FGFR2 inhibitor compound

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 factors (FGFs) are recognized as important mediators of many physiological processes, such as morphogenesis during development, fibrosis, and angiogenesis. The fibroblast growth factor receptor (FGFR) family consists of five members, four of which (FGFR1-4) are glycoproteins composed of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane region, and a cytoplasmic portion containing a tyrosine kinase domain. FGF binding leads to FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient to recruit and activate specific downstream signaling partners involved in regulating diverse processes such as cell proliferation, cell metabolism, and cell survival. Thus, the FGF / FGFR signaling pathway has pleiotropic effects on many biological processes important for tumor cell proliferation, migration, invasion, and angiogenesis. Summary of the Invention

[0002] Provided herein are compounds of the formula:

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

[0004] Provided herein are compounds of the formula:

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

[0006] Provided herein are compounds of the formula:

[0007] [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, Y, Z2, R 2 and R 6 is as defined herein.

[0008] Provided herein are compounds of the formula:

[0009] [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Y5, Y6, Z, Z1, R 2 and R 6 is as defined herein.

[0010] Provided herein are compounds of the formula:

[0011] [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Y5, Y6, Z', R 2 and R 6 is as defined herein.

[0012] Provided herein are compounds of the formula:

[0013] [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Y5, Y6, R 2 and R 6 is as defined herein.

[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 of using compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for treating proliferative disorders such as cancer, particularly for treating FGFR2-associated cancers. The methods comprise administering to a patient in need thereof an effective amount of a compound of Formula (I), (II), (III), (IA), (IIA) or (IIIA), or a pharmaceutically acceptable salt thereof.

[0016] Provided herein is a compound of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, for use in therapy. Further provided herein is a compound of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, particularly for use in the treatment of FGFR2-associated cancer. Also provided is the use of a compound of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, particularly for use in the treatment of FGFR2-associated cancer. DETAILED DESCRIPTION OF THE INVENTION

[0017] Provided herein are compounds that are believed to have clinical use for the treatment of cancer, particularly for the treatment of FGFR2-associated cancers.

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

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

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

[0021] [ka] and A is R 1 and R 1A a pyrazole, triazole, thiadiazole or oxadiazole substituted with R 1 is hydrogen or C1-C3 alkyl, R 1A is hydrogen, halo, CN, or C1-C3 alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH3; X1 and X2 are independently selected from N and C, and when one of X1 or X2 is N, 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 a bond, CHR 7 , CH2-CHR 7, CHR 7 -CH2, CF2, CH2-CF2 or CF2-CH2, Y2 is a bond, CHR 3 , CH2-CHR 3 , CHR 3 -CH2, CF2, CH2-CF2 or CF2-CH2, Y3, CR 4 R 5 or CF2, Y4, CR 3 R 4 or CF2, Y5, CR 13 R 14 , C.R. 13 R 14 CH2 or CH2CR 13 R 14 and Y6, CR 13 R 14 , C.R. 13 R 14 CH2 or CH2CR 13 R 14 and Z is a bond, CHR 9A , C.R. 4 R 4A , C.R. 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, Z is the bond, CR 4 R 4A , C.R. 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, Z1 is a bond or Z is CHR 9A when Z1 is CH2 or CH2-CH2, Z3 is a bond, C(O), SO2 or -NR4 C(O), Z4 is a bond, C(O), SO2 or -NR 4 C(O), R 2 is C1-C5 alkyl or R 8 wherein C1-C5 alkyl is halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 , and R 10 wherein the 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; R 3 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R 3 But R 5 or R 7 condenses with to form CH, CH-CH, or CHOCH, R 4 is hydrogen or C1-C3 alkyl, R 4A is hydrogen, halo, OH, or C1-C3 alkyl; R 5 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R 3 condenses with to form CH, CH-CH, or CHOCH, R 6 is hydrogen, halo, C1-C5 alkyl, CN, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl, wherein the 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered aryl and 5- to 6-membered 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 hydrogen, F, OH, OCH3, C1-C3 alkyl, or one R 3 condenses with to form CH, CH-CH, or CHOCH, R 8 But R 8A a 3- to 6-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl, optionally fused to or substituted with R 8A is a 3- to 6-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl; R 9 is hydrogen, C1-C3 alkyl, or R 9A condensed with to form CH2 or CH2-CH2, R 10 But R 8A a 3- to 6-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl, optionally fused to or substituted with R 11 is C1-C4 alkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl, or N(C1-C3 alkyl)2, wherein the C1-C4 alkyl, C1-C3 alkyl, and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN; R 12 is C1-C4 alkyl, C3-C5 cycloalkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl, or N(C1-C3 alkyl)2, wherein the C1-C4 alkyl, C1-C3 alkyl, and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN; R 13 is hydrogen, halo, or C1-C3 alkyl; R 14 is hydrogen, halo, or C1-C3 alkyl; R 8 , R10 and R 8A halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z4-R 12 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 is as defined above for formula (I), X4 is N or CR 9 and R 9 is hydrogen or C1-C3 alkyl, Z' is a bond, CR 4 R 4A , C.R. 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 is as defined above for formula (I), X4 is N or CR 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 6is as defined above for formula (I).

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

[0026] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), X1 can be C and X2 can be N, forming:

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

[0028] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), X1 can be N and X2 can be C, forming:

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

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

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

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

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

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

[0035] As used herein, the term "alkyl" refers to a hydrocarbon chain, which may be straight or branched, containing the indicated number of carbon atoms. For example, the term "C1-C5 alkyl" as used herein refers to a saturated straight or branched monovalent hydrocarbon radical of 1, 2, 3, 4, or 5 carbon atoms. Examples of C1-C5 alkyl 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 alkyl 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 alkyl include, but are not limited to, methyl, ethyl, 1-propyl, or isopropyl.

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

[0037] As used herein, the term "heterocycloalkyl" refers to a C(O) 0-1 , N, O and S(O) 0-2 For example, the term "5- to 6-membered heterocycloalkyl" as used herein refers to a saturated cyclic group having 5 or 6 ring atoms, 1, 2, or 3 of which are N, O, and S(O). 0-2 The remainder is C(O) 0-1

[0033] The term "heterocycloalkyl" refers to a saturated cyclic ring system in which:

[0034] Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, and isothiazolid-2-onyl.

[0035] Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, piperidyl, piperazinyl, pyrrolidinyl, pyrrolidin-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, the term "5- to 6-membered aryl" as used herein refers to an aromatic cyclic hydrocarbon group having 5 or 6 carbon atoms. Examples of 5- to 6-membered aryl include cyclopentadienyl and phenyl.

[0039] As used herein, the term "heteroaryl" refers to an aromatic cyclic group having the indicated ring atoms selected from C, N, O, and S. For example, the term "5- to 6-membered heteroaryl" refers to an aromatic cyclic group having 5 or 6 ring atoms, 1, 2, or 3 of which are selected from N, O, and S, and the remainder are C. Examples of 5- to 6-membered heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 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 pyridazinyl.

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

[0041] As used herein, the term "haloalkyl" refers to -CH3 in which one or more hydrogen atoms have been replaced with independently selected halo.

[0042] As used herein, the term "oxo" refers to the replacement of CH2 with 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 can be substituted by methyl and ethyl.

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

[0045] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A is R 1 and R 1A The compound 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 the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A is R 1 and R 1A The compound may be a pyrazole, a 1,2,3 triazole or a 1,2,4 triazole substituted with

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

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

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

[0050] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 1 can be C1-C3 alkyl.

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

[0052] [ka] It can be, During the ceremony, * represents the point of attachment to the substituent containing Y1 in formula (IIIA), ** represents the other connection point from A in formula (IIIA), and R 1 can be C1-C3 alkyl.

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

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

[0055] [ka] It can be, During the ceremony, * represents the connection point to Z1 in formula (I) or (IA), ** indicates the point of attachment to A in formula (I) or (IA).

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

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

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

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

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

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

[0062] In the compounds of formula (I) or (IA), Z is CHR 9A Z1 may be selected from CH2 or CH2-CH2, and R 9 is R 9A to form CH2-CH2.

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

[0064] In the compounds of formula (I) or (IA), Z is CHR 9A Z1 can be CH2-CH2, R 9 is R 9A to form CH2-CH2.

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

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

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

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

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

[0070] In 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 the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y can be NH or O.

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

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

[0075] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y is a bond or CHR 7 R 7 is hydrogen, F, OH, or CH3, and Y2 is a bond or CHR 3 R 3 is hydrogen, F, OH or CH3.

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

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

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

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

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

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

[0082] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y is a bond or CHR 7 R 7 is hydrogen, hydrogen, F, OH, or CH3, and Y2 is a bond or CHR 3 R 3 is hydrogen, F, OH or CH3,

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

[0084] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 1A can be hydrogen or C1-C3 alkyl optionally substituted with 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 can be hydrogen or CH3.

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

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

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

[0089] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 2 is halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 and C1-C3 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from: C1-C4 alkyl and C3-C5 cycloalkyl are 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 is F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 and optionally substituted with one or more substituents independently selected from:

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

[0092] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10wherein the 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; * indicates the point of attachment to Y in formula (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 can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 wherein the 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; * indicates the point of attachment to Y in formula (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 can be, These are F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from: *indicates the point of attachment to Y in formula (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 can be, These include F, OH, CN, oxo, -OCH3 and -OC3 cycloalkyl and R 10 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from: * indicates the point of attachment to Y in formula (I), (II), (III), (IA), (IIA) or (IIIA).

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

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

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

[0102] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y3 is CR 4 R 5 R 4 is hydrogen and R 5 is one R 3 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 to form CH2, CH2-CH2, or CH2OCH2.

[0103] In the compounds of formula (I), (II), (III), (IA) or (IIA), Y3 is CR 4 R 5 R 4 is hydrogen and R 5 is one R 3 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 to form CH, CH-CH, or CHOCH,

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

[0105] In the compound of formula (IIIA), Y3 is CR 4 R 5R 4 is hydrogen and R 5 is one R 3 and condenses with the alkyl group to form CH, CH-CH, or CHOCH, and Y is CR 3 R 4 and R 4 is hydrogen and R 3 is R 5 to form CH, CH-CH, or CHOCH,

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

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

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

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

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

[0111] In the compounds of formula (I) or (IA), X4 is CR 9 R 9 is R 9A 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 can be N or CH.

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

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

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

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

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

[0118] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 is R 8A It can be a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl, optionally fused with or substituted by.

[0119] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 is R 8A It can be a 5- to 6-membered cycloalkyl or a 5- to 6-membered heterocycloalkyl, optionally fused with:

[0120] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 is R 8A The group may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, optionally fused with

[0121] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 is R 8A The group may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, optionally fused with

[0122] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 is R 8A R may be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl, optionally fused with 8A can be phenyl or a 6-membered heteroaryl.

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

[0124] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 is R 8A It can be a 3- to 6-membered cycloalkyl, a 5- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl, optionally fused with

[0125] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 is R 8A The aryl group may be a 3- to 6-membered cycloalkyl, a 5- to 6-membered heterocycloalkyl, phenyl, or a 5- to 6-membered heteroaryl, optionally fused with or substituted by.

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

[0127] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 is R 8A

[0047] The aryl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with or substituted by.

[0128] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 is R 8A

[0047] The aryl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with or substituted by.

[0129] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 is R 8A The group may be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, optionally fused with or substituted by.

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

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

[0133] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 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 fused with or substituted by cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

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

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

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

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

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

[0140] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 is R 8A R may be phenyl or pyridinyl, fused with 8A may be pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onylfuranyl, 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 R may be phenyl or pyridinyl, fused with 8A may be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, furanyl, 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 R may be phenyl or pyridinyl, fused with 8Acan be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl or isothiazolid-2-onyl.

[0143] In a compound of formula (I) or (IA), when Z and Z1 are both bonds, they together form a single bond.

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

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

[0146] In the compounds of formula (I), (II), (III), (IA) or (IIA), R 5 is one R 3 to form CH-CH, for example:

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

[0148] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 5 is one R 3 to form CH-CH, for example:

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

[0150] In compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 is R 8A and R 8A may be pyridinyl, for example

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

[0152] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A is R 1 and R 1A wherein Y can be NH or O.

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

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

[0155] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 1 can be C1-C3 alkyl and Y can be NH or O.

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

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

[0158] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A is R 1 and R 1A and Y may be O.

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

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

[0161] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 1 can be C1-C3 alkyl and Y can be O.

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

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

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

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

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

[0167] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl.

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

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

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

[0171] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 6can be CN, F, Cl or CF3.

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

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

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

[0175] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 1 can be C1-C3 alkyl, R 6 can be CN or Cl.

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

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

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

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

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

[0181] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and 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 can be, During the ceremony, * represents the point of attachment to the substituent containing Y1 in formula (IIIA), ** represents the other connection point from A in formula (IIIA), and R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, and Y can be NH or O.

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

[0185] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and 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 can be, During the ceremony, * represents the point of attachment to the substituent containing Y1 in formula (IIIA), ** represents the other connection point from A in formula (IIIA), and R 6 can be CN, F, Cl, or CF3, and Y can be NH or O.

[0188] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A is R 1 and R 1A R may be a pyrazole, 1,2,3 triazole, or 1,2,4 triazole substituted with6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be O.

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

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

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

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

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

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

[0195] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and 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 can be, During the ceremony, * represents the point of attachment to the substituent containing Y1 in formula (IIIA), ** represents the other connection point from A in formula (IIIA), and R 6 can be CN, F, Cl, or CF3, and Y can be O.

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

[0199] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 1 can be 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 can be, During the ceremony, * represents the point of attachment to the substituent containing Y1 in formula (IIIA), ** represents the other connection point from A in formula (IIIA), and R 6 can be CN, F, Cl, or CF3, and Y can be O.

[0202] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A is R 1 and R 1A R may be a pyrazole, 1,2,3 triazole, or 1,2,4 triazole substituted with 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, Y can be NH or O, R 2 is halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 wherein the 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.

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

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

[0205] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 wherein the 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; * indicates the point of attachment to Y in formula (I), (II), (III), (IA), (IIA) or (IIIA).

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

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

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

[0209] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 wherein the 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; * indicates the point of attachment to Y in formula (I), (II), (III), (IA), (IIA) or (IIIA).

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

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

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

[0213] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, Y can be NH or O, R 2 is halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 wherein the 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.

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

[0215] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, Y can be NH or O, R 2 is F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 and optionally substituted with one or more substituents independently selected from:

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

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

[0218] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10wherein the 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; * indicates the point of attachment to Y in formula (I), (II), (III), (IA), or (IIA).

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

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

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

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

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

[0224] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 wherein the 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; * indicates the point of attachment to Y in formula (I), (II), (III), (IA), or (IIA).

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

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

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

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

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

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

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

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

[0233] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 wherein the 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; * indicates the point of attachment to Y in formula (IIIA).

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

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

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

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

[0238] [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z' or Z2 in formula (I), (II), (III), (IA) or (IIA), ** represents the other connection point from A in formula (I), (II), (III), (IA) or (IIA), and R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl, Y can be NH or O, R 2 is halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 Y5 can be C1-C3 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from: 13 R 14 , C.R. 13 R 14 -CH2 or CH2-CR 13 R 14 and R 13 and R 14 is independently selected from H and CH3, and Y6 is CR 13 R 14 , C.R. 13 R 14 -CH2 or CH2-CR 13 R 14 and R 13 and R 14 is H and CH 3. are independently selected from

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

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

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

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

[0243] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 and wherein the C1-C4 and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN; * represents the point of attachment to Y in formula (I), (II), (III), (IA), or (IIA). Y5 is CR 13 R 14 , C.R. 13 R 14 -CH2 or CH2-CR 13 R 14 and R 13 and R 14 is independently selected from H and CH3, and Y6 is CR 13 R 14 , C.R. 13 R 14 -CH2 or CH2-CR 13 R 14 and R 13 and R 14 is H and CH 3. are independently selected from

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

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

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

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

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

[0249] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 and wherein the C1-C4 and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine, and CN; * represents the point of attachment to Y in formula (I), (II), (III), (IA), or (IIA). Y5 is CR 13 R 14 , C.R. 13 R 14 -CH2 or CH2-CR 13 R 14 and R 13 and R 14 is independently selected from H and CH3, and Y6 is CR 13 R 14 , C.R. 13 R 14 -CH2 or CH2-CR 13 R 14 and R 13 and R 14 is H and CH 3. are independently selected from

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

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

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

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

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

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

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

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

[0258] [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 wherein the 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; * represents the point of attachment to Y in formula (IIIA), and Y5 represents CR 13 R 14 , C.R. 13 R 14 -CH2 or CH2-CR 13 R 14 and R 13 and R 14 is independently selected from H and CH3, and Y6 is CR 13 R 14 , C.R. 13 R 14 -CH2 or CH2-CR 13 R 14 and R 13 and R 14 is H and CH 3. are independently selected from

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

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

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

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

[0263] [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof; During the ceremony, * The bond at position

[0264] [ka] It is expressed as:

[0265] For example, for a compound of the formula:

[0266] [ka] During the ceremony, * The bond at position

[0267] [ka] and the following compounds:

[0268] [ka] Form.

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

[0270] [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof, wherein: * The bond at position

[0271] [ka] It is expressed as:

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

[0273] [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof, wherein: * The bond at position

[0274] [ka] It is expressed as:

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

[0276] [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof, wherein: * The bond at position

[0277] [ka] It is expressed as:

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

[0279] [ka]

[0280] [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof, wherein: * The bond at position

[0281] [ka] It is expressed as:

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

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

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

[0285] [ka]

[0286] [ka]

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

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

[0289] [ka]

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

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

[0292] [ka]

[0293] [ka]

[0294] [ka]

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

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

[0297] [ka]

[0298] [ka]

[0299] [ka]

[0300] [ka]

[0301] [ka]

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

[0303] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, provided herein, any or all hydrogens present in the compound, or in specific groups or moieties within the compound, may be replaced with deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyl when from one to a maximum number of hydrogens present can be replaced with deuterium. For example, C2D x H 5-xWhen one to five hydrogens in, for example, C2H5 are replaced with deuterium, ethyl refers to both C2H5 or C2H5.

[0304] The compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA) provided herein may form pharmaceutically acceptable salts. The examples provided herein may form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts are intended to be included. Pharmaceutically acceptable salts and common techniques for preparing them are well known in the art (see, for example, P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2004). nd Revised Edition (Wiley-VCH, 2011), see S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0305] The compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or pharmaceutically acceptable salts thereof, may be mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. More specifically, the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or pharmaceutically acceptable salts thereof, 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 Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, provided herein, can be administered by various routes, including orally and intravenously.

[0307] The compounds of formula (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] The compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, described herein may be components of pharmaceutical compositions with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally one or more additional therapeutic agents, for the treatment of cancer.

[0309] The compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, described herein may be components of pharmaceutical compositions with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally one or more additional therapeutic agents, for the treatment of cancer.

