mineral oil was added. A portion of the NaH in the mineral oil (62 mg, 1.55 mmol, 60% by mass) was added approximately every 10-20 minutes. After 90 minutes, and after adding NaH seven times, H2O was added to the mixture. The mixture was extracted with EA, the organic phase was washed with brine (3 times), dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 20%-50% EA in cHex. The isolated substance was re-purified by silica gel chromatography eluting with 20% EA in MTBE. Impurities co-eluted with the title compound (720 mg, 56%, purity 63%). MS ES+m / z 523[M+H] + .

[0747] Preparation 311 tert-butyl4-[4-[3-chloro-4-[2-(3.5-difluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0748] [ka] A solution of tert-butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridyl)-2-hydroxyethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (0.63 g, 0.78 mmol) in N,N-dimethylacetamide (6 ml) was treated at room temperature with NaH (65 mg, 1.63 mmol, 60 wt%), followed by CH3I (0.08 ml, 1.28 mmol). After stirring at room temperature for 90 minutes, the reaction mixture was quenched with MeOH (0.5 ml) and purified by reverse-phase C18 chromatography eluting under a gradient of 30% to 90% ACN (NH4HCO3 buffer pH 9) in H2O to obtain the title compound (192 mg, 38%) as an orange solid. MS ES+m / z 604 / 606[M+H] + .

[0749] The following compounds were prepared in a manner essentially similar to that of Preparation 311, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0750] [Table 58] 1 The solution was purified by an aqueous solution of NH4HCO3 at pH 9 (5CV), followed by reverse-phase C18 chromatography using 30% to 60% ACN in an aqueous solution of NH4HCO3 at pH 9. 2 Ag2O (3.95 equivalents) was added to the reaction mixture. 3 Purification was performed by silica gel chromatography, which elutes 0% to 50% [DCM:MeOH(9:1)] in DCM. 4 The compound was purified by SCX chromatography. Non-basic impurities were washed away with DCM and 5% MeOH in DCM. The title compound was eluted with methanolic ammonia (2M). 5 THF was used as the solvent. 6Workup: The reaction products were extracted with DCM, washed with H2O (3 times) and brine, dried with MgSO4, filtered, and concentrated. 7 Workup: The reaction mixture was diluted with H2O, extracted with DCM, washed with brine, dried with MgSO4, filtered, and concentrated.

[0751] Preparation 318 tert-butyl4-[4-[3-chloro-4-[2-(3.5-difluoro-2-pyridyl)-2-(dimethylamino)-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate

[0752] [ka] A mixture of tert-butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridyl)-2-methylsulfonyloxyethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (0.50 g, 0.74 mmol) and dimethylamine in THF (2 M solution, 2 ml) was stirred at room temperature for 48 hours. The crude mixture was purified by silica gel chromatography eluting under a gradient of 0% to 100% acetone in DCM to obtain the title compound as a yellow solid (0.15 g, 27.8%, purity >85%). MS ES+m / z( 35 Cl / 37 Cl)617 / 619[M+H] + .

[0753] Preparation 319 4-[1-(1-isopropyltriazol-4-yl)ethoxy]-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonilicate hydrochloride

[0754] [ka] HCl (4M, 2.0 ml, 5.98 mmol) in dioxane was added to a solution of tert-butyl 4-(4-(3-cyano-4-(1-(1-isopropyl-1H-1,2,3-triazole-4-yl)ethoxy)pyrazolo[1,5-a]pyridine-6-yl)-5-methyl-1H-1,2,3-triazole-1-yl)piperidine-1-carboxylate (600 mg, 1.07 mmol) in DCM (10 ml), and the mixture was stirred at room temperature for 2 hours. The reaction product was concentrated under vacuum to obtain the title compound as a hygroscopic beige solid (689 mg, quantitative). MS ES+m / z 461.4[M+H] + .

[0755] The following compounds were prepared in a manner essentially similar to that of Preparation 319, using appropriate reagents, adjusting reaction times to determine the completion of the reaction, and preparing purification systems as necessary. For compounds from which amine salts were isolated, the formation of monovalent, divalent, or trivalent salts depends on the pKa of the amine and acid used to form the salt. The exact monovalent, divalent, or trivalent salt form for each example was not identified.

[0756] [Table 59]

[0757] [Table 60]

[0758] [Table 61] 1 The reaction was carried out in MeOH. After workup, the residue was ground in EA, filtered, and recovered by filtration to obtain the title compound. 2 The reaction products were concentrated in a vacuum. The residue was diluted with EA and slurryed for 1 hour. The precipitate was recovered by filtration.

[0759] Preparation 340 2-[3-chloro-6-[5-methyl-1-(4-piperidyl)triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanol, 2,2,2-trifluoroacetic acid

[0760] [ka] A solution of tert-butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (1.0 g, 1.75 mmol) in DCM (10 ml) was treated with TFA (10 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the crude product was used in the next synthesis step without purification. MS ES+m / z 472[M+H] + .

[0761] The following compounds were prepared in a manner essentially similar to that of Preparation 340, using appropriate reagents, adjusting reaction times to determine the completion of the reaction, and preparing purification systems as necessary. For compounds from which amine salts were isolated, the formation of monovalent, divalent, or trivalent salts depends on the pKa of the amine and acid used to form the salt. The exact monovalent, divalent, or trivalent salt form for each example was not identified.

[0762] [Table 62]

[0763] [Table 63]

[0764] [Table 64] a The material was used in subsequent processes without further characterization.

[0765] Preparation 355 4-[2-(2,4-difluorophenyl)-2-hydroxyethoxy]-6-[5-methyl-1-(4-piperidyl)triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0766] [ka] tert-butyl 4-[4-[3-cyano-4-[2-(2,4-difluorophenyl)-2-hydroxyethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazole-1-yl]piperidine-1-carboxylate (1.0 g, 1.73 mmol) was suspended in 4 M HCl in 1,4-dioxane (20 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was basicized to pH 9 with saturated Na2CO3 aqueous solution (10 ml). The resulting solid was recovered by filtration and washed with H2O (3 × 50 ml) to obtain the title compound (0.80 g, crude) as a brown solid. MS ES+m / z 480[M+H] + .

[0767] The following compounds were prepared in a manner essentially similar to that of Preparation 355, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0768] [Table 65]

[0769] [Table 66] 1 Workup: The reaction product was concentrated. The residue was dissolved in MeOH and applied directly to an SCX cartridge that had been pre-prepared with MeOH. After washing away non-basic impurities with MeOH, the title compound was eluted with methanolic ammonia (2M). 2Workup: The reaction products were concentrated. The residue was suspended in DCM and washed with 2M NaOH aqueous solution, then brine. The organic layer was dried over MgSO4, filtered, and concentrated. 3 Workup: The reaction products were concentrated. The residue was suspended in DCM and washed with 1M aqueous NaOH solution. The layers were separated, the organic layer was dried over MgSO4, filtered, and concentrated. 4 The product contained impurities carried over from the previous step. 5 Workup: The reaction products were concentrated. The residue was dissolved in DCM, the saturated NaHCO3 aqueous solution was dried over MgSO4, filtered, and concentrated. 6 Workup: The reaction products were concentrated. The residue was dissolved in MeOH and then treated with NaHCO3 to pH 8. The mixture was concentrated under vacuum.

[0770] Preparation 369a 6-[1-(7-azaspiro[3,5]nonanane-2-yl)-5-methylpyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0771] [ka] and Preparation 369b 6-[1-(7-azaspiro[3,5]nonanane-2-yl)-3-methylpyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0772] [ka] A solution of tert-butyl 2-[4-[3-cyano-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazole-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate and tert-butyl 2-[4-[3-cyano-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-3-methyl-pyrazole-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate (621 mg, 0.77 mmol, 70%) in DCM (6 ml) was treated with TFA (1.2 ml). After stirring at room temperature for 3 days, the reaction mixture was concentrated and loaded onto an SCX column pre-treated with MeOH. After washing with MeOH, the title compound was eluted with 2M NH3 in MeOH to obtain a mixture of the title compound (398 mg, 96%) as a pale yellow solid. MS ES+m / z 468[M+H] + .

[0773] Preparation 370 [2-[3-cyano-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethyl]methanesulfonate

[0774] [ka] The solution of 4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitride (1.39 g, 2.69 mmol) and NEt3 (0.80 ml, 5.7 mmol) in DCM (14 ml) was cooled to 0°C and purged with N2. The reaction mixture was treated dropwise with MsCl (0.26 mL, 3.4 mmol). The reaction mixture was slowly warmed to room temperature. After 75 minutes, the reaction mixture was cooled again to 0°C, quenched with H2O (15 ml), and the organic layer was removed. The aqueous layer was extracted with DCM (2 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the title compound as a light brown foamy solid (1.80 g, 100% yield, 90% purity), which was used without purification. MS ES+m / z 597[M+H] + .