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

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

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

[0313] Certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR2. For example, certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR2 over another FGFR. For example, certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR2 over FGFR1. For example, certain compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, are at least about 3-fold (e.g., at least about 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more) selective for FGFR2 over FGFR1.

[0314] As used herein, the term "selectivity" of a compound refers to a compound that has more potent activity on a first target than on a second target. Fold selectivity can be calculated by any method known in the art. For example, fold selectivity can be calculated by the IC of a compound against a second target (e.g., FGFR1). 50 The values ​​are expressed as the IC of the same compound against the primary target (e.g., FGFR2). 50 It can be calculated by dividing by the value of IC 50 The value can be determined by any method known in the art, for example, IC 50 Values ​​can be determined as described in the assay below.

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

[0316] As used herein, the term "FGFR2-associated cancer" refers to a cancer associated with or having dysregulated expression or activity or levels of the FGFR2 gene, FGFR2 kinase, or any of them. Non-limiting examples of FGFR2-associated cancers are described herein. As used herein, "FGFR2-associated cancer" includes gastric cancer, hepatobiliary cancer, cancer of unknown primary site, 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 stomach adenocarcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma), glioma (e.g., astrocytoma, oligodendroglioma, ependymoma), non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's 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 cancer, bladder cancer (e.g., urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), gastric cancer, cancer) (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, fibrolamellar hepatocellular carcinoma), skin cancer (e.g., squamous cell skin cancer), melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., head and neck squamous cell carcinoma, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, salivary gland cancer), glioblastoma, endometrial cancer (e.g., endometrioid adenocarcinoma), cervical cancer, and ovarian cancer (e.g., epithelial ovarian cancer).

[0317] As used herein, the term "treating" ("treatment") refers to inhibiting, slowing, halting, or reversing the progression or severity of an existing symptom, condition, or disorder.

[0318] As used herein, the term "patient" refers to a mammal, particularly a human.

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

[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 a compound of Formula (I), (II), (III), (IA), (IIA) or (IIIA), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

[0322] Provided herein is a method of 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 herein include stomach cancer, hepatobiliary cancer, cancer of unknown primary site, 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 stomach adenocarcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma), glioma (e.g., astrocytoma, oligodendroglioma, ependymoma), non-Hodgkin's lymphoma (e.g., B-cell non-Hodgkin's 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 cancer, bladder cancer (e.g., urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), gastric cancer, cancer) (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, fibrolamellar hepatocellular carcinoma), skin cancer (e.g., squamous cell skin cancer), melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., head and neck squamous cell carcinoma, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, salivary gland cancer), glioblastoma, endometrial cancer (e.g., endometrioid adenocarcinoma), cervical cancer, and ovarian cancer (e.g., epithelial ovarian cancer).In particular, the cancers include stomach cancer, hepatobiliary cancer, cancer of unknown primary site, 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 stomach 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 carcinoma), gastric cancer cancer) (e.g., gastric adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), colorectal cancer (e.g., colorectal adenocarcinoma, colon adenocarcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma), skin cancer (e.g., squamous cell skin 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 cavity cancer, salivary gland cancer), glioblastoma, endometrial cancer (e.g., endometrioid adenocarcinoma), and ovarian cancer (e.g., epithelial ovarian cancer). More specifically, the cancer is selected from the group consisting of hepatobiliary cancer, cancer of unknown primary site, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma), breast cancer (e.g., infiltrating ductal carcinoma, invasive lobular carcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma), skin cancer (e.g., squamous cell skin carcinoma), melanoma (e.g., cutaneous melanoma), and endometrial cancer (e.g., endometrioid adenocarcinoma). Most specifically, the cancer is selected from the group consisting of hepatobiliary cancer, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma), breast cancer (e.g., infiltrating ductal carcinoma, invasive lobular carcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma), and endometrial cancer (e.g., endometrioid adenocarcinoma).

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

[0325] Scheme A

[0326] [ka] Scheme A illustrates the preparation of compound (A8), where R' is defined as C1-C3 alkyl, by multiple synthetic routes to give compound (A11), which is further elaborated to formula 1. Alcohol (A1) can be reacted with mesyl chloride or tosyl chloride to give compound (A2a) or (A2b), which can be further reacted with (A3a) to give compound (A4). Treatment of compound (A4) with LDA and an appropriate alkylating agent can give compound (A8). Alternatively, compound A8 can be directly synthesized by alkylating compound A3b with mesylate A2a or tosylate A2b to give compound A8.

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

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

[0329] Scheme A1

[0330] [ka] Scheme A1 shows an alternative route to compound (A8). Reaction of (A5) in the presence of trimethyl(prop-1-yn-1-yl)silane under microwave conditions can give the trimethylsilyl analog of (A5a). Treatment of (A5a) with NBS in the presence of SiO2 gives compound (A8).

[0331] Scheme A2

[0332] [ka] Scheme A2 shows the preparation of compound (A2i'), where R' is defined as C1-C3 alkyl, which is further elaborated to Formula 1. O-protected cyclobutan-1-one (A2a') can be reacted in the presence of NaBH4 to give alcohol (A2b'). Formation of azide (A2c') can be achieved by reacting alcohol (A2b') with PPh3 and DIAD, followed by DPPA. Reaction of azide (A2c') with ethyl acetoacetate can give ester (A2d'). Hydrolysis of (A2d') under basic conditions can give acid (A2e'), which can then be subjected to bromination under basic conditions to give bromide (A2f'). Removal of the protecting group from (A2f') can give alcohol (A2g'). Oxidation of alcohol (A2g') can give ketone (A2h'), which can then be reacted under reductive amination conditions to give (A2i').

[0333] Scheme A3

[0334] [ka] Scheme A3 shows the preparation of compound (A3h'), which is further elaborated to formula 1. A solution of (A3a') can be reacted with N-diazo-1,1,1-trifluoro-methanesulfonamide in the presence of copper sulfate and NaHCO to give azide (A3b'). Treatment of the azide with trimethyl(prop-1-yn-1-yl)silane under microwave conditions gives (A3c'). Formation of bromide (A3d') can be achieved by treating (A3c') with NBS in the presence of SiO. Subjecting (A3d') to Mitsunobu conditions with p-nitrobenzoic acid gives ester (A3f'). Hydrolysis of ester (A3e') under basic conditions gives alcohol (A3f'). Treatment of alcohol (A3f') with (trifluoromethane)sulfonyl trifluoromethanesulfonate in the presence of base can form triflate (A3g'). Displacement of triflate (A3g') with an appropriate amine can give (A3h').

[0335] Scheme B

[0336] [ka] Scheme B shows the preparation of compounds B6, B8, B9 and B10, which are further elaborated to Formula 1. Compounds (B10) and (B10a) can be further elaborated to Formula 2, Formula 3, Formula 4 or Formula 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 catalysis. Hydrolysis of the ethoxyvinyl (B2) can give ketone (B5). Ketone (B5) can be reduced to give alcohol (B6), which can then be reacted with MsCl to give mesylate (B8) or chloride (B9).

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

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

[0340] Scheme B1

[0341] [ka] Scheme B1 shows an alternative route to the alpha-haloketone of (B10a), which can be further elaborated to formula 1. Treatment of (B1b) with i-PrMgCl, followed by addition to chloro-N-methoxy-N-methylacetamide, can provide (B10a), which can be further elaborated to compounds of formula (I).

[0342] Scheme C

[0343] [ka] Scheme C illustrates the preparation of compound (C5), which is further elaborated to formula 1. Treatment of compound (C1) with i-PrMgCl, followed by addition of aldehyde (C2), can provide alcohol (C3). Reaction of alcohol (C3) with the addition of potassium t-butoxide in the presence of methyl iodide can provide compound (C4), which is then deprotected to provide alcohol (C5).

[0344] Scheme C1

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

[0346] Scheme D

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

[0348] Scheme E

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

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

[0351] Scheme F

[0352] [ka] Scheme F illustrates the preparation of compound (F5), which is further elaborated to formula 1. Reaction of (F1) with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of CuI can give (F2). Treatment of (F2) with bis(pinacolato)diboron under palladium catalyzed conditions can give boronic ester (F3). Palladium catalyzed coupling of boronic ester (F3) with an appropriate bromide can give (F4), which is then demethylated with NDM to give (F5).

[0353] Scheme G

[0354] [ka] Scheme G illustrates the preparation of compound G5, which is further elaborated to Formula 1. Reaction of G1 with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) can give G2, where R6 is defined as R6=F. Treatment of G2 with bis(pinacolato)diboron under palladium catalysis can give boronic ester F3. Coupling of F3 with an appropriate bromide in the presence of a palladium catalyst can give G4. Demethylation of G4 with NDM can give G5.

[0355] Scheme H

[0356] [ka] Scheme H shows several methods for the preparation of compounds (H4) and (H6), which are further elaborated in Formula 1. Compound (G1), where Hal is defined as Hal = halogen, can be reacted with bis(pinacolato)diboron under palladium catalyzed conditions to give boronic ester (H1). Boronic ester (H1) can be coupled with an appropriate bromide in the presence of a palladium catalyst to give (H2). Chlorination of (H2) with NSC can give (H3), where R6 is defined as R6 = Cl, which can then be demethylated with NDM to give (H4). Deprotection of (H4) under acidic conditions can give (H5), which can then be subjected to reductive amination with an appropriate ketone to give (H6). Alternatively, boronic ester (H1), where R6 is defined as R6 = H, can be coupled with an appropriate bromide to give (H7). Chlorination of (H7) can be achieved by treatment with NCS to give (H8), where R6 is defined as R6=Cl. (H8) can be demethylated with NDM to give (H6).

[0357] Scheme H also illustrates several methods for preparing compounds (H4) and (H6), where R6 is defined as R6=CN and Hal is defined as Hal=Br, which are further elaborated to formula (I). Compound (G1) can be reacted with bis(pinacolato)diboron under palladium catalyzed conditions to give boronic ester (H1). Boronic ester (H1) can be coupled with an appropriate bromide in the presence of a palladium catalyst to give (H2). Demethylated (H4) can be obtained by subjecting (H2) to NDM. Deprotection of (H4) under acidic conditions can give (H5), which can then be subjected to reductive amination with an appropriate ketone to give (H6). Alternatively, boronic ester (H1) can be coupled with an appropriate bromide to give (H7). Demethylation of (H7) with NDM can give (H6).

[0358] Scheme J

[0359] [ka] Scheme J illustrates the preparation of compounds of Formula 1. (J1) can be alkylated with halogens (B8), (B10), (B10a), or mesylate (B9) to give (K2). Alternatively, (J2) can be obtained by reaction of alcohols (C1e), (C5), or (D7) under Mitsunobu conditions. Deprotection of (J2) under acidic conditions can give (J3), which can then be subjected to reductive amination conditions with an appropriate ketone to give compounds of Formula 1. Alternatively, compounds of Formula 1 can be synthesized by alkylating (J4) with halogens (B8), (B10), (B10a), or mesylate (B9), or alternatively by reacting with alcohols (C1e), (C5), or (D7) under Mitsunobu conditions. Those skilled in the art will recognize that compound (J1) can be exchanged for compounds (G5) or (H4). Additionally, one skilled in the art will recognize that compound (J4) can be exchanged for compounds (F5) or (H6).

[0360] Scheme K

[0361] [ka] Scheme K illustrates the preparation of compounds of Formula 1. Reaction of (K1) with Hal, where Hal=Br, can be alkylated with halides such as (B8), (B10), (B10a), or mesylates such as (B9) to give (L2). Treatment of (K2) with bis(pinacolato)diboron under palladium-catalyzed conditions can give boronic esters (K3). Palladium-catalyzed coupling of (K3) with an appropriate bromide, (A2i'), or (A3h') can give compounds of Formula (I). Alternatively, compounds of Formula (I) can be synthesized by palladium-catalyzed coupling of (K3) with an appropriate bromide to give (K4). Deprotection of (K4) under acidic conditions can give (K5), which can be subjected to reductive amination with an appropriate ketone to give compounds of Formula 1.

[0362] Scheme K1

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

[0364] Scheme L

[0365] [ka] Scheme L shows two methods for preparing compounds of Formula 1. In the first method, treatment of (L1) with NIS can give (L2), which can then be reacted with CuCN to give (L3). Reaction of (L3) with an amine (F4) in the presence of an organic base can give (L4). Treatment of (L4) with bis(pinacolato)diboron under palladium-catalyzed conditions can give boronic ester (L5). Palladium-catalyzed coupling of (L5) with an appropriate bromide can give compounds of Formula 1. Alternatively, in the second method, compounds of Formula 1 can be synthesized by palladium-catalyzed coupling of (L5) with an appropriate bromide to give (L7). Deprotection of (L7) under acidic conditions can give (L8), which can be subjected to reductive amination with an appropriate ketone to give compounds of Formula 1. For compounds of Formula 1, enantiomers can be separated by chiral chromatography.

[0366] Scheme L illustrates the preparation of compounds of Formula 1. Treatment of (L3) with amines (F4) or (F5) under palladium catalysis can provide (L4). Reaction of (L4) with bis(pinacolato)diboron under palladium catalysis can provide boronic esters (L5). Palladium catalyzed coupling of (L5) with an appropriate bromide can provide compounds of Formula 1. For compounds of Formula 1, enantiomers can be separated by chiral chromatography.

[0367] Scheme M

[0368] [ka] Scheme M illustrates the preparation of compounds of Formula 1, where R6 is defined as R6 = Cl, and X1, X2, and X3 are defined as X2 = N, X1, and X3 = C. Treatment of M1, where Hal is defined as Cl, and Y is defined as O, with chloroacetaldehyde in the presence of a base can provide M2. Reaction of M2 with bis(pinacolato)diboron under palladium-catalyzed conditions can provide boronic acid M3. Palladium-catalyzed coupling of M3 with an appropriate bromide can provide M4. Demethylation of M4 with NDM can provide M5, which can then be reacted with an alcohol such as C1e or C5 under Mitsunobu conditions to provide M6. Deprotection of M6 under acidic conditions can provide M7, which can then be subjected to reductive amination with an appropriate ketone to provide compounds of Formula 1. For compounds of formula 1, the enantiomers can be separated by chiral chromatography.

[0369] Scheme N

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

[0371] Compounds of formula 3 can be synthesized by treating compounds of formula 2 with an appropriate Grignard reagent to give compounds of formula 3. For compounds of formula 3, enantiomers can be separated by chiral chromatography.

[0372] Compounds of formula 4 can be synthesized by two routes. In the first route, reduction of the ketone for compounds of formula 2 can be achieved by treatment with NaBH4 to give compounds of formula 4. In the second route, ketone (N2) can be reduced with NaBH4 to give (N4), which can be deprotected under acidic conditions to give (N5). Treatment of (N5) with an appropriate ketone under reductive amination conditions can give compounds of formula 4. For compounds of formula 4, enantiomers can be separated by chiral chromatography.

[0373] Those skilled in the art will recognize that compound (N1) can be exchanged for compound (G5) or compound (H4). Furthermore, those skilled in the art will also recognize that compound (N6) can be exchanged for compound (F5).

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

[0375] Scheme N1

[0376] [ka] Scheme N1 illustrates the asymmetric synthesis of compounds of formulas 4b and 4c. Asymmetric reduction of 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-diphenylethyl methanesulfonamidate)ruthenium(II) to give alcohol (N4a). Deprotection of (N4a) under acidic conditions can give amine (N5a). Reductive amination of (N5a) with an appropriate ketone can give compound of formula 4b.

[0377] Alkylation of alcohol (N4a) with an appropriate alkylating agent can give alkyl ether (N4b). Subsequent deprotection of (N4b) under acidic conditions can give amine (N4c). Reductive amination of (N4c) with an appropriate ketone can give compounds of formula 4c.

[0378] Scheme N2

[0379] [ka] Scheme N2 shows an alternative preparation for compounds of formula 3. Ketone (N2) can be reacted with a Grignard reagent to give tertiary alcohol (N2a). Removal of the protecting group of (N2a) under acidic conditions gives amine (N2b). Reaction of (N2b) with an appropriate ketone under reductive amination conditions gives compounds of formula 3.

[0380] When R6 = H for (N2a), treatment with NCS can give compounds where R6 = Cl for (N2b'). Subsequent treatment of (N2b') under acidic conditions can give the amine (N2b).

[0381] Scheme N3

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

[0383] Scheme P

[0384] [ka] Scheme P illustrates the preparation of compounds of formula 6 or formula 7. To prepare compounds of formula 6, compounds of formula 4 can be reacted with NaH, followed by treatment with an appropriate alkylating agent to give compounds of formula 6. To prepare compounds of formula 6, compounds of formula 4 can be reacted with MsCl to give (P1). Subsequent treatment of (P1) with an appropriate amine can give compounds of formula 7.

[0385] Scheme P1

[0386] [ka] Scheme P1 shows an alternative preparation for compounds of formula 7. Mesylate (P1a) can be prepared by reaction of (N4) with methanesulfonyl chloride. Substitution of mesylate (P1a) with an amine can give alkylamino (P1b). Deprotection of (P1b) under acidic conditions can give amine (P1c), which can be reacted with an appropriate ketone under reductive amination conditions to give compounds of formula 7.

[0387] For clarity, certain stereochemical centers remain unidentified 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 resolved by those skilled in the art by methods such as selective crystallization techniques or chiral chromatography at any convenient point in the synthesis of the compounds of the present invention (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds," Wiley-Interscience, 1994). The designations "Isomer 1" and "Isomer 2" refer to the compounds that elute first and second, respectively, from chiral chromatography under the conditions described herein; if chiral chromatography is initiated early in the synthesis, the same designations apply to subsequent intermediates and examples. Additionally, the intermediates depicted in the following schemes may contain several nitrogen or oxygen protecting groups. The variable protecting groups may be the same or different from one occurrence to the next, depending on the specific reaction conditions and the specific transformation being performed. Protection and deprotection conditions are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis," Fourth Edition, by Peter G.M.Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0388] The name "Isomer 1" was also used when the ketone was subjected to asymmetric reduction using the ruthenium catalyst described herein. The same name was applied to subsequent intermediates and examples unless the examples were subjected to chiral chromatography. Asymmetric reduction of ketones to secondary alcohols using ruthenium catalysts is 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, "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." refers to 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 example, "DMA" refers to dimethylacetamide, "DME" refers to 1,2-dimethoxyethane, and "HA" refers to dimethylacetamide. "TU" refers to N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide, "NDM" refers to 1-dodecanethiol, "DMEA" refers to dimethylethylamine, "NMO" refers to N-methylmorpholine N-oxide, "EtO" refers to diethyl ether, and "DMF" refers to N,"DMSO" refers to N-dimethylformamide, "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 ethyl magnesium bromide, "NFSI" refers to N-fluorobenzenesulfonimide, "FA" refers to formic acid, "h" refers to hour, "hal" refers to halogen, "NIS" refers to N-iodosuccinimide, "IPA" refers to isopropyl alcohol, "IPAm" refers to isopropylamine, "i-PrMgCl" refers to isopropyl magnesium chloride, "L" refers to liter, "LDA" refers to lithium diisopropylamide, "MsCl" refers to methanesulfonyl chloride, "MeMgBr" refers to methyl magnesium bromide, "MTBE" refers to methyl tert-butyl ether "MeTHF" refers to 2-methyltetrahydrofuran, "ml" refers to milliliter, "min" refers to minute, "M" refers to mole, "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 tetrakis(triphenylphosphine). "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, and "t, R" refers to retention time, "sat" refers to saturated, "NaOMe" refers to sodium methoxide, "Na(OAc)3BH" sodium triacetoxyborohydride, "sat." refers to saturated, "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-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate

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

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

[0394] [Table 2]

[0395] Preparation 4 tert-Butyl 6-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 EtN (3.6 ml, 26 mmol), followed by the dropwise addition of methanesulfonyl chloride (1.5 ml, 19 mmol). The reaction was stirred at 0 °C and allowed to warm slowly to room temperature. After stirring for 1 h, the reaction was diluted with EA (75 ml), washed with 50% brine (100 mL), collected, dried over MgSO, filtered, and concentrated to give the title compound (4.3 g, 87%) as a white solid, which was used without purification. MS ES+ m / z 236 [MH- t Bu]+ .

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

[0398] [Table 3]

[0399] Preparation 8 Benzyloxycyclobutanol

[0400] [ka] A mixture of 3-(benzyloxy)cyclobutan-1-one (20 g, 113.5 mmol) and NaBH (4.29 g, 113.5 mmol) in MeOH (50 ml) was stirred at room temperature under N for 2 h. The reaction was quenched with HO at 0 °C, extracted with EA (3 × 100 ml), washed with brine (2 × 100 ml), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 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 solubilizing the solid and then treated with NaN (4 M in HO, 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) with a residence time of 40 min, a temperature of 135 °C, and a BPR of 10 bar. The reaction was diluted with HO (200 mL) and extracted with EA (2 × 100 mL). The combined organics were dried over MgSO, filtered, and concentrated to give 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-azido-3,3-difluoro-piperidine-1-carboxylate

[0404] [ka] A solution of tert-butyl (4R)-4-amino-3,3-difluoro-piperidine-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) at room temperature under N2 and stirred overnight. The reaction 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 give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0406] [Table 4]

[0407] Preparation 12 N-Diazo-1,1,1-trifluoro-methanesulfonamide

[0408] [ka] To a solution of NaN (9.22 g, 142 mmol) and hydrogen tetra(but-1-yl)ammonium sulfate (0.48 g, 1.42 mmol) in distilled H2O (30 mL) cooled to 0 °C was slowly added a solution of (CF3SO2)2O (8.00 g, 28.4 mmol) in heptane (25 mL). The reaction was stirred at 0 °C for 1-2 h. Heptane (25 mL) was added to the reaction, and the layers were separated. The aqueous layer was extracted with heptane (3 × 10 mL). The combined organic layers were dried over NaOH pellets. The organic layer was decanted, and the solution was used immediately 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 HO (15 mL) (v / v) were treated with a freshly prepared stock solution of N-diazo-1,1,1-trifluoro-methanesulfonamide in heptane (4.96 g, 28.3 mmol). Additional MeOH was added in 5 mL portions to the reaction until a homogeneous mixture was obtained (a total of 20 mL added). The reaction 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 in vacuo to give 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-fluoro-piperidine-1-carboxylate

[0412] [ka] To tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (4 g, 18.24 mmol) and PPh (6.22 g, 23.72 mmol) in THF (40 ml) was added dropwise DIAD (5.53 g, 27.37 mmol) under N at 0 °C, followed by DPPA (5.52 g, 20.07 mmol). The reaction was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

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

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

[0416] [ka] A mixture of tert-butyl 4-azido-4-methyl-piperidine-1-carboxylate (4 g, crude) and trimethyl(prop-1-yn-1-yl)silane (5.61 g, 49.94 mmol) was irradiated with microwave radiation at 150 °C for 1 hour. Upon cooling to room temperature, the resulting mixture was concentrated in vacuo to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0418] [Table 6] 1 Toluene was used as the solvent for this transformation. 2 It was purified by silica gel chromatography eluting with PE / EA (5:1 to 3:1). 3 Purified by silica gel chromatography eluting with 0% to 100% EA in heptane. 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-triazol-1-yl)-4-methyl-piperidine-1-carboxylate

[0420] [ka] A mixture of tert-butyl 4-methyl-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate (2.3 g, crude) and SiO (0.78 g, 13.05 mmol) in ACN (15 ml) was treated with NBS (1.74 g, 9.79 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C under N for 2 h. Upon cooling to room temperature, the reaction was quenched with H O and extracted with EA (2 × 200 ml). The combined organic layers were washed with brine (2 × 100 ml), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0422] [Table 7] 1 Purification was carried out by silica gel chromatography eluting with PE / EA (3:1). 2 Purification was carried out by silica gel chromatography eluting with PE / EA (4:1). 3 Purified by silica gel chromatography eluting with 0% to 100% EA in heptane. 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-triazol-1-yl)azepane-1-carboxylate

[0424] [ka] A solution of tert-butyl 4-(p-tolylsulfonyloxy)azepane-1-carboxylate (15 g, 38.57 mmol) in DMSO (120 ml) was stirred under N. A solution of NaN (2.8 g, 42 mmol) in HO (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 mass 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 / HO (8:1) (0.28 M, total 130 ml). The azide intermediate solution was used in the next step.

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

[0426] Preparation 34 tert-Butyl (1R,5S)-3-(4-ethoxycarbonyl-5-methyl-triazol-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-oxobutanoate (2.25 g, 17.3 mmol) in DMSO (29 ml) was added K2CO3 (5.97 g, 43.2 mmol) under N2 at room temperature. The reaction was stirred at 85 °C for 6 h. Upon cooling to room temperature, the reaction was poured into ice / HO (200 ml) with stirring. The resulting cream-colored precipitate was collected by filtration, washed with HO (100 ml), and dried overnight at 40 °C to give the title compound (3.10 g, 59%). MS ES+ m / z 365 [MH- t Bu] + .

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

[0429] [ka] To a stirred mixture of 3-(azidocyclobutoxy)methylbenzene (21 g, 103.32 mmol) and ethyl acetoacetate (14.79 g, 113.66 mmol) in DMF (100 ml) was added KCO (42.84 g, 309.97 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C under N for 2 h. Upon cooling to room temperature, the reaction was concentrated in vacuo. The mixture was diluted with H0 (300 ml) and extracted with EA (3 x 200 ml). The combined organic layers were washed with brine (3 x 200 ml), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50% EA in PE to give the title compound (29 g, 93%) as a tan 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-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 4.1 mmol) in HO (8 ml) was treated with KOH (0.28 g, 5 mmol) and stirred at room temperature for 1 h, then at 55 °C for 2 h, and then at 40 °C overnight. The reaction 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 layers were dried over NaSO, filtered, and concentrated to give 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 the appropriate reagents and adjusting the reaction time to determine completion of the reaction. MeOH can be used as a co-solvent.

[0433] [Table 8]

[0434] Preparation 38a tert-Butyl 6-(4-bromo-5-methyl-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0435] [ka] and Preparation 38b tert-Butyl 6-(4-bromo-3-methyl-pyrazol-1-yl)-2-azaspiro[3.3]heptane-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 CsCO (5.7 g, 17 mmol), and the reaction was stirred at 50 °C for 12 hours and then placed in a refrigerator. After 4 days, the reaction was poured onto ice and H2O, which resulted in the formation of a precipitate. The insoluble material was removed by filtration and washed with H2O to give the title compound (2.7 g, 44%) as a mixture. MS ES+ m / z 300 / 302 [M+H-tBu] + .

[0437] Preparation 39a tert-Butyl 2-(4-bromo-5-methyl-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

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

[0439] [ka] 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) in DMF (10 ml) were treated with CsCO (2.02 g, 6.2 mmol) at room temperature. After stirring at 90 °C for 3.5 hours, the reaction was stirred at room temperature over the weekend. Another portion of 4-bromo-5-methyl-1H-pyrazole (0.67 g, 4.14 mmol) and CsCO (2.02 g, 6.2 mmol) was added, and the reaction 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 reaction was stirred at 90 °C for 1 hour. After cooling to room temperature, the reaction was diluted with H2O (50 ml) and extracted with EA (2 times). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The resulting oil was purified by silica gel chromatography eluting with 33% EA in hexane to give the title compounds (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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0441] [Table 9]

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

[0443] [ka] To a solution of 1-(1-tert-butoxycarbonylazetidin-3-yl)-5-methyl-triazole-4-carboxylate (12.15 g, 39.14 mmol) in THF (75 ml) was added aqueous LiOH (75 ml, 75 mmol, 1 M), and the reaction was stirred at room temperature overnight. After stirring for 18 h, aqueous HCl (1 N) was added until the pH reached 5-6. The mixture was extracted (5 times) with EA and DCM / MeOH (9:1). The combined organic layers were dried over MgSO4, and the filtrate was concentrated to give 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-methyl-triazole-4-carboxylic acid

[0445] [ka] To a stirred solution of tert-butyl 4-(4-ethoxycarbonyl-5-methyl-triazol-1-yl)azepane-1-carboxylate (3.1 g, 8.8 mmol) in THF (15 ml) was added aqueous LiOH (15 ml, 15 mmol, 1 M), and the reaction was stirred at room temperature for 210 min. Aqueous HCl (1 N) was added until the pH was approximately 5-6. The reaction 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 in vacuo to give the title compound (2.89 g, 96%, 95% wt). MS ES+ m / z 296 [M+H] + .

[0446] Preparation 44 tert-Butyl (3S)-3-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate

[0447] [ka] To tert-butyl (3S)-3-(4-bromopyrazol-1-yl)piperidine-1-carboxylate (500 mg, 1.51 mmol) in THF (5 ml) was added LDA in hexane (2.3 ml, 4.6 mmol, 2 M) at -70 °C and stirred for 0.5 h. Then, CHCl (0.19 mL, 3.1 mmol) was added and stirring was continued for 30 min. The reaction was quenched with saturated aqueous NHCl (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 NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether / EA (1:0 to 10:1) to give the title compound (0.4 g, 70% yield) 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0449] [Table 10]

[0450] Preparation 46 tert-Butyl 4-(4-bromo-5-methyl-triazol-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 HO (60 ml) was treated with Br (10.4 g, 66 mmol) in several portions at room temperature. After stirring at room temperature for 3 h, the reaction was extracted with EA (3 × 30 ml). The combined organic layers were washed with brine (2 × 150 mL), dried over NaSO, filtered, and concentrated to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0453] [Table 11] 1 Prior to workup, the reaction was diluted with aqueous NaOH (2N). 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-methyl-triazol-1-yl)cyclobutyl]4-nitrobenzoate

[0455] [ka] To a solution of DIAD (4.18 g, 20.68 mmol) in THF (40 ml) was added PPh (5.88 g, 22.41 mmol) dropwise under N at 0 °C. The reaction was stirred at 0 °C for 30 min. Then, (1r,3r)-3-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)cyclobutan-1-ol (4.0 g, 17.24 mmol) and p-nitrobenzoic acid (3.46 g, 20.68 mmol) were added portionwise under N at room temperature. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 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-triazol-1-yl)cyclobutan-1-ol

[0457] [ka] To a stirred solution of (1s,3s)-[3-(4-bromo-5-methyl-triazol-1-yl)cyclobutyl] 4-nitrobenzoate (8.0 g, crude) in THF (50 ml) was added LiOH·HO (0.79 g, 18.89 mmol) in several portions at room temperature under N. The reaction was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18; mobile phase, 10% to 50% ACN in HO (0.1% FA) to give the title compound (2.5 g, 51%) as a yellow oil. 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-triazol-1-yl)cyclobutanol

[0459] [ka] A mixture of 1-(3-benzyloxycyclobutyl)-4-bromo-5-methyl-triazole (8.5 g, 26.4 mmol) and FeCl (8.56 g, 52.8 mmol) in DCM (100 ml) was stirred at 50 °C under N for 2 h. Upon cooling to room temperature, the mixture was diluted with HO (50 ml) and extracted with EA (3 × 100 ml). The combined organic layers were washed with brine (2 × 100 ml), dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give 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-methyl-triazol-1-yl)piperidine hydrochloride

[0461] [ka] A solution of tert-butyl 4-(4-bromo-5-methyl-triazol-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 was diluted with MTBE (250 ml) and the resulting suspension was stirred at room temperature for 1 hour. The suspension was filtered to give 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-dimethyl-pyrazol-1-yl)piperidine

[0463] [ka] A solution of tert-butyl 4-(4-bromo-3,5-dimethyl-pyrazol-1-yl)piperidine-1-carboxylate (0.97 g, 2.70 mmol) in DCM (15 ml) was treated with TFA (4 ml) and the reaction was stirred at room temperature. After stirring for 45 minutes, the reaction was loaded onto an SCX column pre-treated with MeOH. The column was washed with MeOH. The title compound was eluted with 2M NH3 in MeOH and concentrated to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0465] [Table 12] 1The crude was loaded onto an SCX cartridge. Non-basic impurities were washed off 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-triazol-1-yl)cyclobutanol (4.00 g, 17.23 mmol) and Dess-Martin (10.97 g, 25.85 mmol) in DCM (40 mL) was stirred at room temperature under N for 2 h. The mixture was diluted with HO (100 mL), extracted with EA (3 × 100 mL), washed with brine (2 × 100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse-phase chromatography under the following conditions: column, C18; mobile phase, 20% to 40% ACN in HO (0.1% FA) to give 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-methyl-triazol-1-yl)cyclobutyl]trifluoromethanesulfonate

[0469] [ka] To (1s,3s)-3-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutan-1-ol (1.1 g, 4.74 mmol) and DIEA (3.06 g, 23.70 mmol) in DCM (10 ml) was added trifluoromethanesulfonate (2.01 g, 7.11 mmol) dropwise under N2 at -70 °C. The reaction was stirred at -70 °C for 1 hour. The mixture was used in the next step without further purification, assuming 100% conversion. 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-triazol-1-yl)cyclobutyl)piperazine-1-carboxylate

[0471] [ka] To (1s,3s)-[3-(4-bromo-5-methyl-triazol-1-yl)cyclobutyl]trifluoromethanesulfonate (1.7 g, 4.67 mmol) and DIEA (1.81 g, 14.01 mmol) in DCM (10 ml) was added tert-butyl piperazine-1-carboxylate (1.74 g, 9.34 mmol) in portions at -70 °C under N2. The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 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-triazol-1-yl)cyclobutyl]piperazine-1-carboxylate

[0473] [ka] To 3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanone (1.67 g, 7.25 mmol) and tert-butyl piperazine-1-carboxylate (0.90 g, 4.83 mmol) in MeOH (5 ml) was added CHCOH (0.29 g, 4.83 mmol) in several portions at room temperature. The resulting mixture was stirred at 50 °C under N for 30 min. NaBHCN (0.61 g, 9.66 mmol) was then added in several portions at room temperature under N. The reaction was stirred at 50 °C for 2 h. Upon cooling to room temperature, the reaction was quenched with HO (100 ml) and the pH was adjusted to approximately 7 with saturated aqueous NaHCO. The mixture was extracted with EA (3 × 100 ml). The organic layers were combined, washed with brine (2 x 100 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 1% to 50% EA in PE to give 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 solution (700 mL) of 4-(4-bromo-5-methyl-triazol-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 N and stirred at room temperature for 5 minutes. The reaction was treated with AcOH (11.53 g, 192 mmol), stirred for 5 minutes, and then treated with NaBHCN (35 g, 556.95 mmol) in portions over 1 hour. The reaction was stirred at room temperature for 30 minutes and then at 30°C overnight. After cooling to room temperature, the reaction was quenched with HO (50 mL) and the pH was adjusted to 9 with 2M aqueous KPO (75 mL). The organic solvent was removed in vacuo. The resulting suspension was diluted with HO (30 ml), stirred for 30 min and filtered to give 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-dimethyl-pyrazol-1-yl)-1-(oxetan-3-yl)piperidine

[0477] [ka] NaBH3CN (0.51 g) was added to a solution of 4-(4-bromo-3,5-dimethyl-pyrazol-1-yl)piperidine (0.56 g, 2.18 mmol), oxetan-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 and then at 50 °C for 18 hours. Upon cooling to room temperature, the reaction was concentrated in vacuo. 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 eluting with a gradient of 0% to 100% EA in cHex, followed by 0% to 20% MeOH in DCM to give the title compound (510 mg, 60%) 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0479] [Table 13] 1 Purification was achieved by silica gel chromatography eluting with 0% to 10% MeOH in DCM.

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

[0481] [ka] To a solution of tert-butyl (1R,5S)-3-(4-bromo-5-methyl-triazol-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 in 1,4-dioxane (3 mL, 12 mmol, 4 mol / L) was added, and the mixture was stirred at room temperature for 1 hour, then heated at 50 °C for 1 hour and stirred at room temperature overnight. The reaction was concentrated in vacuo to give the intermediate (1R,5S)-3-(4-bromo-5-methyl-triazol-1-yl)-8-azoniabicyclo[3.2.1]octane hydrochloride as a solid. This material 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) was added 3-oxetanone (0.7 mL, 10 mmol). The mixture was stirred at room temperature for 5 minutes, and then NaBHCN (0.7 g, 10 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was heated at 50 °C for 9 hours. Additional 3-oxetanone (170 μL, 2.79 mmol) and NaBHCN (170 mg, 2.70 mmol) were added, and the reaction was stirred at 50 °C overnight. The reaction was quenched with HO and extracted with EA (3 × 25 ml). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0% to 20% EA in DCM followed by 0% to 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 cyclopropylzinc bromide (30 ml, 15.150 mmol, 0.5 M in THF) was added dropwise at 0 °C. The reaction was stirred overnight, allowing it to slowly warm to room temperature. The reaction was quenched with H2O and extracted with EA. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EA in heptane to give 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 POCl (46.72 g, 304.72 mmol) in ACN (80 ml) was stirred overnight at 80 °C under N. The mixture was cooled to room temperature, poured into H2O / ice (300 ml), and basified to pH 8 with NaHCO. 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 to 10:1) to give 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] A solution 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 HO (10 mL) was treated with KCO (18.85 g, 136.37 mmol) and Pd(PPh) (1.05 g, 0.91 mmol) under N. After stirring at 100 °C for 2 h, the mixture was diluted with HO (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (20 to 10:1) to give 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 at room temperature under N2. The reaction was stirred at 100 °C for 2 h. After cooling to room temperature, the mixture was purified by silica gel column chromatography eluting with PE / EA (30:1 to 12:1) to give the title compound (4.6 g, 77%) as a yellow oil. MS ES+ m / z 219 [M+H] + .