[0775] The following compounds were prepared in a manner essentially similar to that of Preparation 370, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0776] [Table 67]

[0777] Preparation 373 7-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]-5-[[3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propyl]amino]imidazo[1,2-a]pyridine-3-carbonitride

[0778] [ka] A mixture of 7-chloro-5-[[3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propyl]amino]imidazo[1,2-a]pyridine-3-carbonitride (1.2 g, 3.28 mmol), bis(pinacolato)diborone (1.19 g, 4.69 mmol), and KOAc (0.92 g, 9.38 mmol) in dioxane (20 ml) was treated with Xphos Palladacycle Gen 4 (56.06 mg, 0.07 mmol) under N2 at 80°C. The resulting mixture was stirred at 80°C for 2 hours. The reaction product was used in the next step without workup or purification.

[0779] The reaction mixture was cooled and treated under N2 with KF (0.53 g, 9.38 mmol), 4-(4-bromo-5-methyl-1,2,3-triazole-1-yl)-1-(oxetan-3-yl)piperidine (1.20 g, 3.97 mmol), H2O (4 ml), and PdCl2 (DtBPF) (0.10 g, 0.15 mmol). After stirring at 100°C for 2 hours, the reaction mixture was cooled to room temperature, quenched with H2O (100 ml), and extracted with EA (2 × 100 ml). The combined organic layer was washed with brine (150 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (100-20:1) to obtain the title compound (315 mg, 18%) as a white solid. MS ES+m / z 570[M+H] + .

[0780] Preparation 374 (1S)-2-[3-bromo-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanol, isomer 1

[0781] [ka] A solution of (1S)-2-[3-bromo-6-[5-methyl-1-(4-piperidyl)triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanol hydrochloride (7.57 g, 11.0 mmol) in room temperature MeOH (76 ml) was treated with oxetan-3-one (1.97 g, 27.3 mmol), AcOH (1.60 mL, 27.9 mmol), and NaCNBH3 (2.80 g, 44.6 mmol). After 48 hours, the reaction mixture was quenched with saturated 1N K2CO3 (150 ml) and extracted with DCM (300 ml). The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using elution with 0% to 100% acetone in DCM to obtain the title compound as a white solid (0.352 g, 6%).

[0782] Example 1 4-[[2-(5-fluoro-2-pyridyl)-2-methoxy-ethyl]amino]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0783] [ka] 4-[[2-(5-fluoro-2-pyridyl)-2-methoxy-ethyl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.51 mmol, 224 mg), 4-(4-bromo-5-methyl-triazole-1-yl)-1-(oxetan-3-yl)piperidine (278 mg, 0.92 mmol), K2CO3 (142 mg, 1.03 mmol), toluene (2 mL), and H2O (200 μl) were added to the vial. The vial was flushed with N2, and then PdCl2(DtBPF) (51 mg, 0.08 mmol) was added. The reaction mixture was heated at 100°C for 3 hours. The mixture was filtered through DE, and the filtrate was loaded onto an SCX column pre-treated with MeOH. The column was washed with MeOH. The product was eluted with 2M NH3 in MeOH and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 100% cHex (25% EtOH in EA) to obtain the title compound (0.40 g, 16%). MS ES+m / z 532[M+H] + .

[0784] Example 2 4-[1-(7-fluoro-4-isoquinolyl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonilicate

[0785] [ka] 4-[1-(7-fluoro-4-isoquinolyl)ethoxy]-6-[5-methyl-1-(4-piperidyl)triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrilate hydrochloride (305 mg, 0.54 mmol) and DIPEA (0.28 ml, 1.61 mmol) were dissolved in MeOH (5 ml), and activated 4A molecular sieves were added. To this solution, 3-oxetanone (0.17 ml, 2.70 mmol), NaBH3CN (172 mg, 2.74 mmol), and AcOH (0.37 ml, 6.43 mmol) were added sequentially, and the reaction mixture was stirred at 70°C for 2 hours. Upon completion, the reaction mixture was cooled to room temperature and diluted with EA. The mixture was washed with H2O (25 ml) and brine (25 ml), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with MeOH in DCM to obtain the title compound as an off-white solid (35 mg, 15%). MS ES+m / z 553.3[M+H] + .

[0786] The following compounds were prepared in a manner essentially similar to that of Example 2, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0787] [Table 68]

[0788] [Table 69] 1 4A molecular sieves and DIPEA were excluded from the reactants. 2 Purification was performed by silica gel chromatography, which elutes with 0% to 10% MeOH in DCM. 3 Purification was performed by silica gel chromatography, eluting at 5% EA (2 CV) in cHex, 5%–50% EA (20 CV) in cHex, 50%–100% EA (5 CV) in cHex, and 100% EA (10 CV) in cHex. 4 The samples were purified by C18 reverse-phase chromatography eluting with 45%-65% ACN (10 mM NH4HCO3 buffer, pH 9) in H2O; column: XBridge C18, 19 × 150 mm, 5 μm. 5 Column: Luna Hilic, 30 × 150 mm, 5 μm, 10%~20%: Elute with MeOH (10 mM NH4HCO3 pH 8). 6 Purification was performed by silica gel chromatography using elution with 10% to 50% acetone in DCM. 7 Column: Luna Omega Polar, 21 × 150 mm, 5 μm; Elutes in H2O (0.1% FA) with 25% to 55% ACN (0.1% FA). 8 Purification was performed by silica gel chromatography, which elutes with 0% to 10% MeOH in DCM. 9 Purification was performed by silica gel chromatography, which elutes at 50% DCM (10% MeOH in DCM). 10 Chiral method: LUX-2PROP-AMY-CELL-1Amy2-iAmy1.

[0789] Example 12 4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonilicate

[0790] [ka] A suspension of 4-hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.162 g, 0.43 mmol) in ACN (1.8 ml) was treated with K2CO3 (53 mg, 0.53 mmol) and 2-bromo-1-(5-fluoropyridine-2-yl)ethanone (100 mg, 0.44 mmol). The suspension was stirred at 80°C for 16 hours. After cooling to room temperature, EA and H2O were added, and the mixture was filtered. The layers from the filtrate were separated, washed with 2N NaOH, H2O and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 10% EtOH in EA to obtain the title compound (91 mg, 47%). MS ES+m / z 517[M+H] + .

[0791] Example 13 4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 1

[0792] [ka] and Example 14 4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0793] [ka] NaBH4 (3.0 mg, 0.08 mmol) was added in one go over 3 hours at room temperature to a solution of 4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (28.3 mg, 0.05 mmol) in EtOH (0.78 mL) and DCM (0.55 mL). The reaction mixture was quenched with saturated NH4Cl. The layers were separated, the organic layer was washed with brine, dried over MgSO4, and filtered through DE. The filtrate was concentrated to obtain 16 mg. The combined aqueous layer was extracted with DCM, and the organic layer was concentrated to obtain 5 mg. Both lots were combined to obtain 21 mg. This substance was subjected to the following chiral chromatography conditions: column: Chiralpak AD, 30 × 250 mm, 5 μm; elution in CO2 with 35% IPA (0.5% DMEA), and the title compound and isomer 1 (9.0 mg, 32%) (t R The interval is 1.28 minutes, with 98% ee. MS ES+m / z 519[M+H] + ), and the title compound, isomer 2, (9.2 mg, 32%) (t R The duration is 1.60 minutes, with 85% ee. MS ES+m / z 519[M+H] + The following was obtained. The retention time was obtained using analytical method A (see Table A for specific analytical conditions).

[0794] Example 15 4-[[2-(5-fluoro-2-pyridyl)oxetan-2-yl]methoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0795] [ka] t-BuOK (260 mg, 2.29 mmol) was added at room temperature to a suspension of trimethylsulfoxonium iodide (545 mg, 2.40 mmol) in 2-methyl-2-butanol (0.1 M). The sealed vial was stirred at 50°C for 90 minutes under N2. The suspension was cooled to room temperature, and 4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 0.77 mmol) was added all at once. The resulting mixture was vigorously stirred overnight at room temperature under N2 in a sealed tube. The suspension was then heated at 50°C for 3 days, followed by stirring at room temperature for 3 days.