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

[0492] [Table 14] 1 It was purified by silica gel chromatography eluting with PE / EA (10:1 to 5:1). 2 The reaction was quenched with saturated aqueous KF solution. 3 Purified by silica gel chromatography eluting EA 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 SOCl (10 ml) and stirred at reflux for 2 hours. The reaction was concentrated in vacuo and 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 was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with DCM and washed with saturated NaHCO solution, and the combined organic phase was dried over MgSO, filtered, and the filtrate was concentrated in vacuo to give 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 suspension of 5-(trifluoromethyl)pyridine-3-carboxylic acid (4 g, 20.93 mmol) in DCM (60 mL) was treated with 1,1'-carbonyldiimidazole (3.73 g, 23 mmol) and EtN (5.8 mL, 42 mmol). The reaction was stirred at room temperature for 3 hours, diluted with HO, the organic phase was collected, and the aqueous phase was re-extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO, collected, dried over MgSO, filtered, and concentrated to give 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-trimethyl-thiazole-4-carboxamide

[0498] [ka] To an ice-cold solution of 2,5-dimethylthiazole-4-carboxylic acid (1.25 g, 7.95 mmol) and methoxy(methyl)ammonium chloride (1.95 g, 20.0 mmol) in DMF (10 ml) was added NEt (2.85 g, 28 mmol). The mixture was stirred at room temperature for 5 minutes, then HATU (3.6 g, 9.3 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction was poured into HO, the aqueous solution was extracted with DCM (twice), and the combined organic layers were washed with 10% aqueous LiCl, dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 30% EA in cHex to give 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 N for 1 h. The resulting mixture was diluted with HO (10 ml), basified to pH 8 with NaHCO, and extracted with MTBE (3 × 20 ml). The combined organic layers were washed with brine (1 × 10 ml), dried over anhydrous NaSO, collected, and filtered. The filtrate was concentrated to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[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 three vacuum / N2 cycles. Tributyl(1-ethoxyvinyl)tin (1.56 mL, 4.32 mmol) was added, and the mixture was stirred under N2 at 100 °C for 6 h. The reaction was treated with saturated aqueous KF solution (2.5 mL), filtered through a pad of DE, and the cake was washed with EA (30 mL). The phases were separated from the filtrate. The organic phase was washed with saturated aqueous NaHCO3 (3 × 20 mL) and brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the intermediate vinyl ether as a brown oil.

[0505] The intermediate vinyl ether was dissolved in THF (10 ml), then aqueous HCl (2 M, 5 mL) was added and the reaction was stirred at room temperature for 12 hours. The reaction was treated with saturated aqueous NaHCO3 (30 ml) and the mixture was stirred vigorously for 10 minutes. The aqueous phase was extracted with EA (3 x 25 ml) and the combined organic layers were washed with brine (25 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EA in heptane to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[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 weight) in THF (30 ml) at 0° C. was treated dropwise with MeMgBr (10 mL, 14 mmol, 1.4 M in toluene / THF [3:1]) and stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl at 0° C., diluted with HO, and extracted with EA (2×). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The resulting oil was purified by silica gel chromatography eluting with a gradient of 0% to 80% EA in cHex to afford 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0511] [Table 17] a The material was used in the subsequent step without further characterization. 1 It was purified by silica gel chromatography eluting with 0%-30% EA in cHex.

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

[0513] [ka] A 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) in toluene (50 mL) was treated dropwise with KHMDS (51.7 mL, 51.71 mmol, 1.0 M in THF) under a nitrogen atmosphere at −70° C. After stirring for 30 min at −70° C., the reaction was quenched with saturated aqueous NH4Cl at room temperature, acidified to pH 1-2 with aqueous HCl (1.2 M), and extracted with EA (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 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)pyrrolidin-3-ol

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

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

[0517] [ka] MeMgBr (0.21 ml, 1.80 mmol, 3 M) 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) at 0 °C under N. After stirring at 0 °C for 1 h, the reaction was carefully quenched with AcOH (0.13 ml, 2.25 mmol) and diluted with MeOH (2 ml). NaBH (102 mg, 2.70 mmol) was then added in one portion, and the reaction was stirred at 0 °C for 40 min. The reaction was diluted with saturated aqueous NHCl (4 ml) and extracted with EtO (2 × 5 ml) and DCM (2 × 5 ml). The combined organic phases were dried over MgSO, filtered, and the solvent was concentrated in vacuo to give the title compound as a pale yellow oil (174 mg, quantitative). ES+ m / z 180.9[M+H] + .

[0518] Preparation 86 1-(1-methylpyrrolo[2,3-c]pyridin-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)magnesium oxide (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 h, acetaldehyde (2.6 ml, 46.40 mmol) was added at −40° C. The reaction was stirred for 1 h, allowing the temperature to reach −20° C. The reaction was quenched with saturated NH4Cl and then extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give 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]pyridin-4-yl)ethanol

[0522] [ka] To a solution of MeMgBr (1.67 ml, 3.0 M solution, 5.0 mmol) in THF (10 ml) was added n-BuLi (6.25 ml, 1.6 M solution in hexane, 10.0 mmol) under N2 at 0 °C. The reaction was stirred for 30 min 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. The resulting suspension was stirred briefly (approximately 2 min) at 0 °C to completely dissolve the solid. The solution was recooled to -40 °C and stirred for 1 h. Next, acetaldehyde (2.65 ml, 8.9 mmol) was added dropwise. The solution was stirred at -40 °C for 90 min, then the reaction 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 in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give the title compound as a beige solid (372 mg, 44%). MS ES+m / z 178.2 [M+H] + .

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

[0524] [ka] MeMgBr in EtO (2.5 M in EtO, 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) at 0° C. under N, and the reaction was stirred at room temperature for 3 h. The solution was then cooled to 0° C., quenched with saturated NH4Cl (aqueous, 25 ml), and extracted with DCM (3×25 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0526] [Table 18]

[0527] Preparation 92 1-(2-Isopropylthiazol-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 N and cooled to −78° C. A solution of n-BuLi (3.62 ml, 5.79 mmol, 1.6 M in hexanes) was added dropwise. The solution was stirred at −78° C. for 45 min, then acetaldehyde (1.63 ml, 26.31 mmol) was added, and the reaction was allowed to warm slowly to room temperature and then stirred for 18 h. The reaction was quenched with HO (30 mL), extracted with EA (3×15 mL), and the combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with MeOH in DCM to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0530] [Table 19] 1 It was purified by silica gel chromatography eluting with 10%-50% EA in cHex.

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

[0532] [ka] In a separate flask, a degassed (ultrasonic) 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 NEt (6.0 g, 60 mmol) was added to [[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-(p-trisulfonyl)amino]-chloro-ruthenium; 1-isopropyl-4-methyl-benzene (29 mg, 0.05 mmol) at room temperature. The mixture was stirred overnight under N at room temperature. H O and EtOH were added to the mixture and partially evaporated. A saturated aqueous solution of NaHCO was added to ensure a high pH, ​​and the mixture was extracted with EA (4 times). The combined organic layers were dried over Na SO and filtered. DE was added, and the suspension was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of 30% to 90% EA in cHex to give the title compound (815 mg, 94%) as a green oil. MS ES+ m / z 174 [M+H] + .

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

[0534] [Table 20] 1Purification was achieved by silica gel chromatography eluting with 5% EA in cHex (2 CV), 5%-50% EA in cHex (15 CV), 50%-100% EA in cHex (5 CV). 2 It was purified by silica gel chromatography eluting with 0%-50% EA in cHex.

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

[0536] [ka] In a glass pressure flask, 1-(2-bromothiazol-4-yl)ethanol (2.14 g, 9.25 mmol) in MeOH (23 ml) was added to a solution of NaOMe (30% by weight) in MeOH (23 ml). The headspace was purged with N2 and the flask was sealed. The reaction was stirred at 50 °C. After 6 h, the reaction was stirred at room temperature overnight. The next day, heating was resumed for 4 h. Upon cooling to room temperature, the reaction was poured into saturated aqueous NH4Cl (150 ml) and DCM (30 ml) was added. The organic layer was separated and the aqueous layer was extracted with DCM (3 x 20 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DCM, dry loaded onto a DE and purified by silica gel column chromatography eluting with the following conditions: 100% cHex (1 CV), 0% to 35% EA in cHex (16 CV), 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) was added NaBH (48.35 mg, 1.28 mmol) at 0 °C under N. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with H0 (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 NaSO, filtered, and concentrated to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

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

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

[0542] [ka] A solution of methyl 1-(5-bromo-2-pyridyl)-3,3-difluoro-cyclobutanecarboxylate (11.0 g, crude) in THF (100 ml) was treated with LiBH (0.78 g, 35.94 mmol) in several portions at room temperature under N. After stirring at room temperature for 3 h, the reaction was quenched with saturated NH.sub.4Cl and concentrated. The residue was purified on silica gel eluting with PE:EA (5:1) to give the title compound (1.8 g, 16% over 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) at 0 °C under N. After stirring at room temperature for 3 h, the reaction was cooled to 0 °C and treated with 2-(benzyloxy)acetaldehyde (3.10 g, 20.62 mmol). The reaction was stirred at room temperature for 2 h and then quenched with saturated aqueous NH4Cl (200 mL). The reaction 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 give the title compound (1.6 g, 23%) as a pale yellow oil. MS ES+m / z 266[M+H] + .

[0545] Preparation 106 1-(5-fluoropyrimidin-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) was added NMO (17.56 g, 149.86 mmol) under N2 at 0 °C. The resulting mixture was stirred at room temperature under N2 for 2 h. The reaction 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 give the title compound (6.0 g, 51%) as a black oil. MS ES+ m / z 159 [M+H] + .

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

[0548] [ka] To a mixture of 1-(5-fluoropyrimidin-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 added SEM-Cl (4.43 g, 26.56 mmol) dropwise under N at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of MeOH (20 ml) at room temperature. The mixture was stirred for 30 min and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (6:1 to 4:1) to give 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 H NMR(300MHz,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] [ka] A toluene solution (10 ml) of 2-bromo-5-fluoropyridine (1.2 g, 6.82 mmol) at 0 °C was treated dropwise with i-PrMgCl (5.11 ml, 10.23 mmol, 2 M in THF) under N2. The resulting mixture was stirred at 0 °C for 30 min and treated dropwise with 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (1.78 g, 10.23 mmol) over 10 min. The resulting mixture was stirred at 0 °C for 2 h, quenched with HO, and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 5:1) to afford the title compound (420 mg, 23%) as a colorless oil. MS ES+m / z 272[M+H] + .

[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 CHI (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 N at 0 °C. The resulting mixture was stirred at room temperature for 1 h, quenched with saturated aqueous NHCl (100 ml), and extracted with EA (3 × 200 ml). The combined organic layers were washed with brine (2 × 200 ml), dried over NaSO, filtered, and concentrated to give 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-methoxy-ethoxy]-dimethyl-silane

[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 CHCl (7.84 g, 55.27 mmol) in THF (30 ml) at 0° C. was treated with NaH (0.53 g, 22.11 mmol, 60 wt%) in several portions under N. After stirring at room temperature for 2 h, the reaction was quenched with HO (50 ml) and extracted with EA (2×50 ml). The combined organic layers were washed with brine (2×80 ml), dried over anhydrous NaSO, filtered, and concentrated to give the title compound (2.9 g, 92%) as a yellow solid. MS ES+ m / z 286 [M+H] + .

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

[0557] [ka] To a stirred mixture of 1-(5-fluoropyrimidin-2-yl)-2-(2-trimethylsilylethoxymethoxy)ethanol (1.01 g, 3.50 mmol) in THF (10 ml), CHI (746 mg, 5.25 mmol) and AgO (2.43 g, 10.51 mmol) were added portionwise at room temperature under N. The reaction was stirred at 60 °C under N for approximately 4 hours. Upon cooling to room temperature, the reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / EA (2:1 to 3:1) to afford 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-difluoro-cyclobutyl]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 N. After stirring at 50 °C for 2 h, the reaction was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (20:1) to give 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-fluoro-pyridine

[0561] [ka] A solution of 5-bromo-2-[3,3-difluoro-1-(tetrahydropyran-2-yloxymethyl)cyclobutyl]pyridine (2.0 g, 5.5 mmol) in THF (20 ml) was treated dropwise with n-BuLi (2.87 ml, 7.18 mmol, 2.5 M in hexane) at −70° C. under N. The reaction was stirred at −70° C. for 15 minutes and then treated with NFSI (3.48 g, 11.04 mmol). The reaction was stirred at −70° C. for an additional hour and then quenched with HO at room temperature. The resulting mixture was extracted with EA (3×100 ml), and the combined organic layers were washed with brine (2×100 ml), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (20:1). The title compound (930 mg, crude) was obtained as a yellow oil. MS ES+m / z 302[M+H] + .

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

[0563] [ka] A solution of 2-[3,3-difluoro-1-(tetrahydropyran-2-yloxymethyl)cyclobutyl]-5-fluoro-pyridine (900 mg, crude) in THF (10 mL) was treated with aqueous HCl (2.5 mL, 12 M) at room temperature under N. After stirring at room temperature for 3 h, the reaction was diluted with HO (50 mL), basified to pH 7-8 with aqueous NaHCO, and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC: PE / EA (5:1) to give the title compound (450 mg, 69%) as a pale yellow oil. MS ES+ m / z 218 [M+H] + .

[0564] Preparation 115 2-(3,5-Difluoro-2-pyridyl)-2-methoxy-ethanol

[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 at 80 °C under N for 4 h. The reaction was cooled to room temperature, diluted with HO (50 ml), basified to pH 9 with KCO, and extracted with EA (3 × 100 ml). The combined organic layers were washed with brine (2 × 100 ml), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1 to 4:1) to give 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-methoxy-ethanol

[0567] [ka] A solution of tert-butyl-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]-dimethyl-silane (2.9 g, 10.16 mmol) in DCM (5 ml) was treated dropwise with 4 M HCl in 1,4-dioxane (30 ml) at room temperature under N. Upon completion, the reaction was concentrated and the residue was dissolved in 50 ml of HO, basified to pH 9 with saturated aqueous NaCO, and extracted with EA (2 x 60 ml). The combined organic layers were washed with brine (2 x 40 ml), dried over NaSO, and concentrated to give the title compound (1.6 g, crude) as a yellow oil. MS ES+ m / z 172 [M+H] + .

[0568] Preparation 117 2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethanol

[0569] [ka] To 2-[[2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethoxy]methoxy]ethyl-trimethyl-silane (925 mg, 3.06 mmol) in MeOH (9 ml) was added concentrated HCl (3 ml) at room temperature under N2. The reaction was stirred at room temperature for 2 hours and then quenched with H2O (100 ml). The mixture was basified to pH 8 with NaHCO3. The aqueous layer was extracted with EA (3 x 100 ml). The combined organic layers were concentrated in vacuo to give 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]ethanamine

[0571] [ka] A solution of 1-[5-(trifluoromethyl)-3-pyridyl]ethanone (0.77 g, 4.06 mmol) in EtOH (30 ml) was treated with NHOAc (4.7 g, 61 mmol) and stirred at room temperature for 20 minutes. The reaction was treated with NaBHCN (0.54 g, 8.12 mmol) and stirred at room temperature for 1 hour, then at 85 °C for 1.25 hours. The reaction was cooled to room temperature and concentrated. The resulting oil was loaded onto an SCX cartridge. Non-basic impurities were washed off the cartridge with MeOH, and the title compound was then eluted with methanolic ammonia (2 M). The resulting oil was purified by reverse-phase (Claricep C) chromatography, eluting with 20%-50% aqueous NHCO in ACN, to give the title compound (1.9 g, 77%) as a yellow oil. 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 solution of (3.4 g, 17.79 mmol) in THF (30 ml) was treated with benzylamine (3.81 g, 35.58 mmol) under N2. After stirring at 50 °C for 2 h, the reaction was cooled to room temperature, diluted with HO (100 ml), and extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (20:1 to 10:1) to give 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) was added Pd / C (2.50 g, 23.47 mmol) and Pd(OH) / C (2.82 g, 20.11 mmol) under N. The resulting mixture was stirred at room temperature under H for 2 hours. The mixture was filtered and washed with MeOH (3 x 10 ml). The filtrate was concentrated to give 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)pyridin-3-yl]ethanol (36.00 g, 188 mmol) in DCM (400 ml) was added SOCl (44.81 g, 376 mmol) at room temperature under N. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with H0 (500 ml). The mixture was extracted with DCM (3 x 500 ml). The combined organic layers were washed with brine (1 x 500 ml) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 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-Isopropylthiazol-4-yl)ethanol (344 mg, 2.22 mmol) was dissolved in SOCl (3 mL) and toluene (3 mL) and then refluxed for 1 h. The reaction was concentrated in vacuo to give the title compound as a brown oil (365 mg, quantitative). This material was used immediately in the next step.