[0796] In a separate tube, t-BuOK (260 mg, 2.29 mmol) was added at room temperature to a suspension of trimethylsulfoxonium iodide (545 mg, 2.40 mmol) in 2-methyl-2-butanol (0.1 M). The sealed vial was stirred at 50°C for 90 minutes under N2. The reaction product was added to this suspension all at once, and the resulting mixture was stirred overnight at 50°C under N2 in a sealed tube. The reaction product was poured into a saturated aqueous NH4Cl solution and extracted with DCM, and the aqueous layer was extracted with DCM. The combined organic layers were washed with 1N NaOH (twice), then H2O, then brine, and dried over MgSO4. The obtained residue was purified by reverse-phase chromatography using a Claricep C-series column, eluting with a linear gradient of 30% ACN (NH4HCO3pH9) in H2O (2CV), followed by 30%–60% ACN (NH4HCO3pH9) in H2O (8CV) and 60% ACN (NH4HCO3pH9) in H2O (8CV). The fraction containing the title compound was partially evaporated, DCM was added, and the two-layer mixture was passed through a hydrophobic filter. The filtrate was dried over MgSO4, filtered, and evaporated.

[0797] The substance isolated after reverse-phase chromatography was subjected to the following chiral chromatography conditions: column: Chiralpak IA, 20 × 250 mm, 5 μm; elution with 40% IPA (0.5% DMEA) in CO2 to obtain the title compound (29 mg, 7%). R is 2.82 (Method P), ee>98%ee; MS ES+m / z 545[M+H] + The retention time was obtained using analytical method P.

[0798] Example 16 6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]-4-[1-[5-(trifluoromethyl)pyridazine-3-yl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0799] [ka] DIAD (384 mg, 1.90 mmol) was added dropwise to a solution of PPh3 (539 mg, 2.06 mmol) in THF (10 ml) under N2 at 0°C. The resulting mixture was stirred at 0°C for 0.5 hours, then added to 4-hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (600 mg, 1.58 mmol) and 1-[5-(trifluoromethyl)pyridazine-3-yl]ethanol (456 mg, 2.37 mmol) in THF (10 ml), and stirred overnight. The reaction mixture was acidified to pH 5 with concentrated HCl, diluted with H2O (80 ml), and extracted with EA (3 × 50 ml). The aqueous phase was basicized to pH 8 with saturated NaHCO3 aqueous solution, extracted with CHCl3:IPA (3:1) (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was prepared under the following conditions: Column: XB-C18, 50 × 250 mm, 10 μm; The title compound was purified by reverse-phase chromatography using elution in H2O (10 mM FA) with a gradient of 35% to 55% ACN to obtain a racemic mixture (345 mg, 39%) as a green solid. MS ES+m / z 554[M+H] + .

[0800] A racemic mixture (345 mg) was subjected to chiral chromatography using 248 / 208 nm under the following conditions: column: CHIRALPAK IC, 2 × 25 cm, 5 μm; elution with 50% MeOH (10 mM NH3-MeOH) in MTBE to obtain the title compound (117 mg, 34%). R The time was 9.82 minutes, with 100% ee. MS ES+m / z 554[M+H] + .

[0801] The following compounds were prepared in a manner essentially similar to that of Example 16, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0802] If retention time is obtained from the analysis column, the method is listed in the last column. Refer to Table A for specific analysis conditions for each method.

[0803] [Table 70] 1 Purification was performed by silica gel chromatography using DCM:MeOH (20:1) elution. 2 The sample was purified by reverse chromatography using H2O with elution of 28%-35% ACN (0.1% NH4HCO3): column: Welch-XB C18, 50×250 mm, 10 μm. 3 The residue was dissolved in MeOH, treated with TFA, and then applied directly to an SCX cartridge that had been pre-prepared with MeOH. After washing away non-basic impurities with MeOH, the title compound was eluted with methanolic ammonia (2M). 4Column: Chiralpak IA, 20 × 250 mm, 5 μm; Elutes with 35% EtOH (0.5% DMEA) in CO2.

[0804] Example 19 4-[1-(3,6-dimethylpyrazine-2-yl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 1

[0805] [ka] A mixture of 1-(3,6-dimethylpyrazine-2-yl)ethylmethanesulfonate (395 mg, 1.71 mmol), K2CO3 (546 mg, 3.95 mmol), and 4-hydroxy-6-{5-methyl-1-[1-(oxetan-3-yl)piperidine-4-yl]-1,2,3-triazole-4-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.32 mmol) in ACN (10 ml) was stirred at 80°C for 2 hours under N2. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated under vacuum. The residue was purified by reverse-flash C18 chromatography, eluting with a gradient of 20% to 40% ACN in H2O, to obtain the title compound (450 mg, 66%) as a brown solid.

[0806] Brown solids, under the following conditions: The title compound (163 mg, 36%) was obtained by chiral chromatography using a CHIRALPAK AD-H column, 3 × 25 cm, 5 μm; elution with 40% MeOH in CO2. R It was 5.77 minutes, with 100% ee.

[0807] The following compounds were prepared in a manner essentially similar to that of Example 19, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary. Cs2CO3 and DMF can be used.

[0808] If retention time is obtained from the analysis column, the method is listed in the last column. Refer to Table A for specific analysis conditions for each method.

[0809] [Table 71] 1 Purification was performed by silica gel chromatography, which elutes with 0% to 50% EA (25% EtOH) in cHex. 2 Column: Chiralpak IA, 20 × 250 mm, 5 μm; elutes in CO2 with 35% IPA (0.5% DMEA). 3 Purification was performed by flash reverse-phase C18 chromatography, eluting 40% to 70% ACN (NH5CO3 pH9 buffer) in H2O. 4 Chiralpak AD, 20 × 250 mm, 5 μm; elutes in CO2 with 35% IPA (0.5% DMEA). 5 Chiralcel OJ, 20×250mm, 5μm; elutes in CO2 with 20% MeOH (0.5% DMEA). 6 Purification was performed by flash reverse-phase C18 chromatography, eluting 30% to 60% ACN (NH5CO3 pH9 buffer) in H2O. 7 Column: Chiralcel OJ, 20 × 150 mm, 5 μm; Elutes with MeOH (0.5% DMEA) in CO2. 8 Purification was performed by silica gel chromatography, which elutes with 20% to 60% EA in cHex. 9 Column: Chiralcel OJ, 20 × 250 mm, 5 μm; Elution with 30% MeOH (0.5% DMEA) in CO2, flow rate: 80 ml / min. 1020% 3:1EA / EtOH(2CV) in cHex, 20%~65% gradient 3:1EA / EtOH(25CV) in cHex, 65% 3:1EA / EtOH(10CV) in cHex, 65%~100% gradient 3:1EA / EtOH(15CV) in cHex, Purification was performed by silica gel chromatography using elution with 100% cHex 3:1EA / EtOH (10CV). 11 Chiralpak AD, 20 × 250 mm, 5 μm; elutes in CO2 with 35% EtOH (0.5% DMEA).

[0810] Example 26 4-[2-(5-fluoro-2-pyridyl)-2-pyrroridine-1-ylethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridin-3-carbonitrile, isomer 1

[0811] [ka] and Example 27 4-[2-(5-fluoro-2-pyridyl)-2-pyrroridine-1-ylethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridin-3-carbonitrile, isomer 2

[0812] [ka] [2-[3-cyano-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethyl]methanesulfonate (155 mg, 0.26 mmol) was placed in a screw-cap vial and dissolved in ACN (0.65 ml) under N2 conditions. Pyrrolidine (183 mg, 0.002 mmol) was added. The reaction mixture was heated at 50°C for 46 hours. The reaction product was concentrated, and the residue was treated with DCM (4 ml) and brine (2 ml). The organic layer was separated, washed with brine (2 × 2 ml), dried over Na₂SO₄, and filtered. The filtrate was concentrated to obtain a brown oily substance (160 mg).

[0813] The brown oily substance was subjected to the following chiral chromatography conditions: column: Amylose-1, 30 × 250 mm, 5 μm; elution in CO2 with 40% IPA (0.5% DMEA), and the title compound, isomer 1 (59 mg, 37%) (t R is 1.83, ee>98%ee;572[M+H] + (is), and the title compound, isomer 2 (47 mg, 29%) (t R The value is 2.58, and ee > 98%ee. MS ES+m / z 572[M+H] + The following was obtained. The retention time was obtained using analytical method G (see Table A for specific analytical conditions).

[0814] The following compounds were prepared in a manner essentially similar to that of Examples 26 and 27, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0815] If retention time is obtained from the analysis column, the method is listed in the last column. Refer to Table A for specific analysis conditions for each method.

[0816] [Table 72] 1The reaction was carried out at room temperature in dimethylamine (2M) in THF. 2 Column: Chiralpak AD, 20 × 250 mm, 5 μm; Elutes with 35% IPA (0.5% DMEA) in CO2. 3 Cs2CO3 was used as the base. 4 Column: XBridge C18, 19×150mm, 5μm; Elutes in 45%~75% ACN (NH4HCO3 10mM pH9) in H2O. 5 Column: Chiralpak AD, 20 × 250 mm, 5 μm; Elutes with 45% EtOH (0.5% DMEA) in CO2. 6 The mixture was refluxed for 5 hours, then stirred at room temperature for 10 days. 7 The solution was purified by reverse-phase chromatography, eluting 0% to 50% (10% MeOH in DCM) (20 CV) first, followed by 50% (10% MeOH in DCM) (20 CV) in DCM. 8 Column: Chiral Art Amylose C, 30 × 250 mm, 5 μm; Elutes in CO2 with 40% IPA (0.5% DMEA).

[0817] Example 31 4-[4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]-1-piperidyl]tetrahydrofuran-3-ol, isomer 1

[0818] [ka] and Example 32 4-[4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazole-1-yl]-1-piperidyl]tetrahydrofuran-3-ol, isomer 2

[0819] [ka] 3,6-Dioxabicyclo[3.1.0]hexane (157 mg, 1.73 mmol) was added to a solution of 3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-methoxyethoxy]-6-[5-methyl-1-(4-piperidyl)triazole-4-yl]pyrazolo[1,5-a]pyridine (350 mg, 0.72 mmol) in EtOH (3 ml), and the mixture was stirred overnight at 80°C. Additional 3,6-Dioxabicyclo[3.1.0]hexane (157 mg, 1.73 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (50 ml) and washed with H2O (2 × 20 ml) and brine (20 ml). The crude product was purified by silica gel chromatography eluting with MeOH in DCM to obtain a brown oily substance. The oily substance was subjected to SFC elution with 55% CO2 (50% 2-propanol in ACN) (0.1% DEA). After chiral separation, both diastereomer pairs were individually purified by flash chromatography and eluted with a MeOH gradient in DCM. The substances isolated from each purified product were ground in pentane and washed with pentane, followed by Et2O to obtain the title compound, isomer 1, (36 mg, 8%) (t R 6.46 min, 96% EE, MS ES+ m / z 572 [M+H] + (is), and title compound, isomer 2, (45 mg, 11%) (t R 6.86 min, 96% EE, MS ES+ m / z 572 [M+H] + (is obtained.)

[0820] Example 33 2-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanol, isomer 2

[0821] [ka] 2-[3-chloro-6-[5-methyl-1-(4-piperidyl)triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanol 2,2,2-trifluoroacetic acid (800 mg, 1.37 mmol) was stirred in MeOH (20 ml), to which 3-oxetanone (611 mg, 8.48 mmol) was added at room temperature. The resulting mixture was stirred under N2 at 50°C for 1 hour. NaBH3CN (426 mg, 6.78 mmol) was added to the above mixture in several portions at room temperature. The resulting mixture was stirred further under N2 at 50°C for 2 hours. After cooling to room temperature, the reaction product was diluted with H2O (50 ml), and the mixture was basicized to pH 9 with saturated Na2CO3 aqueous solution. The mixture was extracted with EA (3 × 150 ml). The combined organic layers were washed with brine (2 × 50 ml), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by reverse flash chromatography using the following conditions: column, C₁₈; elution in 30%-35% ACN (0.1% NH₃H₂O) to obtain a racemic mixture (420 mg, 58%) of the title compound as a yellow solid. MS ES+m / z 528[M+H] + .

[0822] Yellow solids, under the following conditions: CHIRAL ART Amylose-SA, 2 × 25 cm, 5 μm; 50% MeOH (10 mM NH 3 Elution with -MeOH; flow rate: 20 mL / min; subjected to chiral chromatography using 214 / 244 nm to extract the title compound (140 mg, 19%). R =10.92, ee=100% was obtained. MS ES+m / z 528[M+H] + .

[0823] Example 34 4-[1-(1-isopropyltriazol-4-yl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 1

[0824] [ka] 4-[1-(1-isopropyltriazole-4-yl)ethoxy]-6-[5-methyl-1-(4-piperidyl)triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (689 mg, 1.29 mmol) and DIPEA (0.67 ml, 3.87 mmol) were dissolved in MeOH (10 ml), and activated 4A molecular sieves were added. 3-oxetanone (0.46 ml, 6.46 mmol), NaBH3CN (406 mg, 6.46 mmol), and AcOH (0.89 ml, 15.50 mol) were added sequentially, and the reaction mixture was stirred at 70°C for 90 minutes. After cooling to room temperature, the reaction mixture was diluted with EA. The mixture was washed with H2O (1 × 25 ml) and brine (1 × 25 ml), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with MeOH in DCM to obtain an off-white solid (490 mg, 73%). The off-white solid was subjected to SFC elution with 50% EtOH (0.1% DEA) in CO2 to obtain the title compound (140 mg, 21%). The RT was 6.93 mins. MS ES+m / z 517.3[M+H] + .

[0825] The following compounds were prepared in a manner essentially similar to that of Example 34, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0826] If retention time is obtained from the analysis column, the method is listed in the last column. Refer to Table A for specific analysis conditions for each method.

[0827] [Table 73]

[0828] [Table 74]

[0829] [Table 75]

[0830] [Table 76]

[0831] [Table 77]