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

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

[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-cyclopropylthiazol-4-yl)ethanol (320.5 mg, 1.76 mmol) and NEt (0.49 ml, 3.5 mmol) in DCM (7 ml) cooled to 0 °C under N. The reaction was stirred at 0 °C for 1 h, then the cooling bath was removed. After 3.5 h, the reaction was recooled to 0 °C and quenched by the slow addition of HO (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 NaSO, filtered, and concentrated to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0585] [Table 23]

[0586] Preparation 130 1-(3,6-dimethylpyrazin-2-yl)ethyl methanesulfonate

[0587] [ka] MsCl (903.09 mg, 7.88 mmol) was added dropwise to a stirred mixture of 1-(3,6-dimethylpyrazin-2-yl)ethanol (1 g, 6.57 mmol) and DIEA (127.38 mg, 0.99 mmol) in DCM (10 ml) under N at 0 °C and stirred for 2 h. The reaction was removed from the cooling bath, quenched with HO (10 ml), and extracted with DCM (3 × 10 ml). The combined organic layers were washed with brine (3 × 10 ml), dried over NaSO, filtered, and concentrated to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0589] [Table 24]

[0590] [Table 25] a The material was used in the subsequent step 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 portionwise over 5-10 min to a solution of 3-chloro-2-(1-ethoxyvinyl)-5-fluoro-pyridine (1.22 g, 6.06 mmol) in a mixture of THF (12 ml) and HO (3 ml) at 0 °C. The reaction was stirred at 0 °C for 1 h, then diluted with EA (50 ml), washed with HO (50 ml) and brine (50 ml), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EA in heptane to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0594] [Table 26] 1 Purified by silica gel chromatography eluting 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 solution of 1-(3,5-difluoro-2-pyridyl)ethanone (20 g, 120.93 mmol) in THF (181 mL) 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 x 100 mL). The combined filtrate was concentrated to give a brown oil, which was purified by silica gel chromatography eluting with a gradient of 10% to 50% DCM in cHex to give the title compound (15 g, 42%) as a yellow oil. 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

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

[0599] Preparation 145 2-chloro-1-(5-fluoropyrimidin-2-yl)ethanone

[0600] [ka] To a stirred solution of 2-bromo-5-fluoropyrimidine (3.0 g, 16.95) in toluene (30 ml) was added i-PrMgCl (1 M in THF) (10.17 mL, 20.340 mmol) dropwise at 0° C. under N. The reaction was stirred at room temperature for 2 h. To the above mixture was added 2-chloro-N-methoxy-N-methylacetamide (2.33 g, 16.95 mmol) dropwise over 20 min at 0° C. under N. The reaction was stirred at room temperature for 1 h and then quenched with saturated aqueous NH.sub.4Cl (200 ml). The mixture was extracted with EA (2.times.300 ml). The combined organic layers were washed with brine (2.times.300 ml), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give 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 in vacuo. The residue was purified by silica gel chromatography eluting with a linear gradient of 0% to 100% EA in heptane. The fractions containing the title compound were concentrated in vacuo and combined with the filtered solid to give 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). N was bubbled through the mixture for 5 minutes, then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.9 g, 20 mmol) was added and the reaction was stirred at 80° C. for 2 hours. Upon cooling to room temperature, the reaction 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 give 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]octane bis(tetrafluoroborate) (7.04 g, 22.02 mmol) in ACN (50 mL) was stirred overnight at room temperature under N. The resulting mixture was diluted with HO (50 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous NaSO, 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% to 40% ACN (0.1% FA) in HO; to give 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-methyl-pyrazolo[1,5-a]pyridine

[0608] [ka] Et3Si (8.0 ml, 50.20 mmol) was added dropwise to a solution of (6-bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)methanol (6.45 ml, 25.10 mmol) in TFA (50 ml) at 0°C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated in vacuo, and the residue was dissolved in DCM, washed with saturated aqueous Na2CO3 (twice), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with EA in heptane to give 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-methoxy-imidazo[1,2-a]pyridine

[0610] [ka] A solution of 4-chloro-6-methoxypyridin-2-amine (7.00 g, 44.14 mmol), chloroacetaldehyde (8.32 g, 52.99 mmol, 50%), and NaHCO (11.12 g, 132.42 mmol) in n-BuOH (140 mL) was divided into 14 batches and stirred overnight at 65 °C in sealed tubes. The solution was cooled to room temperature, diluted with HO (200 mL), and extracted with EA (3 × 200 mL). The organic layers were combined, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50% EA in PE to give 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 portion with a solution of NaOH (31.7 g, 793 mmol) in HO (100 mL) at 40 °C, followed by NDM (161 g, 793 mmol). After stirring at 50 °C for 1 h, the reaction was cooled to 0 °C and quenched with 37% aqueous HCl (100 mL) to a final pH of 5. The reaction was diluted with HO (4 L), and the resulting solid was collected by filtration and washed with HO (1 L) and heptane (500 mL) to give 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-iodo-imidazo[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 with NIS (12.03 g, 53.47 mmol) in several portions at room temperature under N. After stirring at room temperature for 2 h, the reaction was diluted with HO (100 ml) and extracted with DCM (3 x 50 ml). The combined organic layers were washed with brine (3 x 50 ml), dried over NaSO, filtered, and concentrated to give 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 solution of 5,7-dichloro-3-iodo-imidazo[1,2-a]pyridine (11.00 g, 35.15 mmol) in DMF was treated with CuCN (6.30 g, 70.31 mmol) in several portions at room temperature under N. After stirring at 100 °C for 2 h, the reaction was cooled to room temperature, treated dropwise with NHOH (100 mL) over 5 min, diluted with HO (300 mL), and stirred at room temperature for 2 h. The reaction was extracted with DCM (3 × 400 mL), and the combined organic layers were washed with brine (3 × 300 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1 to 1:2) to give 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-methoxy-ethoxy]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 N at 0 °C. After stirring at room temperature for 2 h, the reaction was quenched with saturated aqueous NH4Cl, 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 with a gradient of 40% to 50% ACN in HO to give the title compound as a light 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] To 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (45.43 g, 190.84 mmol) in DMF (350 ml) were added K2CO3 (79.13 g, 572.52 mmol) and 3-(1-chloroethyl)-5-(trifluoromethyl)pyridine (40 g, crude) in portions over 2 min at 80 °C. The reaction was stirred under N2 at room temperature for 2 h. 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 to 2:1) to give the title compound (32 g, 40.78%) as a yellow solid. MS ES+ m / z ( 79 Br / 81 Br)411 / 413[M+H] + .

[0621] The racemate of the title compound (32 g) was subjected to the following chromatographic conditions: SFC, column: NB_CHIRAL ART Cellulose-SB; 5 x 25 cm, 5 μm, elution with 15% IPA (0.2% DEA) in CO2, to give the title compound, isomer 2 (13.5 g, 42.19%). R The result was 6.58 min, 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-carbonitrile tosylate

[0623] [ka] A solution of PPh3 (34.1 g, 130 mmol) in THF (300 mL) was treated dropwise with DIAD (23.2 g, 115 mmol) at room temperature over 4 minutes. After stirring at room temperature for 30 minutes, a 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) in THF (100 mL) was added dropwise over 6 minutes. After stirring at room temperature for 45 minutes, the reaction mixture was concentrated in vacuo. The residue was slurried 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 at room temperature overnight. The solid was collected by filtration and washed with MTBE (3 x 50 mL) to give 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-fluoropyrimidin-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine

[0625] [ka] To PPh3 (3.50 g, 13.34 mmol) in THF (10 mL) was added dropwise DIAD (2.52 g, 12.45 mmol) under N2 at 0 °C. The reaction was stirred at 0 °C for 0.5 h. Next, 6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-ol (1.1 g, 4.45 mmol) and 2-(5-fluoropyrimidin-2-yl)-2-methoxyethanol (918.26 mg, 5.334 mmol, 1.2 equiv.) in THF (10 mL) were added at room temperature. The reaction was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by reverse flash chromatography eluting with the following conditions: column, C18; mobile phase, 50% to 55% ACN in HO to give 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 CsCO (8.21 g, 25.2 mmol) in ACN (20 ml) was stirred under N at room temperature for 0.5 h. 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 was stirred at room temperature for 1 h. The reaction was diluted with HO (100 ml) to give a suspension. The solid was collected by filtration and washed with HO to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0629] [Table 28] 1 DIPEA was used as the base for this transformation. 2 Workup: The reaction was concentrated in vacuo. The residue was dissolved in MeOH and triturated with H 2 O. The precipitated product was collected by filtration. 3 The reaction was heated at 80°C. 4 Workup: The reaction was concentrated in vacuo. The residue was triturated with H 2 O. The precipitated product was collected by filtration. 5 Workup: The reaction was diluted with H2O, extracted with EA, dried over Na2SO4, filtered and concentrated in vacuo. 6 It was purified by silica gel chromatography eluting with EA in DCM (1:30 to 1:15).

[0630] Preparation 162 1-(6-bromopyrazolo[1,5-a]pyridin-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)ethenon (3 g, 8.57 mmol) in THF (10 ml) was added to a stirred solution of MeMgBr (3 M in EtO, 14.3 ml, 42.84 mmol) in THF (30 ml) at room temperature under N2, and the reaction was stirred for 2 hours. The solution was quenched with H2O (50 ml) and extracted with EA (3 x 50 ml). The combined organic layers were washed with brine (3 x 50 ml), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (3 g, crude) as a brown oil. 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0633] [Table 29] 1 The reaction was quenched with saturated aqueous NH4Cl (30 ml) at 0°C. 2 It was purified by silica gel chromatography eluting with DCM / PE (1:2 to 2:1). 3 Purification was achieved by preparative TLC PE / EA (8:1).

[0634] Preparation 165 6-Bromo-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]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 NaBH (0.85 g, 22.47 mmol) in one portion. The reaction was stirred at 0° C. for 5 minutes and then at room temperature for 1 hour. The reaction was concentrated and the residue was dissolved in DCM and washed with H O and brine. The organic layer was collected, dried over MgSO, filtered, and concentrated to give 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 that of Preparation 165, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0637] [Table 30] 1 Workup: The reaction was concentrated in vacuo. The residue was triturated in H2O and the precipitate was collected by filtration.

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

[0639] [ka] To 2-(6-bromo-3-chloro-pyrazolo[1,5-a]pyridin-4-yl)oxy-1-(5-fluoro-2-pyridyl)ethanol (1.62 g, 4.19 mmol) in THF (10 ml) was added NaH (335 mg, 8.38 mmol, 60%) in portions at 0 °C under N. To the mixture was added CHI (2.97 g, 20.95 mmol) dropwise at 0 °C. The reaction was stirred at room temperature for 2 h and then quenched with HO (50 ml). The mixture was extracted with EA (3 × 100 ml), and the organic layers were combined, washed with brine (3 × 50 ml), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 5:1) to give the title compound (1.01 g, 60%) as a light yellow solid. MS ES+m / z 402[M+H] + .

[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-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (3 g, 7.95 mmol) and CHCl (2.26 g, 15.91 mmol) in THF (30 mL) was added NaH (60%) (636 mg, 15.91 mmol) in portions at 0 °C under N. The mixture was stirred at room temperature for 2 h and then quenched with H0 (20 mL). The mixture was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1 to 1:1) to give 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 N. After stirring at 100 °C for 24 h, the reaction was purified by reverse flash C18 chromatography using the following conditions: column, C18; elution with a gradient of 50% to 70% ACN in HO to give 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] A pressure flask was charged with Pd(dba) (0.05 g, 0.05 mmol), dppf (0.06 g, 0.1 mmol), KPO (1.3 g, 6 mmol), and DME (5 mL). The suspension was degassed by bubbling N through 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 N was bubbled through the mixture for an additional few minutes. The tube was capped, and the reaction was heated to 207 °C for 15 minutes. After stirring overnight at room temperature, the reaction was recharged with DME (5 mL), Pd(dba) (0.05 g, 0.05 mmol), and dppf (0.06 g, 0.1 mmol). After degassing the mixture, the reaction was capped and heated at 100 °C for 8 h. The reaction was cooled to room temperature, diluted with HO, and extracted with EA (3 times). The combined organic layers were dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% EA in cHex to give the title compound (393 mg), which was used in the next synthetic 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0647] [Table 31] 1Purification was by silica gel chromatography, eluting with 0% to 100% EA in cHex. 2 It was purified by silica gel chromatography eluting with 0%-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] A high-pressure flask was charged with 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)diboron (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). N was bubbled through the mixture for several minutes, then the flask was closed and the reaction was heated at 90 °C for 5.5 h. After cooling to room temperature, the reaction was diluted with HO and extracted with EA (3 times). The combined organic layers were dried over MgSO, filtered, concentrated, and the residue was purified by silica gel chromatography eluting with 0% to 80% EA in cHex to give the title compound (0.39 g, 82%) as a thick brown oil. MS ES+ m / z 376 [M+H] as the boronic acid + .

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

[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-dioxaborolane (61.0 g, 240.3 mmol) in 1,4-dioxane (500 mL) was degassed with N at room temperature for 15 minutes. KOAc (64.0 g, 652.1 mmol) was added, followed by the addition of Pd(dppf)Cl (6.0 g, 8.2 mmol) in several portions at 25°C under N. The mixture was degassed with N for 15 minutes. The reaction was stirred at 80°C under N for 12 hours. The reaction was cooled to 25°C and filtered through a DE. The filter cake was washed with 1,4-dioxane (3 x 100 ml). The filtrate was concentrated in vacuo at 45°C to give an oily black residue. The residue was purified by silica gel plug filtration (300 g, column diameter 12 cm). The plug was eluted with 20:1 to 3:1 c-Hex:EA to give 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 stirred solution of 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (20.0 g, 79.34 mmol) in 1,4-dioxane (200 mL) was treated with bis(pinacolato)diboron (30.22 g, 119.01 mmol), KOAc (23.36 g, 238.03 mmol), and Pd(dppf)Cl (2.90 g, 3.97 mmol) under N at room temperature. The reaction was stirred at 80 °C for 1 hour, after which the crude reaction mixture was used in the next synthetic 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0657] [Table 33]

[0658] [Table 34] 1 It was purified by silica gel chromatography eluting with 0%-50% EA in cHex. 2 It was purified by silica gel chromatography eluting with 0%-80% EA in cHex. 3 The compound resolves by MS. The MS data indicates a mixture of boronic ester and boronic acid. 4 The compound resolves by MS. The MS data is consistent with a boronic acid. 5 Xphos Palladacycle Gen 4 was used as the catalyst for this transformation. 6 Pd(dppf)Cl2.CH2Cl2 was used as the catalyst for this transformation. 7 The reaction was heated to 100.degree. aThe material was used in the subsequent step without further characterization. 8 Purified by silica gel chromatography eluting with EA in heptane.

[0659] Preparation 189 tert-Butyl (3S,4R)-4-[4-[3-chloro-4-[2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-fluoro-piperidine-1-carboxylate

[0660] [ka] To 6-bromo-3-chloro-4-[2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine (626 mg, 1.56 mmol) and bis(pinacolato)diboron (475 mg, 1.87 mmol) in dioxane (7 mL) was added Pd(dppf)Cl·CHCl (64 mg, 0.08 mmol) and KOAc (459 mg, 4.68 mmol) in portions at room temperature under N. The reaction was stirred at 100 °C under N for 2 h and then cooled to room temperature. Next, tert-butyl (3S,4R)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylate (534 mg, 1.47 mmol), K2CO3 (554 mg, 4.01 mmol), PdCl2(DtBPF) (44 mg, 0.07 mmol), and HO (2 ml) were added at room temperature under N2. The mixture was stirred at 100 °C overnight. Upon cooling to room temperature, the reaction was quenched by the addition of HO (100 ml). The mixture was extracted with EA (3 × 100 ml), and the organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0662] [Table 35] 1 It was purified by silica gel chromatography eluting with PE / EA (2:3 to 1:4). 2 It was purified by silica gel chromatography eluting with PE / EA (1:3 to 1:4). 3 It was purified by silica gel chromatography eluting with PE / EA (1:2 to 1:3). 4 It was purified by silica gel chromatography eluting with PE / EA (1:2 to 1:3).

[0663] Preparation 194 tert-Butyl 4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[0664] [ka] The mixture resulting 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 with tert-butyl 4-(4-bromo-5-methyl-triazol-1-yl)piperidine-1-carboxylate (27.70 g, 80.23 mmol), KCO (27.72 g, 200.57 mmol), PdCl(DtBPF) (2.18 g, 3.34 mmol), and HO (50 mL) at room temperature under N. The reaction was stirred at 80 °C for 1 h and cooled to room temperature. The reaction was diluted with HO (300 mL) and extracted with EA (3 × 300 mL). The combined organic layers were washed with brine (3 x 300 ml), dried over Na2SO4, filtered and concentrated to give the title compound (15.31 g, 44% yield over two steps) as a yellow solid. MS ES+ m / z 438 [M+H] + .

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

[0666] [ka] To 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) was added a solution of tert-butyl 4-(4-bromo-5-methyl-triazol-1-yl)piperidine-1-carboxylate (7.0 g, 20.28 mmol) in toluene (50 mL), followed by HO (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 continued for an additional 5 minutes. The reaction was heated at 90 °C for 18 hours. Upon cooling to room temperature, the reaction was concentrated in vacuo to remove most of the toluene. The residue was diluted with H2O to give 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 and the mixture was heated to 50°C and then cooled to room temperature. The yellow solid was collected by filtration to give 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 give the title compound (2.0 g, 24%) as an oily yellow solid. MS ES+ m / z 413.2 [M+H] + .

[0667] Preparation 196 tert-Butyl 4-[4-[3-cyano-4[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-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-carbonitrile (5.0 g, 12.81 mmol), tert-butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate (5.0 g, 14.53 mmol) in toluene (50 mL) was degassed with N for 5 minutes. Next, a solution of KCO (4.0 g, 28.94 mmol) in HO (12.5 mL) was added, and the mixture was degassed for an additional 5 minutes. PdCl(DtBPF) (500 mg, 0.77 mmol) was added, and the mixture was degassed with N while the reaction was heated to 60 °C. At this point, the N bubbling was stopped. The reaction was then heated to 100° C. under N 2 .

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

[0670] The following compounds were prepared in a manner essentially similar to that of Preparation 196, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed. KPO can be used in place of KCO.

[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 the catalyst for this transformation. 3 It was purified by silica gel chromatography eluting with 10%-100% EA in cHex. 4 Purified by silica gel chromatography eluting with 0% to 100% EA in hexanes followed by 0% to 20% MeOH in EA. 5 Purification was achieved by silica gel chromatography eluting with 0% to 100% EA in cHex. 6 Purification was carried out by silica gel chromatography eluting with EA / EtOH (30:1). 7 Dioxane was used as the solvent. 8 The reaction was heated at 80°C. 9 Workup: The reaction was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. 10 The product was purified by silica gel column chromatography eluting with PE / EA (10:1 to 3:1). 11 Purification was achieved by silica gel column chromatography eluting with 50% EA in PE. 12 Workup: The reaction was concentrated. The residue was slurried in H2O and the resulting insoluble material was collected by filtration. 13 It was purified by reversed-phase C18 chromatography eluting with 40%-60% ACN in H2O. 14 Workup: The reaction was diluted with H2O and extracted with EA. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. 15Purified by silica gel chromatography eluting with 20% EA in PE. 16 Workup: The reaction was concentrated. 17 It was purified by silica gel column chromatography eluting with 50%-75% EA in PE. 18 Purification was achieved by silica gel column chromatography eluting with 10% MeOH in DCM. 19 Pd(dppf)Cl was used as a catalyst for this transformation. The reaction was heated at 90 °C. 20 Purified by silica gel chromatography eluting with MeOH in DCM. 21 It was purified by silica gel column chromatography eluting with DCM / MeOH (15:1 to 10:1). 22 Purification was carried out by silica gel column chromatography eluting with DCM / MeOH (10:1).

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

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

[0676] [ka] A mixture of tert-butyl 2-(4-bromo-5-methyl-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate, tert-butyl 2-(4-bromo-3-methyl-pyrazol-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-carbonitrile (1.33 g, 3.41 mmol) in toluene (40 ml) and HO (4 ml) was treated with KCO (1.14 g, 8.25 mmol). After bubbling N2 through the reaction for 2 min, PdCl2(DtBPF) (135 mg, 0.21 mmol) was added and the tube was sealed. After stirring at 90 °C for 20 h, the reaction 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 give the title compound (621 mg, 74%) as a thick 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0678] [Table 39]

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

[0680] [ka] N was bubbled through 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 wt%), KCO (40 g, 289 mmol), and 4-(4-bromo-5-methyl-triazol-1-yl)-1-(oxetan-3-yl)piperidine (42.6 g, 135 mmol) in toluene (390 mL) and HO (116 mL). After 10 min, PdCl(DtBPF) (0.68 g, 1.04 mmol) was added, and N was bubbled through the reaction for an additional 5 min. The reaction was stirred at 90 °C for 8 h and then at room temperature for approximately 60 h. The reaction was diluted with HO (100 ml) and the mixture was concentrated to remove the toluene. The resulting suspension was stirred at room temperature for 15 minutes, filtered, and the solid was washed with HO (2 x 30 mL) to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0682] [Table 40] 1 Purified by silica gel chromatography eluting with 0% to 100% EA in cHex followed by 0% to 10% MeOH in DCM.

[0683] Preparation 219 tert-Butyl 4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl)piperidine-1-carboxylate

[0684] [ka] A solution of tert-butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-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 h, another portion of NSC (700 mg, 5.24 mmol) was added and stirring continued for another 24 h. The reaction was treated with HO (100 ml) and the layers were separated. The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 100% EA in cHex to give 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]triazol-4-yl]pyrazolo[1,5-a]pyridine

[0686] [ka] 4-Methoxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-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 N. After stirring at room temperature for 18 hours, additional NCS (6.5 g, 49 mmol) was added and stirred overnight. After dilution with HO (200 mL), the layers were separated, and the organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 10% MeOH in DCM to give the title compound (16 g, 45%) as an amber 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0688] [Table 41]

[0689] [Table 42] 1 Purification was achieved by silica gel chromatography eluting with 0% to 100% EA in cHex. 2 The reaction 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 step without purification. 6 Workup: The reaction was concentrated. 7 Workup: The reaction was quenched with 40% aqueous NaHSO3, the layers were separated, and the organic layer was dried over MgSO4, filtered, and concentrated. 8 Purification was by back-flush, eluting with 40%-50% MeOH in H2O. 9 Column: XB-Phenyl, 50 x 250 mm, 10 µm; eluted with 60-70% ACN in HO (10 mM NH-HO). 10 NBS was used instead of NCS. 11 Purification was by back-flush, eluting with 45%-55% ACN in H2O.

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

[0691] [ka] To a mixture of 4-methoxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (20 g, 45.75 mmol) in DMA (250 mL) was added NDM (21.9 mL, 91.51 mmol) and aqueous NaOH (7.25 mL, 137.3 mmol, 18.94 mol / L) under N. The reaction was degassed with N for 15 minutes and then heated at 50 °C for 2 hours. Upon cooling to room temperature, HO (2 L) was added. After stirring for 15 minutes, the pH was adjusted to 6.9 by the addition of aqueous HCl (10% w / w) followed by KHPO. The reaction was stirred for 15 minutes. The insoluble material was collected by filtration and washed with H2O (2 x 25 ml) to give the title compound as a light grey solid (11.0 g, 62% yield). MS ES+ m / z 380 [M+H] + .

[0692] Preparation 230 tert-Butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl)piperidine-1-carboxylate

[0693] [ka] To tert-butyl 4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (3.4 g, 7.5 mmol) in DMA (20 ml) under a N atmosphere was added NDM (5.5 ml, 23 mmol) and NaOH (18.94 mol / L) in HO (1.4 ml). The reaction was heated at 60° C. overnight. Upon cooling to room temperature, the mixture was diluted with HO (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 collected by filtration, and the solid was rinsed with HO to give the title compound (1.4 g, 43%). MS ES+ m / z 433 [M+H] + .

[0694] Preparation 231 tert-Butyl 4-[4-(3-cyano-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[0695] [ka] NaOH (50% aqueous solution) (36.57 g, 457.14 mmol) was added dropwise to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (40.00 g, 91.43 mmol) and NDM (55.51 g, 274.28 mmol) in DMA (400 ml) at 0 °C. The mixture was stirred at 50 °C for 8 h. The mixture was diluted with HO (400 ml), acidified to pH 6 with FA, filtered, and the filter cake was washed with HO and dried under vacuum. The solid was triturated with hexane (200 ml) and EtO (200 ml), filtered, and then stirred in MeOH (400 ml) at 60 °C for 2 h. The mixture was filtered and the filter cake was concentrated in vacuo to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0697] [Table 43] 1 Workup: The reaction was cooled to room temperature, then aqueous citric acid (3%) was added until the pH was approximately 5. The resulting insoluble material was isolated by filtration, triturated in cHex, filtered, and rinsed with cHEx followed by MTBE. 2 Workup: The reaction was neutralized to pH 7-8 with NH4Cl solution and concentrated in vacuo. The residue was treated with DCM and HO, the layers were separated, and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was triturated with heptane, filtered, and washed with heptane. 3 Workup: The reaction was cooled to room temperature, then aqueous citric acid (3%) was added. The resulting precipitate was isolated by filtration and washed with HO and then cHex. The solid was dissolved in DCM, then cHex was added. The solution was sonicated until a precipitate formed. The precipitate was collected by filtration. 4 It was purified by silica gel chromatography eluting with 0% to 50% acetone in DCM.

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

[0699] [ka] A solution of tert-butyl 4-[4-(3-cyano-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (50 g, 118.07 mmol) in MeOH (100 ml) was treated with 4 M HCl in MeOH (300 ml) at room temperature under N. The reaction was concentrated to give the title compound (40 g, HCl salt, crude) 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

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

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

[0703] [ka] A solution of 4-hydroxy-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (40 g, HCl salt, crude) in MeOH (300 mL) was basified to pH 12 with NaOH (5 g) and then acidified to pH 5-6 with AcOH (10 g) and then treated with 3-oxetanone (53.49 g, 742.21 mmol) at room temperature under N. After stirring at 50 °C for 2 h, the reaction was treated with NaBHCN (23.32 g, 371.10 mmol) at room temperature and then stirred at 50 °C for 2 h. After cooling to room temperature, the reaction was concentrated, and the residue was suspended in HO (500 mL) and basified to pH 8 with solid NaHCO. The suspension was filtered, the solid washed with MTBE (3 x 100 ml) and the solid lyophilized to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[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]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0707] [ka] To a suspension of 4-hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (1 g, 2.64 mmol) in ACN (10 ml) was added CsCO (1.12 g, 3.43 mmol). 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 was vigorously stirred at room temperature for approximately 8 hours. HO was added, and the suspension was stirred for 10 minutes and then allowed to stand overnight. The suspension was further diluted with HO and then filtered. The solid was rinsed with EA, followed by c-Hex, and then dried in vacuo to give the title compound (1.2 g, 83% yield). MS ES+m / z 517[M+H] + .

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

[0709] [ka] A solution of tert-butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-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) at room temperature under N. After stirring at 50 °C for 1 h, the reaction was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EA (1:1 to 1:2) to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed. Cs2CO3 can be used in place of DIPEA.

[0711] [Table 46]

[0712] [Table 47]

[0713] [Table 48]

[0714] [Table 49] 1 Purification was by reversed-phase flash C18 chromatography using the following conditions: column, C18; elution with 75%-80% CHCl in H2O. 2 It was purified by reversed-phase C18 chromatography eluting with 50%-60% CAN (0.1% FA) in H2O. 3 Workup: The reaction was concentrated, diluted with H2O and the insoluble material was collected by filtration. 4 Cs2CO3 was used as the base in this synthesis. 5 Purified by silica gel chromatography eluting with MeOH in DCM. 6 Purification was achieved by silica gel chromatography eluting with 5% (EA / EtOH 3:1) in cHex (2 CV), 5% to 50% (EA / EtOH 3:1) in cHex (20 CV), then 100% EA / EtOH (3:1). 7Workup: The reaction was concentrated, diluted with H2O and the insoluble material was collected 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 reaction was concentrated in vacuo. The residue was dissolved in H2O and acetone. The solution was concentrated until a solid precipitated. The suspension was stirred overnight, then the solid was collected by filtration. 10 Purification was by silica gel chromatography eluting with DCM (5 CV), 2% MeOH in DCM (15 CV), 5% MeOH in DCM (10 CV) and MeOH (5 CV). 11 Workup: H2O was added to the reaction and then concentrated. The residue was triturated in H2O and the insoluble material was collected by filtration. 12 Workup: The reaction was diluted with H2O and triturated for 30 min. The insoluble material was collected by filtration and washed with H2O, MTBE, and cHex. 13 Purification was achieved by silica gel chromatography eluting with 0% to 50% acetone in DCM (25 CV), 50% to 100% acetone in DCM (5 CV), then 100% acetone. 14 Workup: H2O was added to the reaction 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 reaction and then concentrated. The resulting suspension was diluted with H2O, triturated, and the insoluble material was collected by filtration. 16 Purified by silica gel chromatography eluting with 5% MeOH in DCM. 17 The isolated material was sonicated in 2M aqueous Na2CO3 for 10 minutes, then filtered and washed with water. 18Workup: H2O was added and the resulting precipitate was collected by filtration.

[0715] Preparation 269 tert-Butyl 4-[4-[3-cyano-4-[1-(1-isopropyltriazol-4-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[0716] [ka] CsCO (1.41 g, 4.31 mmol) was added to a degassed solution of tert-butyl 4-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-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 h. The reaction was diluted with EA (25 ml) and washed with HO (25 ml) and brine (25 ml). The organic layer was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give the title compound as a pale yellow oil (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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0718] [Table 50]

[0719] [Table 51] 1 Purified by silica gel chromatography eluting with MeOH in DCM. 2 It was purified by silica gel chromatography eluting with 20% to 100% EA in cHex. 3 Purification was achieved by silica gel chromatography eluting with 20% to 40% (3:1 EA:EtOH) in cHex. 4 Purification was achieved by silica gel chromatography eluting with 5% EA in 5% cHex (2 CV), 5% to 50% EA in cHex (20 CV), 50% to 100% EA in cHex (10 CV), then 100% EA. 5 Purification was achieved by silica gel chromatography eluting with 10% 3:1 EA / EtOH in cHex (3 CV), a 10% to 20% gradient 3:1 EA / EtOH in cHex (12 CV), 20% 3:1 EA / EtOH in cHex (2 CV), and a 20% to 50% gradient 3:1 EA / EtOH in cHex (18 CV). 6 Upon cooling to room temperature, the reaction was treated with H 2 O. The insoluble material was collected by filtration to give the title compound. a The material was used in the subsequent step without further characterization.

[0720] Preparation 281 tert-Butyl 4-[4-[4-[2-(3,5-difluoro-2-pyridyl)-2-methoxy-ethoxy]-3-fluoro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[0721] [ka] A solution of PPh3 (1.04 g, 3.96 mmol) in THF (10 ml) at 0 °C was treated dropwise with DIAD (0.77 g, 3.83 mmol) under N2. The reaction was stirred at 0 °C for 0.5 h and then added to a mixture of 2-(3,5-difluoro-2-pyridyl)-2-methoxy-ethanol (0.30 g, 1.59 mmol) and tert-butyl 4-[4-(3-fluoro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (0.55 g, 1.32 mmol) in THF (10 ml). The resulting mixture was stirred at room temperature for 2 h 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% to 55% CAN (0.1% FA) in H2O to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0723] [Table 52] 1 Purification was performed by flash reversed-phase C18 chromatography eluting with 30%-50% CHCl (0.1% NH4HCO3) in H2O. 2 It was purified by flash reversed-phase C18 chromatography eluting with 60%-70% CHCl in H2O.

[0724] Preparation 284 tert-Butyl 4-[4-[3-chloro-5-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,2-a]pyridin-7-yl]-5-methyl-triazol-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]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1.4 g, 2.54 mmol) in DMF (15 ml) at 0 °C was treated with DCDMH (400 mg, 2.03 mmol). After stirring at 0 °C for 0.5 h, 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 HO to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0727] [Table 53] 1 It was purified by reversed-phase C18 chromatography eluting with 45%-50% AcCN in H2O. 2 Purification was carried out by preparative TLC (PE / EA 1:3).

[0728] Preparation 287 tert-Butyl 4-[4-[3-cyano-4-[2-(3,5-difluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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-diphenylethyl methanesulfonamidate)ruthenium(II) (25 mg, 0.04 mmol, 98% by weight) was added to a stirred mixture of FA NEt complex (5:2 ratio) (18 mL, 42.21 mmol) and tert-butyl 4-[4-[3-cyano-4-[2-(3,5-difluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (3.5 g, 4.2 mmol) in DCM (14 mL, 218 mmol). The reaction was heated at 45° C. under N for 75 h. Upon cooling to room temperature, the reaction was diluted with DCM and washed with H O, saturated aqueous NaHCO, H O, and brine. The organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 20% acetone in DCM to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0731] [Table 54] 1 Purified by silica gel flash chromatography eluting with MeOH in DCM. 2 The crude material was used in the next step after aqueous workup.

[0732] Preparation 291 4-[2-(5-Fluoro-2-pyridyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-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]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (4.01 g, 6.58 mmol) in MeOH (65 ml) was added NaBH (1.0 g, 26.43 mmol) in one portion at 0 °C. The mixture was stirred at 0 °C for 5 minutes and then at room temperature for 1 hour. The reaction was diluted with HO (100 ml). The resulting precipitate was collected by filtration and washed with HO / MeOH (4:1) (20 ml). The resulting solid was dried under vacuum at 40 °C to give the title compound (3.40 g, 91%). MS ES+ m / z 519 [M+H] + .

[0734] Preparation 292 tert-Butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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-triazol-1-yl]piperidine-1-carboxylate (1 g, 1.75 mmol) in MeOH (20 ml) was treated with NaBH (66.37 mg, 1.75 mmol) at room temperature under N. After stirring at room temperature for 1 hour, the reaction was quenched with HO (50 ml) and extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (2 x 50 ml), dried over NaSO, filtered, and concentrated to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed. DCM can be used as a co-solvent.

[0737] [Table 55]

[0738] [Table 56] 1 Purification was achieved by silica gel chromatography eluting with 0% to 10% MeOH in DCM. 2 Purification was achieved by silica gel chromatography eluting with DCM (5 CV), 2% MeOH in DCM (10 CV), 5% MeOH in DCM (10 CV). 3 Purified by silica gel chromatography eluting with 0% to 40% (10% MeOH in DCM) in DCM. 4 Purified by silica gel chromatography eluting with 0% to 40% (10% MeOH in DCM) in DCM.

[0739] Preparation 307 tert-Butyl 4-[4-[4-[2-(3,5-difluoro-2-pyridyl)-2-hydroxy-propoxy]-3-fluoro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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-fluoro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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) pre-cooled at 0 °C under N. Additional DCM (2 mL) was added and the reaction was stirred overnight. The reaction was quenched with aqueous NH.sub.4Cl, extracted with DCM, and washed with HO and brine. The organic phase was concentrated to give a residue. The residue was purified by silica gel chromatography eluting with 0% to 20% acetone in DCM to give the title compound (175 mg, 0.25 mmol, 24%, 85% by weight) as a yellow oil. MS ES+ m / z 588 [M+H] + .

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

[0742] [Table 57] 1 Purified by silica gel chromatography eluting with 30% (10% MeOH in DCM) in DCM.

[0743] Preparation 309 tert-Butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridyl)-2-methylsulfonyloxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[0744] [ka] A solution of tert-butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (0.60 g, 0.74 mmol) in DCM (6 ml) was treated successively with NEt (0.152 g, 1.51 mmol) and MsCl (0.13 g, 1.2 mmol) at 0 °C. After 15 min, the cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 h, the mixture was washed with H O (1.5 ml), dried over MgSO and concentrated in vacuo to give 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-Butyl 4-[4-[3-cyano-4-[2-(3,5-difluoro-2-pyridyl)-2-isopropoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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-hydroxyethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1.0 g, 1.3 mmol, 75% by weight), AgO (600 mg, 2.59 mmol), and 2-iodopropane (2.6 mL, 26 mmol) in DMF (10 mL) was added NaH in mineral oil (62 mg, 1.55 mmol, 60% by weight) under N at room temperature. The reaction was stirred at room temperature for 10 minutes, and then additional NaH in mineral oil (62 mg, 1.55 mmol, 60% by weight) was added. Portions of NaH in mineral oil (62 mg, 1.55 mmol, 60% by weight) were added approximately every 10-20 min. After 90 min and seven NaH additions, HO was added to the mixture. The mixture was extracted with EA, and the organic phase was washed with brine (3 times), dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 20%-50% EA in cHex. The isolated material was repurified by silica gel chromatography eluting with 20% EA in MTBE. An impurity co-eluted with the title compound (720 mg, 56%, 63% pure). MS ES+ m / z 523 [M+H] + .

[0747] Preparation 311 tert-Butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (0.63 g, 0.78 mmol) in N,N-dimethylacetamide (6 mL) was treated with NaH (65 mg, 1.63 mmol, 60 wt%) followed by CHCl (0.08 mL, 1.28 mmol) at room temperature. After stirring at room temperature for 90 minutes, the reaction was quenched with MeOH (0.5 mL) and purified by reverse-phase C18 chromatography eluting with a gradient of 30% to 90% ACN in HO (NHHCO buffer pH 9) to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

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

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

[0752] [ka] A mixture of tert-butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridyl)-2-methylsulfonyloxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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 with a gradient of 0% to 100% acetone in DCM to give 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-carbonitrile hydrochloride

[0754] [ka] HCl in dioxane (4M, 2.0 ml, 5.98 mmol) was added to a solution of tert-butyl 4-(4-(3-cyano-4-(1-(1-isopropyl-1H-1,2,3-triazol-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-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 was concentrated in vacuo to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting the purification system as needed. For compounds in which the amine salt was isolated, the formation of a monovalent, divalent, or trivalent salt 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 triturated in EA, filtered and collected by filtration to give the title compound. 2 The reaction was concentrated in vacuo. The residue was diluted with EA and slurried for 1 h. The precipitate was collected by filtration.

[0759] Preparation 340 2-[3-chloro-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-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-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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 was concentrated and the crude product was used in the next synthetic 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting the purification system as needed. For compounds in which the amine salt was isolated, the formation of a monovalent, divalent, or trivalent salt 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 the subsequent step without further characterization.

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

[0766] [ka] tert-Butyl 4-[4-[3-cyano-4-[2-(2,4-difluorophenyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-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 was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was basified to pH 9 with saturated aqueous Na2CO3 (10 ml). The resulting solid was collected by filtration and washed with HO (3 x 50 ml) to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0768] [Table 65]

[0769] [Table 66] 1 Workup: The reaction was concentrated. The residue was dissolved in MeOH and applied directly onto an SCX cartridge pre-conditioned with MeOH. After washing off non-basic impurities with MeOH, the title compound was eluted with methanolic ammonia (2M). 2Workup: The reaction was concentrated. The residue was suspended in DCM and washed with 2M aqueous NaOH, then brine. The organic layer was dried over MgSO4, filtered and concentrated. 3 Workup: The reaction was concentrated. The residue was suspended in DCM and washed with aqueous NaOH (1 M). The layers were separated and 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 was concentrated, the residue was dissolved in DCM and saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated. 6 Workup: The reaction was concentrated. The residue was dissolved in MeOH and then treated with NaHCO3 to pH 8. The mixture was concentrated in vacuo.