[0832] [Table 78] 1 Purification was performed by silica gel chromatography using MeOH elution in DCM. 2 SFCs elute in CO2 with 60% MeOH (0.1% DEA). 3 SFCs that elute in CO2 with 50% EtOH (0.1% DEA). 4 Column: Chiralpak IG, 3 × 25 cm column, 5 μm; elutes with 60% ACN (0.5% DEA) in H2O. 5 Purified by preparative TLC (DCM / MeOH20:1). 6 Column: Chiralpak IA, 2 × 25 cm column, 5 μm; Elution occurs with 20% MeOH (0.5% 2M NH3 in MeOH) in 1:1 hexane / MTBE. 7 Column: AQ-C18, 250 × 50 mm, 10 μm; Purified by reverse-phase chromatography eluting with 20% to 35% ACN in FA aqueous solution. 8 Column: Chiralpak IG, 2 × 25 cm column, 5 μm; Elute with 25% MeOH (10 mM NH3-MeOH) in MTBE. 9Purification was performed by silica gel chromatography using elution with 0% to 100% acetone in DCM. 10 Column: Amylose-C, 20 × 250 mm column, 5 μm; elutes in CO2 with 45% EtOH (0.5% DMEA). 11 Purification was performed by reverse-phase C18 chromatography, eluting 30% to 60% ACN (NH4CO3 pH9 buffer) in H2O. 12 Column: Chiralpak AD, 20 × 250 mm, 5 μm; Elutes with 45% EtOH (0.5% DMEA) in CO2. 13 The product was purified by silica gel chromatography using elution in 100% DCM (2 CV), 0%-2% gradient MeOH in DCM (13 CV), 2% MeOH in DCM (10 CV), 2%-5% gradient MeOH in DCM (10 CV), 5%-10% gradient MeOH in DCM (2 CV), and 10% MeOH in DCM (15 CV). 14 Column: Chiralart Amylose C, 30 × 250 mm, 5 μm; Elutes with 40% EtOH (0.5% DMEA) in CO2. 15 Column: Chiralpak AD, 30 × 250 mm, 5 μm; Elutes with 40% IPA (0.5% DMEA) in CO2. 16 The sample was purified by silica gel chromatography using DCM / MeOH (10:1) elution. 17 Column: CHIRALPAK IE-3, 4.6 × 50 cm, 3 μm; Elutes with 50% EtOH in MTBE (0.1% DEA). 18 Column: Chiralpak IA, 2 × 25 cm column, 5 μm; Elution occurs with 50% EtOH (10 mM NH3-MeOH) in MTBE. 19 SFCs leach out in CO2 with 50% IPA (0.1% DEA). 20 Column: Chiralpak AD, 20 × 250 mm, 5 μm; Elutes with 35% EtOH in CO2. 21 4A molecular sieves, DIPEA, and AcOH were excluded from the reactants. 22 Purified by preparative TLC (PE / EA1:1). 23 Column: CHIRALPAK IE, 3 × 25 cm, 5 μm; Elutes with 50% MeOH (0.5% 2M NH3-MeOH) in MTBE. 24 Purification was performed by reverse-phase C18 chromatography, which elutes with 50% to 60% ACN in H2O. 25 Column: CHIRALPAK ID, 2×25cm, 5μm; Elutes with 30% MeOH (10mM NH3-MeOH) in MTBE. 26 Workup: The reaction products were concentrated. The residue was dissolved in DCM and Na2CO3 aqueous solution, and then filtered through a phase separator. The organic phase was dried over MgSO4, filtered, and concentrated. 27 The solution was purified by reverse-phase flash chromatography using 30% ACN (2CV) in an aqueous solution of NH4HCO3 at pH 9, 30% to 60% ACN (8CV) in an aqueous solution of NH4HCO3 at pH 9, 60% ACN (2CV) in an aqueous solution of NH4HCO3 at pH 9, and then eluted with 100% ACN. 28 Chiralpak AD, 20 × 250 mm, 5 μm; elutes in CO2 with 45% IPA (0.5% DMEA). 29 The reaction was carried out at 50°C. 30 Workup: The reaction mixture was quenched with H2O at room temperature, the pH was adjusted to 8 with NaHCO3 aqueous solution, extracted with EA (3 x 30 ml), washed with brine (2 x 20 ml), dried with Na2SO4, filtered, and concentrated. 31 Purified by preparative TLC (5% MeOH in DCM). 32 Column: CHIRALPAK ID, 3×25cm, 5μm; Elutes with 30% EtOH (0.1% 2M NH3-MeOH) in 2:1 DCM / MeOH. 33 4A molecular sieves and DIPEA were excluded from the reactants. 34 Workup: The reaction mixture was diluted at room temperature with saturated K2CO3 (30 ml), extracted with EA (3 x 50 ml), washed with brine (3 x 50 ml), dried over Na2SO4, filtered, and concentrated. 35 Column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Elutes with 50% MeOH (0.5% 2M NH3-MeOH) in MTBE. 36 Workup: The reaction mixture was quenched at room temperature with saturated NaHCO3 (20 ml), extracted with 25% i-PrOH in CHCl3 (3 x 30 ml), washed with brine (2 x 20 ml), dried over Na2SO4, filtered, and concentrated. 37 Column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Elutes with 50% MeOH (10 mM NH3-MeOH) in MTBE. 38 Workup: The reaction mixture was concentrated, diluted with H2O (10 ml), extracted with 20% i-PrOH (3 x 30 ml) on CHCl3, dried over Na2SO4, filtered, and concentrated again. 39 Purified by preparative TLC 100% EA. 40 Purification was performed by silica gel chromatography, which elutes at 40% DCM (10% MeOH in DCM). 41 SFC chromatography that elutes in 60% CO2 with 40% EtOH (1% DEA). 42 Workup: The reaction mixture was quenched with H2O at room temperature, the pH was adjusted to 8 with NaHCO3 aqueous solution, extracted with CHCl3:IPA, dried with Na2SO4, filtered, and concentrated. 43 The product was purified by silica gel chromatography using MeOH (1:30~1:20) in EA. 44Column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Elutes with 30%~50% MeOH (0.5% 2M NH3-MeOH) in MTBE. 45 Column: Chiralpak IA, 2 × 25 cm column, 5 μm; Elution occurs with 15% ACN:EtOH (2:1) in MTBE (10 mM NH3 in MeOH). 46 Column: Ultimate XB-C18, 50 × 250 mm, 10 μm; Purified by reverse-phase C18 chromatography with elution of 20% to 50% ACN (0.5% NH3H2O) in H2O. 47 Column: CHIRALPAK ID, 2 × 25 cm, 5 μm; Elutes in 50% MeOH [MeOH in DCM (1:1) (2M NH3-MeOH)]. 48 Column: CHIRALPAK ID, 2×25cm, 5μm; Elutes in 50% MeOH [MeOH in DCM (1:1) (0.1% 2M NH3-MEOH)]. 49 Workup: The reaction mixture was quenched with H2O at room temperature, the pH was adjusted to 8-9 with an aqueous solution of Na2CO3, extracted with i-PrOH in CHCl3, washed with brine, dried over Na2SO4, filtered, and concentrated. 50 Purified by preparative TLC DCM using MeOH(1-15). 51 Column: CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 μm; Elutes with 50% MeOH (10 mM NH3-MeOH) in MTBE. 52 Purified by preparative TLC (DCM / MeOH10:1). 53 Column: Chiralpak IA, 2 × 25 cm column, 5 μm; Elution is performed with 50% MeOH (10 mM NH3-MeOH) in MTBE. 5 Purification was performed by reverse-phase C18 chromatography, eluting with 10% to 40% ACN (10 mmol / L NH3H2O) in H2O.

[0833] Example 66 6-[3,5-dimethyl-1-[1-(oxetan-3-yl)-4-piperidyl]pyrazole-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0834] [ka] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (95 mg, 0.21 mmol), 4-(4-bromo-3,5-dimethylpyrazole-1-yl)-1-(oxetan-3-yl)piperidine (73 mg, 0.23 mmol), and K2CO3 (78 mg, 0.56 mmol) were degassed under N2 sonication. PdCl2(DtBPF) (9 mg, 0.14 mmol) was added, the container was sealed, and stirred overnight at 80°C. The reaction mixture was diluted with EA and H2O. The layers were separated, the organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0%-60% EtOH (1:3) in EA to obtain the title compound (91 mg, 76%) as a green solid. MS ES+m / z 566[M+H] + .

[0835] The following compounds were prepared in a manner essentially similar to that of Example 66, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0836] [Table 79] 1Workup: The reaction products were concentrated. The residue was diluted with H2O, and a 35% HCl aqueous solution was added to adjust the pH to 1. i-PrOH was gradually added until a solution was obtained. Charcoal was added, and the reaction products were stirred for 1 hour. DE was added, and the mixture was stirred for 30 minutes. The suspension was filtered, and the solid was washed with i-PrOH:H2O (1:2). The pH of the filtrate was adjusted to 10 with a 10M NaOH aqueous solution. The resulting insoluble material was recovered by filtration to obtain the title compound.

[0837] Example 68 6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethylamino]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 1

[0838] [ka] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethylamino]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.39 g, 0.45 mmol), 4-(4-bromo-5-methyl-triazole-1-yl)-1-(oxetan-3-yl)piperidine (0.17 g, 0.55 mmol), K2CO3 (0.16 g, 1.12 mmol), toluene (8 ml), and H2O (1 ml) were added to a pressure tube. The mixture was degassed by blowing N2 into it for several minutes, then PdCl2(DtBPF) (0.02 g, 0.03 mmol) was added, and the mixture was degassed for another 2 minutes. The tube was capped, and the reaction mixture was heated at 95°C for 6 hours. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EA (3 times). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, and eluted with 0%-100% EA in cHex, followed by 0%-5% MeOH in DCM to obtain a brown foamy substance (184 mg, 65%). MS ES+m / z 552[M+H] + .

[0839] The brown foamy substance was subjected to chiral chromatography using the following conditions: column: Chiralpak IH, 3 × 100 mm, 3 μm; elution in CO2 with 10%~50% EtOH (0.2% IPAm), to obtain the title compound (69 mg, 24%). R The result was 1.70, with ee > 98%. MS ES+m / z 552[M+H] + Retention times were obtained using analytical method K (see Table A for specific analytical conditions).

[0840] The following compounds were prepared in a manner essentially similar to that of Example 68, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary. K3PO4 and IPA may also be used.

[0841] If retention time is obtained from the analysis column, the method is listed in the last column. Refer to Table A for specific analysis conditions for each method.

[0842] [Table 80] 1 The solution was eluted in cHex at 0% to 100% (25% EtOH:EA) and purified by silica gel chromatography. 2 Column: Chiralpak AD, 20 × 250 mm, 5 μm; Elutes with 45% MeOH (0.2% DMEA) in CO2. 3 Column: Chiralpak IH, 3×100mm, 3μm; Elutes in CO2 with 10%~50% EtOH (0.2% IPAm). 4 Column: Chiralpak IA, 3 × 100 mm, 3 μm; Elutes in CO2 with 25%~50% EtOH (0.2% IPAm). 5 The following conditions: Column, C18; Purification was performed by reverse-phase flash C18 chromatography using elution in H2O with 20% to 60% ACN (NH5CO3 pH 9). 6 Column: Chiralcel OD, 20 × 250 mm, 5 μm; Elutes with 45% MeOH (0.5% DMEA) in CO2.