[0770] Preparation 369a 6-[1-(7-Azaspiro[3.5]nonan-2-yl)-5-methyl-pyrazol-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]nonan-2-yl)-3-methyl-pyrazol-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-pyrazol-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-pyrazol-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 compounds were eluted with 2M NH3 in MeOH to give a mixture of the title compounds (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]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethyl]methanesulfonate

[0774] [ka] A solution of 4-[2-(5-fluoro-2-pyridyl)-2-hydroxyethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (1.39 g, 2.69 mmol) and NEt (0.80 mL, 5.7 mmol) in DCM (14 mL) was cooled to 0 °C and purged with N. The reaction was treated dropwise with MsCl (0.26 mL, 3.4 mmol). The reaction was allowed to warm slowly to room temperature. After 75 min, the reaction was recooled to 0 °C, quenched with HO (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 give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0776] [Table 67]

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

[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-carbonitrile (1.2 g, 3.28 mmol), bis(pinacolato)diboron (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) at 80° C. under N. The resulting mixture was stirred at 80° C. for 2 hours. The reaction was used in the next step without workup or purification.

[0779] The reaction was cooled and treated with KF (0.53 g, 9.38 mmol), 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)-1-(oxetan-3-yl)piperidine (1.20 g, 3.97 mmol), HO (4 ml), and PdCl(DtBPF) (0.10 g, 0.15 mmol) under N. After stirring at 100 °C for 2 h, the reaction was cooled to room temperature, quenched with HO (100 ml), and extracted with EA (2 × 100 ml). The combined organic layers were washed with brine (150 ml), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (100 to 20:1) to afford 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]triazol-4-yl]pyrazolo[1,5-a]pyridin-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)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanol hydrochloride (7.57 g, 11.0 mmol) in MeOH (76 mL) at room temperature was treated with oxetan-3-one (1.97 g, 27.3 mmol), AcOH (1.60 mL, 27.9 mmol), and NaCNBH (2.80 g, 44.6 mmol). After 48 hours, the reaction was quenched with saturated 1N KCO (150 mL) and extracted with DCM (300 mL). The organic phase was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0% to 100% acetone in DCM to give 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]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0783] [ka] To a vial was added 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-triazol-1-yl)-1-(oxetan-3-yl)piperidine (278 mg, 0.92 mmol), KCO (142 mg, 1.03 mmol), toluene (2 mL), and HO (200 μl). The vial was flushed with N, and then PdCl(DtBPF) (51 mg, 0.08 mmol) was added. The reaction was heated at 100 °C for 3 h. 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% (25% EtOH in EA) in cHex to give 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]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0785] [ka] 4-[1-(7-Fluoro-4-isoquinolyl)ethoxy]-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile 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 the solution were added 3-oxetanone (0.17 mL, 2.70 mmol), NaBHCN (172 mg, 2.74 mmol), and AcOH (0.37 mL, 6.43 mmol), sequentially, and the reaction was stirred at 70 °C for 2 h. Upon completion, the reaction was cooled to room temperature and diluted with EA. The mixture was washed with HO (25 mL) and brine (25 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give 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 the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[0787] [Table 68]

[0788] [Table 69] 1 4A molecular sieves and DIPEA were omitted from the reaction. 2 Purification was achieved by silica gel chromatography eluting with 0% to 10% MeOH in DCM. 3 Purification was achieved by silica gel chromatography eluting with 5% EA in cHex (2 CV), 5%-50% EA in cHex (20 CV), 50%-100% EA in cHex (5 CV), 100% EA (10 CV). 4 Purification was performed by C18 reverse-phase chromatography eluting with 45%–65% ACN in HO (10 mM NH4HCO3 buffer, pH 9): Column: XBridge C18, 19 × 150 mm, 5 μm. 5 Column: Luna Hilic, 30 x 150 mm, 5 μm, eluted with 10%-20% MeOH (10 mM NH4HCO3 pH 8). 6 It was purified by silica gel chromatography eluting with 10% to 50% acetone in DCM. 7 Column: Luna Omega Polar, 21 x 150 mm, 5 µm; elution with 25%-55% ACN (0.1% FA) in HO (0.1% FA). 8 Purification was achieved by silica gel chromatography eluting with 0% to 10% MeOH in DCM. 9 Purified by silica gel chromatography eluting with 50% (10% MeOH in DCM) 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]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

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

[0791] Example 13 4-[2-(5-Fluoro-2-pyridyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 1

[0792] [ka] and Example 14 4-[2-(5-Fluoro-2-pyridyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0793] [ka] NaBH4 (3.0 mg, 0.08 mmol) was added in one portion to a solution of 4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-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) at room temperature over 3 h. The reaction was quenched with saturated NH4Cl. The layers were separated, and the organic layer was washed with brine, dried over MgSO4, and filtered through a DE filter. The filtrate was concentrated to give 16 mg. The combined aqueous layer was extracted with DCM, and the organic layer was concentrated to give 5 mg. Both lots combined to give 21 mg. This material was subjected to the following chiral chromatography conditions: Column: Chiralpak AD, 30 x 250 mm, 5 μm; elution with 35% IPA (0.5% DMEA) in CO2 to give the title compound, Isomer 1 (9.0 mg, 32%) (t R 1.28 min, 98% ee. MS ES+ m / z 519 [M+H] + ), and the title compound, isomer 2, (9.2 mg, 32%) (t R 1.60 min, 85% ee. MS ES+ m / z 519 [M+H] + ) were obtained. Retention times were 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]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0795] [ka] t-BuOK (260 mg, 2.29 mmol) was added to a suspension of trimethylsulfoxonium iodide (545 mg, 2.40 mmol) in 2-methyl-2-butanol (0.1 M) at room temperature. The sealed vial was stirred at 50° C. under N for 90 minutes. 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]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 0.77 mmol) was added in one portion. The resulting mixture was vigorously stirred overnight at room temperature under N in a sealed tube. The suspension was then heated at 50° C. for 3 days and then stirred at room temperature for 3 days.

[0796] In a separate tube, t-BuOK (260 mg, 2.29 mmol) was added to a suspension of trimethylsulfoxonium iodide (545 mg, 2.40 mmol) in 2-methyl-2-butanol (0.1 M) at room temperature. The sealed vial was stirred under N at 50 °C for 90 min. The above reaction was added in one portion to this suspension, and the resulting mixture was stirred in a sealed tube under N at 50 °C overnight. The reaction was poured into saturated aqueous NH Cl and extracted with DCM, and the aqueous layer was extracted with DCM. The combined organic layers were washed with 1 N NaOH (twice), then HO, then brine, and dried over MgSO. The resulting residue was purified by reverse-phase chromatography (Claricep C-series column) eluting with 30% ACN (NHHCO3 pH 9) in HO (2 CV), followed by a linear gradient of 30% to 60% ACN (NHHCO3 pH 9) in HO (8 CV) and 60% ACN (NHHCO3 pH 9) in HO. Fractions containing the title compound were partially evaporated, DCM was added, and the biphasic mixture was passed through a hydrophobic filter. The filtrate was dried over MgSO4, filtered, and evaporated.

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

[0798] Example 16 6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]-4-[1-[5-(trifluoromethyl)pyridazin-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 PPh (539 mg, 2.06 mmol) in THF (10 ml) at 0 °C under N. The resulting mixture was stirred at 0 °C for 0.5 h and then added to 4-hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (600 mg, 1.58 mmol) and 1-[5-(trifluoromethyl)pyridazin-3-yl]ethanol (456 mg, 2.37 mmol) in THF (10 ml) and stirred overnight. The reaction was acidified to pH 5 with concentrated HCl, diluted with HO (80 ml), and extracted with EA (3 × 50 ml). The aqueous phase was basified to pH 8 with saturated aqueous NaHCO, extracted with CHCl:IPA (3:1) (3 x 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified under the following conditions: Column: XB-C18, 50 x 250 mm, 10 μm; Purification by reverse-phase chromatography using a gradient elution of 35% to 55% ACN in HO (10 mM FA) afforded the racemic title compound (345 mg, 39%) as a green solid. MS ES+ m / z 554 [M+H] + .

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

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

[0802] If retention times were obtained from an analytical column, the method is listed in the last column. See Table A for specific analytical conditions for each method.

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

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

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

[0806] The brown solid was purified under the following conditions: Chiral chromatography using a column: CHIRALPAK AD-H, 3 x 25 cm, 5 μm; elution with 40% MeOH in CO2 gave the title compound (163 mg, 36%). R The result was 5.77 minutes and 100% ee.

[0807] The following compounds were prepared in essentially a manner similar to that of Example 19, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed. CsCO and DMF can be used.

[0808] If retention times were obtained from an analytical column, the method is listed in the last column. See Table A for specific analytical conditions for each method.

[0809] [Table 71] 1 Purification was achieved by silica gel chromatography eluting with 0% to 50% EA (25% EtOH) in cHex. 2 Column: Chiralpak IA, 20 x 250 mm, 5 μm; eluted with 35% IPA (0.5% DMEA) in CO2. 3 It was purified by flash reversed-phase C18 chromatography eluting with 40%-70% ACN in H2O (NH5CO3 pH 9 buffer). 4 Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 35% IPA (0.5% DMEA) in CO2. 5 Chiralcel OJ, 20 x 250 mm, 5 μm; eluted with 20% MeOH (0.5% DMEA) in CO2. 6 It was purified by flash reversed-phase C18 chromatography eluting with 30%-60% ACN in H2O (NH5CO3 pH 9 buffer). 7 Column: Chiralcel OJ, 20 x 150 mm, 5 μm; eluted with MeOH (0.5% DMEA) in CO2. 8 It was purified by silica gel chromatography eluting with 20%-60% EA in cHex. 9 Column: Chiralcel OJ, 20 x 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 by silica gel chromatography eluting with 100% 3:1 EA / EtOH in cHex (10 CV). 11 Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 35% EtOH (0.5% DMEA) in CO2.

[0810] Example 26 4-[2-(5-Fluoro-2-pyridyl)-2-pyrrolidin-1-yl-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 1

[0811] [ka] and Example 27 4-[2-(5-Fluoro-2-pyridyl)-2-pyrrolidin-1-yl-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[0812] [ka] [2-[3-cyano-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-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 N. Pyrrolidine (183 mg, 0.002 mmol) was added. The reaction mixture was heated at 50° C. for 46 hours. The reaction 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 NaSO, and filtered. The filtrate was concentrated to give a brown oil (160 mg).

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

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

[0815] If retention times were obtained from an analytical column, the method is listed in the last column. See Table A for specific analytical conditions for each method.

[0816] [Table 72] 1The reaction was carried out in dimethylamine (2M) in THF at room temperature. 2 Column: Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 35% IPA (0.5% DMEA) in CO2. 3 Cs2CO3 was used as the base. 4 Column: XBridge C18, 19 x 150 mm, 5 µm; elution with 45%–75% ACN in HO (NH4HCO3 10 mM pH 9). 5 Column: Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 45% EtOH (0.5% DMEA) in CO2. 6 The mixture was refluxed for 5 hours and then stirred at room temperature for 10 days. 7 Purification was by reverse phase chromatography eluting with 0% to 50% (10% MeOH in DCM) in DCM (20 CV) then 50% (10% MeOH in DCM) in DCM (20 CV). 8 Column: Chiral Art Amylose C, 30 x 250 mm, 5 μm; eluted with 40% IPA (0.5% DMEA) in CO2.

[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-triazol-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-triazol-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-methoxy-ethoxy]-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine (350 mg, 0.72 mmol) in EtOH (3 mL), which was stirred at 80 °C overnight. Additional 3,6-dioxabicyclo[3.1.0]hexane (157 mg, 1.73 mmol) was added, and the reaction was stirred overnight. The reaction was diluted with DCM (50 mL) and washed with HO (2 × 20 mL) and brine (20 mL). The crude material was purified by silica gel chromatography eluting with MeOH in DCM to give a brown oil. The oil was subjected to SFC eluting with 55% (50% 2-propanol in ACN) (0.1% DEA) in CO. After chiral separation, both diastereomeric pairs were purified individually by flash chromatography, eluting with a gradient of MeOH in DCM. The material isolated from each purification was triturated with pentane and washed with pentane followed by Et.sub.2O to give the title compound, Isomer 1, (36 mg, 8%) (t R 6.46 min, 96% EE, MS ES+ m / z 572 [M+H] + ), and the title compound, isomer 2, (45 mg, 11%) (t R 6.86 min, 96% EE, MS ES+ m / z 572 [M+H] + (which is

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

[0821] [ka] To a stirred mixture of 2-[3-chloro-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridyl)ethanol 2,2,2 trifluoroacetic acid (800 mg, 1.37 mmol) in MeOH (20 ml) was added 3-oxetanone (611 mg, 8.48 mmol) at room temperature. The resulting mixture was stirred at 50 °C under N for 1 h. To the above mixture was added NaBHCN (426 mg, 6.78 mmol) in several portions at room temperature. The resulting mixture was stirred at 50 °C under N for an additional 2 h. Upon cooling to room temperature, the reaction was diluted with H O (50 ml) and the mixture was basified to pH 9 with saturated aqueous Na CO . The mixture was extracted with EA (3 × 150 ml). The combined organic layers were washed with brine (2 x 50 ml), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18; elution with 30%-35% ACN in HO (0.1% NHHO) to give the racemic title compound (420 mg, 58%) as a yellow solid. MS ES+ m / z 528 [M+H] + .

[0822] The yellow solid was prepared under the following conditions: CHIRAL ART Amylose-SA, 2 × 25 cm, 5 μm; 50% MeOH (10 mM NH 3 -MeOH); flow rate: 20 mL / min; 214 / 244 nm to give the title compound (140 mg, 19%), t R = 10.92, ee = 100%. 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-Isopropyltriazol-4-yl)ethoxy]-6-[5-methyl-1-(4-piperidyl)triazol-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), NaBHCN (406 mg, 6.46 mmol), and AcOH (0.89 mL, 15.50 mol) were added sequentially, and the reaction was stirred at 70 °C for 90 min. Upon cooling to room temperature, the reaction was diluted with EA. The mixture was washed with HO (1 × 25 mL) and brine (1 × 25 mL), dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give an off-white solid (490 mg, 73%). The off-white solid was subjected to SFC eluting with 50% EtOH (0.1% DEA) in CO to give the title compound (140 mg, 21%). RT is 6.93 min. MS ES+ m / z 517.3 [M+H] + .

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

[0826] If retention times were obtained from an analytical column, the method is listed in the last column. See Table A for specific analytical conditions for each method.

[0827] [Table 73]

[0828] [Table 74]

[0829] [Table 75]

[0830] [Table 76]

[0831] [Table 77]

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

[0833] Example 66 6-[3,5-Dimethyl-1-[1-(oxetan-3-yl)-4-piperidyl]pyrazol-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-dimethyl-pyrazol-1-yl)-1-(oxetan-3-yl)piperidine (73 mg, 0.23 mmol), and KCO (78 mg, 0.56 mmol) in toluene (0.85 mL) and HO (0.21 mL) were degassed under N by sonication. PdCl(DtBPF) (9 mg, 0.14 mmol) was added, the vessel was sealed, and the mixture was stirred at 80 °C overnight. The reaction was diluted with EA and HO. The layers were separated, and the organic layer was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 60% EtOH in EA (1:3) to give the title compound (91 mg, 76%) as a green solid. MS ES+ m / z 566 [M+H] + .

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

[0836] [Table 79] 1Workup: The reaction was concentrated. The residue was diluted with HO and 35% aqueous HCl was added to adjust the pH to 1. i-PrOH was added slowly until a solution was obtained. Charcoal was added and the reaction was stirred for 1 h. DE was added and stirred for 30 min. The suspension was filtered and the solid was washed with i-PrOH:HO (1:2). The pH of the filtrate was adjusted to 10 with aqueous NaOH (10 M). The resulting insoluble material was collected by filtration to give the title compound.

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

[0838] [ka] A pressure tube was charged with 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-triazol-1-yl)-1-(oxetan-3-yl)piperidine (0.17 g, 0.55 mmol), KCO (0.16 g, 1.12 mmol), toluene (8 mL), and HO (1 mL). The mixture was degassed by bubbling N through it for several minutes, then PdCl(DtBPF) (0.02 g, 0.03 mmol) was added and degassed for an additional 2 minutes. The tube was capped, and the reaction was heated to 95 °C for 6 hours. The reaction was cooled to room temperature, diluted with H2O, and extracted with EA (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 100% EA in cHex, then 0% to 5% MeOH in DCM to give a brown foam (184 mg, 65%). MS ES+ m / z 552 [M+H] + .

[0839] The brown foam was subjected to chiral chromatography using the following conditions: Column: Chiralpak IH, 3 x 100 mm, 3 μm; elution with 10% to 50% EtOH (0.2% IPAm) in CO2 to give the title compound (69 mg, 24%), t R 1.70, 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 essentially a manner similar to that of Example 68, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed. KPO and IPA can also be used.

[0841] If retention times were obtained from an analytical column, the method is listed in the last column. See Table A for specific analytical conditions for each method.

[0842] [Table 80] 1 Purification was by silica gel chromatography eluting with 0% to 100% (25% EtOH:EA) in cHex. 2 Column: Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 45% MeOH (0.2% DMEA) in CO2. 3 Column: Chiralpak IH, 3 x 100 mm, 3 µm; eluted with 10% to 50% EtOH (0.2% IPAm) in CO. 4 Column: Chiralpak IA, 3 x 100 mm, 3 µm; eluted with 25%-50% EtOH (0.2% IPAm) in CO. 5 The following conditions: column, C18; Purification was by reversed-phase flash C18 chromatography using 20%-60% ACN (NH5CO3 pH 9) in H2O. 6 Column: Chiralcel OD, 20 x 250 mm, 5 μm; eluted 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]pyrazol-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0844] [ka] A solution of 6-[5-methyl-1-(4-piperidyl)pyrazol-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 NEt (90 μL, 0.65 mmol) and ZnCl (10 mL, 0.02 mmol, 1.9 M in MeTHF), and the reaction was stirred at 50 °C. After stirring overnight, the reaction was cooled to room temperature and treated with NaBHCN (33 mg, 0.53 mmol). After stirring at 50 °C for 3 days, the reaction was quenched with HO and EA. The phases were separated, and the aqueous phase was extracted with EA. The organic layers were combined, dried over MgSO, filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 5% MeOH in DCM to give the title compound (50 mg, 66%) as an amber 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]pyrazol-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-methyl-pyrazol-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 treated with NEt (100 μL, 0.72 mmol), 3-oxetanone (25 μL, 0.43 mmol), and Na(OAc)BH (89 mg, 0.42 mmol) in DCE (3 mL). The reaction was stirred at room temperature for 16 h. An additional aliquot of 3-oxetanone (25 μL, 0.43 mmol) was added, and the reaction was stirred at 50 °C for 4 h. The reaction was diluted with EA (25 ml) and the organic layer was washed with saturated aqueous NaHCO3 (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 eluting with a gradient of 0% to 15% MeOH in DCM to give the title compound (26 mg, 31%) 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)azetidin-3-yl]triazol-4-yl]pyrazolo[1,5-a]pyridin-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)azetidin-3-yl]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(3,5-difluoro-2-pyridyl)ethanol (126 mg) was subjected to the following chiral chromatography conditions: Column: Amylose-C, 30 x 250 mm column, 5 μm; elution with 40% IPA in CO to give the title compound (32 mg, 25%). R 2.51, 90% ee, MS ES+ m / z 518.2 [M+H] + Retention times were obtained using analytical method H (see Table A for specific analytical conditions).