[0843] Example 73 6-[5-methyl-1-[1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)-4-piperidyl]pyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonilicate

[0844] [ka] A solution of 6-[5-methyl-1-(4-piperidyl)pyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (55 mg, 0.13 mmol) and 2,2,6,6-tetramethyltetrahydropyran-4-one (36 mg, 0.23 mmol) in MeOH (3 ml) was treated with NEt3 (90 μl, 0.65 mmol) and ZnCl2 (10 ml, 0.02 mmol, 1.9 M in MeTHF), and the reaction mixture was stirred at 50°C. After stirring overnight, the reaction mixture was cooled to room temperature and treated with NaBH3CN (33 mg, 0.53 mmol). After stirring at 50°C for 3 days, the reaction mixture was quenched with H2O and EA. The phases were separated, and the aqueous phase was extracted with EA. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 5% MeOH in DCM to obtain the title compound (50 mg, 66%) as an amber-colored oil. MS ES+m / z 568[M+H] + .

[0845] Example 74 6-[5-methyl-1-[2-(oxetan-3-yl)-2-azaspiro[3,3]heptan-6-yl]pyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0846] [ka] 6-[1-(2-azaspiro[3,3]heptan-6-yl)-5-methylpyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, 2,2,2-trifluoroacetic acid (106 mg, 0.16 mmol) was dissolved in DCE (3 ml), and NEt3 (100 μl, 0.72 mmol), 3-oxetanone (25 μl, 0.43 mmol), and Na(OAc)3BH (89 mg, 0.42 mmol) were treated with DCE (3 ml), and the reaction mixture was stirred at room temperature for 16 hours. An additional aliquot of 3-oxetanone (25 μl, 0.43 mmol) was added, and the reaction mixture was stirred at 50°C for 4 hours. The reaction mixture was diluted with EA (25 ml), and the organic layer was washed with saturated NaHCO3 aqueous solution (50 ml) and brine (50 ml). The organic layer was collected, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using a gradient of 0% to 15% MeOH in DCM, and the title compound (26 mg, 31%) was obtained as an off-white solid. MS ES+m / z 496[M+H] + .

[0847] Example 75 2-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)azetidine-3-yl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(3,5-difluoro-2-pyridyl)ethanol, isomer 2

[0848] [ka] 2-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)azetidine-3-yl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(3,5-difluoro-2-pyridyl)ethanol (126 mg) was subjected to the following chiral chromatography conditions: column: Amylose-C, 30 × 250 mm column, 5 μm; elution in 40% IPA in CO2 to obtain the title compound (32 mg, 25%). R The voltage is 2.51, 90%ee, MS ES+m / z 518.2[M+H] + The retention time was obtained using analytical method H (see Table A for specific analytical conditions).

[0849] The following compounds were prepared in a manner essentially similar to that of Example 75, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0850] [Table 81]

[0851] [Table 82]

[0852] [Table 83] 1 Purification was performed by silica gel chromatography using MeOH elution in DCM. 2 SFC chromatography using 60% 2-propanol (0.1% DEA) in 40% CO2 for elution. 3 SFC chromatography using 60% MeOH (0.1% DEA) in 40% CO2 to elute the substance. 4 Column: Chiralpak IE-3; 4.6 × 50 cm column, 3 μm; Elution occurs with 50% EtOH (0.1% DEA) in MTBE. 5 Column: Chiral ART Cellulose-SB, 2×25cm column, 5μm; Elution with 10% EtOH (10mM NH3-MeOH) in MTBE. 6 Column: Chiral Art AmylC, 30 × 250 mm, 5 μm; Elutes with 45% EtOH (0.5% DMEA) in CO2. 7 Column: Amylose-C, 30 × 250 mm column, 5 μm; elutes in CO2 with 45% EtOH (0.5% DMEA). 8 Column: Chiralpak AD, 30 × 250 mm, 5 μm; Elutes with 55% IPA (0.5% DMEA) in CO2. 9 Column: Chiral Art AmylC, 20×250mm column, 5μm; elutes in CO2 with 60% IPA (0.5% DMEA). 10 Column: Chiral Art Amylose C, 30 × 250 mm, 5 μm; Elutes in CO2 with 40% IPA (0.5% DMEA).

[0853] Example 88 1-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-2-(3,5-difluoro-2-pyridyl)propan-2-ol, isomer 1

[0854] [ka] To an ice-cold solution of 2-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(3,5-difluoro-2-pyridyl)ethanone (190 mg, 0.19 mmol, 55% by mass) in DCM (4 ml) under N2 conditions, a solution of MeMgBr (0.26 ml, 0.78 mmol, 3 M) was added dropwise over 5 minutes. The resulting mixture was stirred for 3 hours, then diluted in DCM and slowly quenched with MeOH (2 mL). NaBH4 (5 mg, 0.132161 mmol) was added, and the mixture was stirred for 20 minutes. The reaction products were purified by silica gel chromatography eluting at 0% to 50% in DCM (10% MeOH in DCM). The substance was crushed in a column, dissolved using 50% MeOH in DCM, and the title compound was eluted along with impurities. The residue was further purified by reverse-phase chromatography using an XBridge C18 column (19 × 150 mm, 5 μm) eluted with 45%–75% ACN (10 mM NH4HCO3, pH 9) in H2O.

[0855] The substance isolated after reverse-phase chromatography was subjected to the following chiral chromatography conditions: Chiral Art Amylose C, 30 × 250 mm, 5 μm; elution in 40% IPA (0.5% DMEA) in CO2 to obtain the title compound and isomer 1 (7.5 mg, 7%). R 2.36, ee>98%ee; MS ES+m / z 560 / 562[M+H] + That was the case.

[0856] Example 89 1-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-2-(5-fluoro-2-pyridyl)butan-2-ol, isomer 2

[0857] [ka] EtMgBr (0.25 ml, 0.75 mmol, 3 M in Et2O) was treated with ZnCl2 (0.09 ml, 0.2 mmol, 1.9 M in MeTHF) under N2 at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was added dropwise with a solution of 2-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanone (304 mg, 0.58 mmol) in DCM (1 ml), and stirred at 0°C for 2 hours. The reaction mixture was diluted with DCM and slowly quenched with aqueous NH4Cl solution. The reaction mixture was passed through a phase separator and washed with DCM. The eluate was concentrated, the residue was dissolved in MeOH (5 ml), treated with NaBH4 (15 mg, 0.40 mmol), and stirred at room temperature for 1 hour. The reaction mixture was quenched with H2O, MeOH was removed under vacuum, extracted with DCM, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography with elution under a gradient of 0% to 5% MeOH in DCM to obtain a colorless oil (125.6 mg, 35%). The colorless oil was subjected to the following chiral chromatography conditions: column: Cellulose-1, 30 × 250 mm column, 5 μm; elution with 35% IPA (0.5% DMEA) in CO2 to obtain the title compound (18 mg, 6%). R The result was 2.64, 98%ee. MS ES+m / z( 35 Cl / 37 Cl)556 / 558[M+H] + Retention time was obtained using analytical method M.

[0858] The following compounds were prepared in a manner essentially similar to that of Example 89, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0859] If retention time is obtained from the analysis column, the method is listed in the last column. Refer to Table A for specific analysis conditions for each method.

[0860] [Table 84] 1 Purification was performed by silica gel chromatography, which elutes 0% to 40% of DCM (DCM in 9:1 MeOH). 2 Column: Chiralpak IH, 20 × 250 mm column (5 μm). Elution occurs in CO2 with 35% MeOH (0.5% DMEA).

[0861] Example 92 4-[1-(6-cyclopropylpyrazine-2-yl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0862] [ka] 4-[1-(6-bromopyrazine-2-yl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (182.2 mg, 0.32 mmol) and cyclopropylboronic acid (48 mg, 0.56 mmol) were dissolved in 1,4-dioxane (3 ml), and CsF (197 mg, 1.30 mmol) was added. The mixture was degassed, then PdCl2 (DtBPF) (21 mg, 0.03 mmol) was added, and the mixture was stirred overnight at 90°C. When cooled to room temperature, EA was added to the reaction product. The mixture was washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 20% to 100% EA in cHex to obtain a pale yellow solid (120 mg, 67%). The yellow solid was subjected to chiral chromatography using the following conditions: column: Chiralpak IH, 20 × 250 mm, 5 μm; elution with 25% MeOH (0.5% DMEA) in CO2 to obtain the title compound (47 mg, 28%). R The duration was 2.32 minutes, with 97% ee. MS ES+m / z 526[M+H] +Retention time was obtained using analytical method N.

[0863] Example 93 6-[5-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3,5]nonane-2-yl]pyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0864] [ka] and Example 94 6-[3-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3,5]nonane-2-yl]pyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0865] [ka] A solution of 6-[1-(7-azaspiro[3.5]nonan-2-yl)-5-methylpyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitride, 6-[1-(7-azaspiro[3.5]nonan-2-yl)-3-methylpyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitride (101 mg, 0.19 mmol) and oxetane-3-one (20 mg, 0.28 mmol) in MeOH (5 ml) was treated with AcOH (21 μl, 0.37 mmol) and NaBH3CN (35 mg, 0.56 mmol), and stirred at room temperature for 2 hours, then at 50°C for 18 hours. The reaction mixture was cooled and then concentrated. The residue was suspended in saturated NaHCO3 aqueous solution and extracted by DCM (twice). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography with elution under a gradient of 0% to 10% acetone in DCM to obtain a pale yellow solid containing two compounds. The compounds were separated using the following conditions: column, Chiralpak IH, 20 × 250 mm, 5 μm; column eluted with 20% MeOH in CO2 to obtain 6-[3-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3.5]nonane-2-yl]pyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (27 mg; 27%). MS ES+m / z 524[M+H] + , t R = 1.80 minutes (analytical chiral chromatography method N, Table A), 1H NMR(400MHz,DMSO-d6):8.60-8.58(m,3H),7.85(td,J=7.8,1.8Hz,1H),7.69-7.62(m,2H),7.34(ddd,J=7.5,4. 9,1.1Hz,1H),6.92(s,1H),5.87(q,J=6.4Hz,1H),4.89(quintet,J=8.2Hz,1H),4.51(t,J=6.5Hz,2H),4.41(t,J =6.1Hz,2H),2.29-2.18(m,11H),1.71(d,J=6.4Hz,5H),1.60(t,J=5.4Hz,2H) and 6-[5-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3.5]nonan-2-yl]pyrazole-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (14mg, 14%) MS ES+m / z 524[M+H] + , t R = 1.69 minutes (analytical chiral chromatography method N, Table A), 1 H NMR(400MHz,DMSO-d6):8.60-8.52(m,3H),8.13(s,1H),7.85(td,J=7.7,1.7 Hz,1H),7.65(d,J=7.8Hz,1H),7.35(ddd,J=7.5,4.8,1.2Hz,1H),7.03(s,1H ),5.89(q,J=6.4Hz,1H),4.78(quintet,J=8.4Hz,1H),4.51(t,J=6.5Hz,2H) ,4.41(t,J=6.1Hz,2H),2.33-2.18(m,11H),1.72-1.61(m,7H) as a thick colorless oil.

[0866] The following compounds were prepared in a manner essentially similar to that of Example 94, using appropriate reagents, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0867] [Table 85] 1Diameter: Chiralpak AD 20×250mm, 5µm; a 1 H NMR(400MHz,DMSO-d6):8.60-8.58(m,2H),8.50(d,J=1.0Hz,1H),8.14(s,1H),7.85(td ,J=7.7,1.9Hz,1H),7.66(d,J=7.8Hz,1H),7.35(ddd,J=7.6,4.9,1.2Hz,1H),7.07(s,1H). ),5.91(q,J=6.4Hz,1H),4.54(td,J=6.5,2.4Hz,2H),4.42-4.35(m,3H),3.66(quintet, J=6.4Hz,1H),2.45-2.41(m,4H),2.19(s,7H),1.88-1.79(m,1H),1.71(d,J=6.4Hz,4H). b 1 H NMR(400MHz,DMSO-d6):8.60-8.58(m,2H),8.50(d,J=1.0Hz,1H),8.14(s,1H),7.85(td ,J=7.7,1.9Hz,1H),7.66(d,J=7.8Hz,1H),7.35(ddd,J=7.6,4.9,1.2Hz,1H),7.07(s,1H). ),5.91(q,J=6.4Hz,1H),4.54(td,J=6.5,2.4Hz,2H),4.42-4.35(m,3H),3.66(quintet, J=6.4Hz,1H),2.45-2.41(m,4H),2.19(s,7H),1.88-1.79(m,1H),1.71(d,J=6.4Hz,4H). c 1H NMR(400MHz,DMSO):8.68-8.56(m,2H),8.50(d,J=1.0Hz,1H),8.14(s,1H),7.85(td,J=7.7,1.8Hz,1H),7.6 6(dt,J=7.9,1.1Hz,1H),7.37-7-34(dd,J=7.5,1.2Hz,1H),7.36-7.32(dd,J=7.5,1.2Hz,1H),7.07(d,J=1. 1Hz,1H),5.91(q,J=6.4Hz,1H),4.55(td,J=6.5,2.5Hz,2H),4.44-4.32(m,2H),3.66(p,J=6.4Hz,1H),2.50 -2.38(m,4H),2.19(s,3H),2.15-1.95(m,4H),1.88-1.77(m,1H),1.71(d,J=6.4Hz,3H),1.69-1.58(m,2H).

[0868] Example 98 1-(5-fluoro-2-pyridyl)-2-[6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]-3-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]oxyethanol, isomer 1

[0869] [ka] (1S)-2-[3-bromo-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazole-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanol (0.066 g, 0.10 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.115 g, 0.54 mmol), and XPhos Pd G4 (0.02 g, 0.02 mmol) were treated with an aqueous solution of K2CO3 (1 M, 0.55 mL, 0.55 mmol) at room temperature, and then heated to 90°C. After 5 hours, additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (0.35 g, 1.62 mmol), XPhos Pd G4 (0.02 g, 0.02 mmol), and H2O (0.65 ml) were added. After 7 hours, the reaction mixture was cooled to room temperature, and EA (10 ml) was added. The layers were separated, the organic phase was dried, filtered, and concentrated. The residue was purified by reverse chromatography eluting with 20%-60% ACN in NH4CO3 aqueous solution (pH=9) to obtain the title compound as a white solid (0.017 mg, 28%). MS ES+m / z 574[M+H] + .

[0870] Example 99 6-[1-[(3S,4R)-3-fluoro-1-(oxetan-3-yl)-4-piperidyl]-5-methyl-triazole-4-yl]-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonilicate

[0871] [ka] 6-[1-[(3S,4R)-3-fluoro-4-piperidyl]-5-methyl-triazole-4-yl]-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile; 3-oxetanone (1.49 g, 20.63 mg) was added to the hydrochloride (2 g, crude product) of 6-[1,5-a]pyridine-3-carbonitrile; MeOH (20 mL) at room temperature under N2 conditions. The resulting mixture was stirred at 50°C for 60 minutes. Next, NaBH3CN (432 mg, 6.88 mmol) was added at room temperature. The mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction was quenched with H2O (30 mL), and the mixture was basicized to pH 9 with saturated Na2CO3 aqueous solution. The mixture was extracted with EA (2 × 80 mL). The combined organic layers were washed with...

Claims

1. The following compound is given by the formula: 【Chemistry 1】 During the ceremony, Z ２ but, 【Chemistry 2】 And, A is R １ and R １Ａ A pyrazole or triazole substituted with, R １ However, CH ３ And, R １Ａ However, hydrogen or CH ３ And, X １ and X ２ are independently selected from N and C, X １ or X ２ when one of them is N, the other is C, X ３ However, it is N or CH, X ４ However, N or C-R ９ And, Y is NH, O, S, or a bond. Y １ However, bonding, CHR ７ ,CH ２ - CHR ７ _CHR ７ -CH ２ CF ２ ,CH ２ -CF ２ or CF ２ -CH ２ And, Y ２ However, bonding, CHR ３ ,CH ２ - CHR ３ _CHR ３ -CH ２ CF ２ ,CH ２ -CF ２ or CF ２ -CH ２ And, Y ３ However, CR ４ R ５ or CF ２ And, Y ４ However, CR ３ R ４ or CF ２ And, Y ５ However, CR １３ R １４ CR １３ R １４ -CH ２ or CH ２ CR １３ R １４ And, Y ６ However, CR １３ R １４ CR １３ R １４ -CH ２ or CH ２ CR １３ R １４ And, Z is bonded, CR ４ R ４Ａ , cyclobutyl or azetidine, Z １ But is it a combination? Or Z ２ -Z １ -Z has the following structure: 【change】 (In the formula, ＊ (This represents the connection point to A.) Forming, Z ３ However, the bond, C(O), SO ２ or -NR ４ C(O) and Z ４ However, the bond, C(O), SO ２ or -NR ４ C(O) and R ２ is C １ -C ５ alkyl or R ８ and C １ -C ５ alkyl is optionally substituted with one or more substituents independently selected from halo, OH, CN, oxo, -OC １ -C ４ alkyl, -OC ３ -C ５ cycloalkyl, -Z ３ -R １１ and R １０ , and C １ -C ４ alkyl and C ３ -C ５ cycloalkyl is optionally substituted with one or more substituents independently selected from halo, OH, OCH ３ , methylamine, N,N-dimethylamine and CN, R ３ is hydrogen, F, OH, OCH ３ , C １ -C ３ alkyl or cyclopropyl, or one R ３ is condensed with R ５ or R ７ to form CH ２ , CH ２ -CH ２ or CH ２ OCH ２ , R ４ However, hydrogen or C １ -C ３ It is alkyl, R ４Ａ However, hydrogen, halo, OH or C １ -C ３ It is alkyl, R ５ However, hydrogen, F, OH, OCH ３ , C １ -C ３ Alkyl, cyclopropyl, or one R ３ It condenses with CH ２ ,CH ２ -CH ２ Or CH ２ OCH ２ Forming, R ６ However, hydrogen, halo, C １ -C ５ The alkyl, CN, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl is such that the 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl are halo, methyl, halomethyl, OH, or OCH ３ It is optionally substituted with one or more substituents independently selected from C １ -C ５ Alkyl is halo, OH and OCH ３ It is optionally substituted with one or more substituents independently selected from the original, R ７ However, hydrogen, F, OH, OCH ３ , C １ -C ３ Alkyl or one R ３ It condenses with CH ２ ,CH ２ -CH ２ Or CH ２ OCH ２ Forming, R ８ However, R ８Ａ A 3-6 member cycloalkyl, 4-6 member heterocycloalkyl, 5-6 member aryl, or 5-6 member heteroaryl is optionally condensed with or substituted with such a cycloalkyl, R ８Ａ However, these are 3-6 member cycloalkyls, 4-6 member heterocycloalkyls, 5-6 member aryls, or 5-6 member heteroaryls. R ９ However, hydrogen, C １ -C ３ It is alkyl, R １０ However, R ８Ａ A 3-6 member cycloalkyl, 4-6 member heterocycloalkyl, 5-6 member aryl, or 5-6 member heteroaryl is optionally condensed with or substituted with such a cycloalkyl, R １１ However, C １ -C ４ Alkyl, NH ２ NHC １ -C ３ Alkyl, NHC ３ -C ５ Cycloalkyl or N(C) １ -C ３ Alkyl) ２ C １ -C ４ Alkyl, C １ -C ３ Alkyl and C ３ -C ５ Cycloalkyl groups are halo, OH, OCH ３ , optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine and CN, R １２ However, C １ -C ４ Alkyl, C ３ -C ５ Cycloalkyl, NH ２ NHC １ -C ３ Alkyl, NHC ３ -C ５ Cycloalkyl or N(C) １ -C ３ Alkyl) ２ C １ -C ４ Alkyl, C １ -C ３ Alkyl and C ３ -C ５ Cycloalkyl groups are halo, OH, OCH ３ , optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine and CN, R １３ However, hydrogen, halo, or C １ -C ３ It is alkyl, R １４ However, hydrogen, halo, or C １ -C ３ It is alkyl, R ８ , R １０ and R ８Ａ However, halo, OH, CN, -OC １ -C ４ Alkyl, -OC ３ -C ５ Cycloalkyl and -Z ４ -R １２ It is optionally substituted with one or more substituents independently selected from C １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl groups are halo, OH, OCH ３ , a compound optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine, and CN, or a pharmaceutically acceptable salt thereof.

2. X １ However, N is X ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein C is C.

3. X ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is CH.

4. A is R １ and R １Ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a triazole substituted with .

5. R １Ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is O.

7. R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is CN, F, or Cl.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

9. Z １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is bonded.

10. X ４ However, CR ９ And R ９ However, hydrogen or CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. Y １ However, bonding, CHR ７ ,CH ２ - CHR ７ or CHR ７ -CH ２ And R ７ However, hydrogen, F, OH and CH ３ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

12. Y ２ However, bonding, CHR ３ ,CH ２ - CHR ３ or CHR ３ -CH ２ And R ３ However, hydrogen, F, OH and CH ３ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

13. Y ３ However, CR ４ R ５ or CF ２ And R ４ However, hydrogen or CH ３ And R ５ However, hydrogen, F, OH, or CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. Y ４ However, CR ３ R ４ or CF ２ And R ４ However, hydrogen or CH ３ And R ３ However, hydrogen, F, OH, or CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. Y ５ and Y ６ However, CH ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. R ２ However, halo, OH, CN, oxo, -OC １ -C ４ Alkyl, -OC ３ -C ５ Cycloalkyl, -Z ３ -R １１ and R １０ C optionally substituted with 1, 2, 3, or 4 substituents independently selected from １ -C ３ It is alkyl, C １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl groups are halo, OH, OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine, and CN.

17. R ２ However, halo, OH, CN, oxo, -OC １ -C ４ Alkyl, -OC ３ -C ５ Cycloalkyl, -Z ３ -R １１ and R １０ Optionally substituted with 1, 2, 3, or 4 substituents independently selected from 【Chemistry 4】 Selected from, C １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl groups are halo, OH, OCH ３ The compound according to claim 16, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine, and CN, wherein * indicates a connection point to Y.

18. R １０ However, R ８Ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted with or condensed with a 4-6 member heterocycloalkyl or 5-6 member heteroaryl.

19. R １０ However, R ８Ａ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally substituted with or condensed with cyclopropane, cyclobutane, cyclopropane, pyrrolidine, thiazole, pyrazole, triazole, phenyl, pyridine, pyrazine, and pyridazine.

20. R １０ and R ８Ａ However, F, Cl, C １ -C ３ Alkyl, CH ２ F, CHF ２ CF ３ and -OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from the compound. 【Request Item 21】 【Chemistry 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

23. A cancer treatment agent comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof.

24. The aforementioned cancers include stomach cancer, hepatobiliary cancer, cancer of unknown primary origin, gallbladder cancer, gallbladder adenocarcinoma, bile duct cancer, intrahepatic bile duct cancer, extrahepatic bile duct cancer, sarcoma, esophagogastric cancer, esophagogastric junction adenocarcinoma, remnant gastric adenocarcinoma, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, glioma, astrocytoma, oligodendroglioma, ependymoma, non-Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, gastrointestinal stromal tumor, breast cancer, invasive breast cancer, invasive lobular carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma and small cell lung cancer, urothelial carcinoma, bladder cancer, urothelial bladder cancer, nonmuscle-invasive bladder cancer, muscle-invasive bladder cancer, and gastric cancer. The therapeutic agent according to claim 23, selected from the group consisting of cancer, gastric adenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, prostate cancer, prostate adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, colon adenocarcinoma, multiple myeloma, liver cancer, hepatocellular carcinoma, fibrous hepatocellular carcinoma, skin cancer, squamous cell carcinoma, melanoma, cutaneous melanoma, head and neck cancer, head and neck squamous cell carcinoma, hypopharyngeal cancer, laryngeal cancer, lip and oral cancer, salivary gland cancer, glioblastoma, endometrial cancer, endometrioid adenocarcinoma, cervical cancer, ovarian cancer, and epithelial ovarian cancer.

25. The therapeutic agent according to claim 23, wherein the cancer is selected from the group consisting of hepatobiliary tract cancer, cancer of unknown primary origin, gallbladder cancer, gallbladder adenocarcinoma, bile duct cancer, intrahepatic bile duct cancer, extrahepatic bile duct cancer, breast cancer, invasive breast cancer, invasive lobular carcinoma, liver cancer, hepatocellular carcinoma, fibrous hepatocellular carcinoma, skin cancer, squamous cell carcinoma, melanoma, cutaneous melanoma, endometrial cancer, and endometrioid adenocarcinoma.

26. The therapeutic agent according to claim 23, wherein the cancer is selected from the group consisting of hepatobiliary tract cancer, gallbladder cancer, gallbladder adenocarcinoma, bile duct cancer, intrahepatic bile duct cancer, extrahepatic bile duct cancer, breast cancer, invasive breast cancer, invasive lobular carcinoma, liver cancer, hepatocellular carcinoma, fibrous hepatocellular carcinoma, endometrial cancer, and endometrioid adenocarcinoma.

27. The therapeutic agent according to claim 26, wherein the cancer is FGFR2-related cancer.

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