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

[0850] [Table 81]

[0851] [Table 82]

[0852] [Table 83] 1 Purified by silica gel chromatography eluting with MeOH in DCM. 2 SFC chromatography eluting with 60% 2-propanol (0.1% DEA) in 40% CO2. 3 SFC chromatography eluting with 60% MeOH (0.1% DEA) in 40% CO2. 4 Column: Chiralpak IE-3; 4.6 x 50 cm column, 3 μm; eluted with 50% EtOH (0.1% DEA) in MTBE. 5 Column: Chiral ART Cellulose-SB, 2 x 25 cm column, 5 μm; eluted with 10% EtOH in MTBE (10 mM NH3-MeOH). 6 Column: Chiral Art Amyl C, 30 x 250 mm, 5 μm; eluted with 45% EtOH (0.5% DMEA) in CO2. 7 Column: Amylose-C, 30 x 250 mm column, 5 μm; eluted with 45% EtOH (0.5% DMEA) in CO2. 8 Column: Chiralpak AD, 30 x 250 mm, 5 μm; eluted with 55% IPA (0.5% DMEA) in CO2. 9 Column: Chiral Art AmylC, 20 x 250 mm column, 5 μm; eluted with 60% IPA (0.5% DMEA) in CO2. 10 Column: Chiral Art Amylose C, 30 x 250 mm, 5 μm; eluted with 40% IPA (0.5% DMEA) in CO2.

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

[0854] [ka] To an ice-cooled solution of 2-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(3,5-difluoro-2-pyridyl)ethanone (190 mg, 0.19 mmol, 55% by weight) in DCM (4 mL) under N was added dropwise over 5 min a solution of MeMgBr (0.26 mL, 0.78 mmol, 3 M). The resulting mixture was stirred for 3 h, then diluted with DCM and slowly quenched with MeOH (2 mL). NaBH (5 mg, 0.132161 mmol) was added, and the mixture was stirred for 20 min. The reaction was purified by silica gel chromatography eluting with 0% to 50% DCM (10% MeOH in DCM). The material was crushed in a column and dissolved using 50% MeOH in DCM to elute the title compound along with impurities. The residue was further purified by reverse-phase chromatography eluting with 45% to 75% ACN in HO (10 mM NHHCO, pH 9) on a column: XBridge C18, 19 × 150 mm, 5 μm.

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

[0856] Example 89 1-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridin-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 EtO) was treated with ZnCl (0.09 ml, 0.2 mmol, 1.9 M in MeTHF) under N at 0 °C. After stirring at 0 °C for 1 h, the reaction was treated dropwise with a solution of 2-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridin-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 h. The reaction was diluted with DCM and slowly quenched with aqueous NH Cl. The reaction was passed through a phase separator and washed with DCM. The eluate was concentrated, and the residue was dissolved in MeOH (5 ml), treated with NaBH (15 mg, 0.40 mmol), and stirred at room temperature for 1 hour. The reaction was quenched with HO, the MeOH was removed in vacuo, extracted with DCM, washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 5% MeOH in DCM to give 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 CO to give the title compound (18 mg, 6%). R The m / z value was 2.64, 98% ee. 35 Cl / 37 Cl)556 / 558[M+H] + Retention times were obtained using analytical method M.

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

[0859] If retention times were obtained from an analytical column, the method is listed in the last column. See Table A for specific analytical conditions for each method.

[0860] [Table 84] 1 Purification was achieved by silica gel chromatography eluting with 0% to 40% DCM (9:1 DCM in MeOH). 2 Column: Chiralpak IH, 20 x 250 mm column (5 μm) eluted with 35% MeOH (0.5% DMEA) in CO2.

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

[0862] [ka] 4-[1-(6-Bromopyrazin-2-yl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-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, and then PdCl(DtBPF) (21 mg, 0.03 mmol) was added, and the mixture was stirred at 90 °C overnight. Upon cooling to room temperature, EA was added to the reaction. The mixture was washed with saturated aqueous NaHCO and brine. The organic phase was dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 20% to 100% EA in cHex to give a pale yellow solid (120 mg, 67%). The yellow solid was subjected to chiral chromatography using the following conditions: Column: Chiralpak IH, 20 x 250 mm, 5 μm; elution with 25% MeOH in CO (0.5% DMEA) to give the title compound (47 mg, 28%). R The result was 2.32 min, 97% ee. MS ES+ m / z 526 [M+H] +Retention times were obtained using analytical method N.

[0863] Example 93 6-[5-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3.5]nonan-2-yl]pyrazol-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]nonan-2-yl]pyrazol-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-methyl-pyrazol-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, 6-[1-(7-azaspiro[3.5]nonan-2-yl)-3-methyl-pyrazol-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (101 mg, 0.19 mmol) and oxetan-3-one (20 mg, 0.28 mmol) in MeOH (5 mL) was treated with AcOH (21 μL, 0.37 mmol) and NaBHCN (35 mg, 0.56 mmol) and stirred at room temperature for 2 h and then at 50 °C for 18 h. The reaction was cooled and then concentrated. The residue was suspended in saturated aqueous NaHCO3 and extracted with DCM (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 10% acetone in DCM to give a pale yellow solid containing two compounds. The compounds were separated using the following conditions: column, Chiralpak IH, 20 x 250 mm, 5 μm; column eluted with 20% MeOH in CO2 to give 6-[3-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3.5]nonan-2-yl]pyrazol-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 min (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 = 6.1 Hz, 2H), 2.29-2.18 (m, 11H), 1.71 (d, J = 6.4 Hz, 5H), 1.60 (t, J = 5.4 Hz, 2H) and 6-[5-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3.5]nonan-2-yl]pyrazol-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (14 mg, 14%) MS ES+ m / z 524 [M+H] + , t R = 1.69 min (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 essentially a manner similar to that of Example 94, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting purification systems as needed.

[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]triazol-4-yl]-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy-ethanol, isomer 1

[0869] [ka] A solution of (1S)-2-[3-bromo-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidyl]triazol-4-yl]pyrazolo[1,5-a]pyridin-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) in toluene (1.3 mL) was treated with aqueous KCO solution (1 M, 0.55 mL, 0.55 mmol) at room temperature and then heated to 90 °C. After 5 h, 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 HO (0.65 ml) were added. After 7 h, the reaction was cooled to room temperature, and EA (10 ml) was added. The layers were separated, and the organic phase was dried, filtered, and concentrated. The residue was purified by reverse chromatography, eluting with 20% to 60% ACN in aqueous NH4CO3 (pH = 9), to give 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-triazol-4-yl]-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0871] [ka] To 6-[1-[(3S,4R)-3-fluoro-4-piperidyl]-5-methyl-triazol-4-yl]-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile; hydrochloride (2 g, crude) in MeOH (20 mL) was added 3-oxetanone (1.49 g, 20.63) at room temperature under N. The resulting mixture was stirred at 50 °C for 60 min. NaBHCN (432 mg, 6.88 mmol) was then added at room temperature. The mixture was stirred at 50 °C for 2 h. Upon cooling to room temperature, the reaction was quenched with HO (30 mL) and the mixture was basified to pH 9 with saturated aqueous NaCO. The mixture was extracted with EA (2 × 80 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by C18 reverse flash chromatography, eluting with 30%-50% ACN in HO (0.1% NHHO) to give the title compound (1.4 g, 73.97%) as a white solid. MS ES+ m / z 551 [M+H] + .

[0872] Biological assays The following assays demonstrate that the compounds provided herein are FGFR2 inhibitors. The following assays demonstrate that certain compounds provided herein selectively target FGFR2 over FGFR1.

[0873] FGFR2 and FGFR1 enzyme assays FGFR1 and FGFR2 proteins were purchased from ThermoFisher Scientific (catalog numbers PR4660A and PR5332A, respectively). Enzyme activity was monitored using the KinEASE™-TK Assay Kit (CisBio, catalog number 62TK0PEC) according to the manufacturer's instructions. All assays were performed with the respective KmATP for each kinase in KinEASE™ Kinase Buffer. Reactions were performed in white, small-volume polystyrene 384-well plates.

[0874] Incubations were performed with each protein, 50 nM TK-biotin substrate (CisBio), 6.25 nM streptavidin-XL665 (CisBio), and 0.25× anti-phosphorylated TK-biotin-cryptate (CisBio). Final enzyme concentrations were 0.08 nM for FGFR1 and 0.04 nM for FGFR2 in a 10 μL reaction. Compound titration was performed using a 1:3 serial dilution in 100% dimethyl sulfoxide (DMSO) starting at 2.5 μM. Each protein and compound was preincubated for 15 min at room temperature before initiating the reaction with adenosine triphosphate (ATP). The reaction proceeded for 30 min at 30°C. The plate was quenched by adding an anti-TK-cryptate antibody / streptavidin-XL665 mixture. After 1 hour in stop solution, plates were read on an Envision plate reader (PerkinElmer) (Ex. Filter. 320 nm and Em1 665 nm / Em2 615 nm).

[0875] The ratio was converted to a percent of control (POC) using the specific emission coefficient. 100 POC was measured without test compound (DMSO alone) and 0 POC was measured in the presence of 2.5 μM of the appropriate control inhibitor. A four-parameter logistic curve was fitted to the POC values ​​as a function of compound concentration, and the IC50 value was the point where the best-fit curve intersected the 50 POC.

[0876] FGFR2 and FGFR1 cell-based assays HEK293 cells transfected with doxycycline (dox)-inducible human wild-type FGFR1 and human wild-type FGFR2 were seeded at 10,000 cells / well onto poly-D-lysine-coated 384-well plates (Becton Dickinson, catalog no. 356663) in Dulbecco's modified Eagle's medium (Sigma, catalog no. D5796) containing 10% FBS (Sigma, catalog no. F2442), 1% penicillin-streptomycin (Gibco, catalog no. 15140), and 1 μg / ml doxycycline and allowed to attach for 24 hours at 37°C and 5% CO2. NCI-H716 cells (ATCC, catalog no. CCL-251) were seeded at 5,000 cells / well onto poly-D-lysine-coated 384-well plates (Becton Dickinson, catalog no. 356663) in RPMI 1640 medium (Gibco, catalog no. A10491) containing 10% FBS and 1% penicillin-streptomycin and allowed to attach for 24 hours at 37°C and 5% CO2.

[0877] Cells were treated with compounds using 1:3 serial dilutions at a maximum final concentration of 3 μM. Compounds were incubated on the cells for 1 hour at 37°C, 5% CO2. Cells were fixed with formaldehyde for 20 minutes at room temperature and permeabilized with 0.3% Triton-X 100 for 15 minutes at room temperature. Cells were then blocked with 1% bovine serum albumin in 0.05% Tween for 1 hour at room temperature, and incubated with anti-phospho-FGFR primary antibodies (Cell Signaling, Cat. No. 52928 for HEK293 FGFR1, Millipore, Cat. No. 06-1433 for the rest of the cell lines) in blocking solution overnight at 4°C. The next day, cells were incubated with goat anti-rabbit IgG Alexa 488-labeled secondary antibody (Invitrogen, Cat. No. A11008) for 1 hour at room temperature, and a solution containing 0.4 μg / ml DAPI (Sigma, Cat. No. D9564) and 50 μg / mL ribonuclease A (Sigma, Cat. No. R-6513) was added to stain nuclei. The fluorescent plate was scanned with an Acumen Explorer laser scanning fluorescent microplate cytometer (SPT Labtech) to quantify cell number and FGFR phosphorylation, and the percentage of phospho-FGFR-positive cells was calculated.

[0878] A 100 POC was measured without test compound (DMSO alone) and a 0 POC was measured in the presence of 3 μM of the appropriate control inhibitor. A four-parameter logistic curve was fitted to the POC values ​​as a function of compound concentration to determine the IC. 50 The value was the point where the best fit curve intersected 50 POC.

[0879] Biological Assay Results In the above enzyme assay, all of the compounds of Examples 1 to 33, 35 to 60, and 62 to 99 had an IC value of less than 200 nM for FGFR2. 50 It presented value.

[0880] In the above enzyme assay, the compounds of Examples 1, 2, 4, 7, 9-11, 13-16, 18-24, 26-28, 31-35, 38, 40, 42-59, 61-67, 69, 71-73, 75-77, 79-85, 87-93, 95-97 and 99 all had an IC of less than 100 nM for FGFR2. 50 The antibody exhibits a potent anti-FGFR activity and is at least three-fold selective for FGFR2 over FGFR1.

[0881] In the above enzyme assay, the compounds of Examples 1, 2, 7, 9-11, 15-16, 18, 20-22, 27-28, 31, 33-34, 40, 42, 44, 47-53, 55-57, 61-67, 69, 71, 73, 79, 81-82, 87-89, 91, 92, 96 and 99 all had an IC of less than 50 nM for FGFR2. 50 The antibody exhibits a potent anti-FGFR2 activity and is at least 8-fold selective for FGFR2 over FGFR1.

[0882] In the above cell-based assay, all of the compounds of Examples 1 to 99 had an IC of less than 60 nM against FGFR2. 50 It presented value.

[0883] In the above cell-based assay, the compounds of Examples 1-14, 16-29, 31-40, 42, 44, 45, 47-71, 73-75, 77, 79, 81-82, 84, and 86-99 all had an IC of less than 30 nM for FGFR2. 50 The antibody exhibits a potent anti-FGFR activity and is at least 5-fold selective for FGFR2 over FGFR1.

[0884] In the above cell-based assay, the compounds of Examples 3-5, 7-9, 14, 16, 18-23, 28, 33, 42, 44, 51-53, 56, 60-63, 66-67, 69, 74-75, 77, 81, 88-89, 91, 95-97 and 99 all had an IC of less than 10 nM against FGFR2. 50 The antibody exhibits a potent anti-FGFR2 activity and is at least 10-fold selective for FGFR2 over FGFR1.

Claims

1. A compound of the formula: 【Chemistry 1】 During the ceremony, Z ２ but, 【Chemistry 2】 and A is R １ and R １Ａ a pyrazole, triazole, thiadiazole or oxadiazole substituted with R １ is hydrogen or C １ -C ３ is alkyl, R １Ａ is hydrogen, halo, CN, or halo, OH and OCH ３ C optionally substituted with one or more substituents independently selected from １ -C ３ is alkyl, X １ and X ２ is independently selected from N and C; X １ Or X ２ is N, then the other is C; X ３ is N or CH; X ４ But N or C-R ９ and Y is NH, O, S or a bond; Y １ is a bond, CHR ７ , C.H. ２ -CHR ７ , CHR ７ -CH ２ , C.F. ２ , C.H. ２ -CF ２ Or CF ２ -CH ２ and Y ２ is a bond, CHR ３ , C.H. ２ -CHR ３ , CHR ３ -CH ２ , C.F. ２ , C.H. ２ -CF ２ Or CF ２ -CH ２ and Y ３ But, CR ４ R ５ Or CF ２ and Y ４ But, CR ３ R ４ Or CF ２ and Y ５ But, CR １３ R １４ , C.R. １３ R １４ -CH ２ or CH ２ CR １３ R １４ and Y ６ But, CR １３ R １４ , C.R. １３ R １４ -CH ２ or CH ２ CR １３ R １４ and Z is a bond, CHR ９Ａ , C.R. ４ R ４Ａ , C.R. ４ R ４Ａ -CH ２ , C.H. ２ -CR ４ R ４Ａ , cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine; Z is a bond, CR ４ R ４Ａ , C.R. ４ R ４Ａ -CH ２ , C.H. ２ -CR ４ R ４Ａ , cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine; １ is a bond or Z is CHR ９Ａ If Z １ But, CH ２ Or CH ２ -CH ２ and Z ３ is a bond, C(O), SO ２ Or -NR ４ C(O), Z ４ is a bond, C(O), SO ２ Or -NR ４ C(O), R ２ But, C １ -C ５ Alkyl or R ８ And C １ -C ５ Alkyl is halo, OH, CN, oxo, -OC １ -C ４ Alkyl, -OC ３ -C ５ Cycloalkyl, -Z ３ -R １１ , and R １０ and optionally substituted with one or more substituents independently selected from １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl is halo, OH, OCH ３ , optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine, and CN; R ３ is hydrogen, F, OH, OCH ３ , C １ -C ３ alkyl, cyclopropyl, or one R ３ But, R ５ Or R ７ Condenses with CH ２ , C.H. ２ -CH ２ Or CH ２ OCH ２ Forming R ４ is hydrogen or C １ -C ３ is alkyl, R ４Ａ is hydrogen, halo, OH or C １ -C ３ is alkyl, R ５ is hydrogen, F, OH, OCH ３ , C １ -C ３ alkyl, cyclopropyl, or one R ３ Condenses with CH ２ , C.H. ２ -CH ２ Or CH ２ OCH ２ Forming R ６ But hydrogen, halo, C １ -C ５ alkyl, CN, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl, wherein the 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered aryl and 5- to 6-membered heteroaryl are halo, methyl, halomethyl, OH or OCH ３ and optionally substituted with one or more substituents independently selected from １ -C ５ Alkyl is selected from halo, OH and OCH ３ and optionally substituted with one or more substituents independently selected from R ７ is hydrogen, F, OH, OCH ３ , C １ -C ３ alkyl or one R ３ Condenses with CH ２ , C.H. ２ -CH ２ Or CH ２ OCH ２ Forming R ８ But, R ８Ａ 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl, optionally fused to or substituted with R ８Ａ is a 3- to 6-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl; R ９ is hydrogen, C １ -C ３ alkyl or R ９Ａ Condenses with CH ２ Or CH ２ -CH ２ Forming R １０ But, R ８Ａ 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl, optionally fused to or substituted with R １１ But, C １ -C ４ Alkyl, NH ２ , N.H.C. １ -C ３ Alkyl, NHC ３ -C ５ Cycloalkyl or N(C １ -C ３ Alkyl) ２ And C １ -C ４ Alkyl, C １ -C ３ Alkyl and C ３ -C ５ Cycloalkyl is halo, OH, OCH ３ , optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine, and CN; R １２ But, C １ -C ４ Alkyl, C ３ -C ５ Cycloalkyl, NH ２ , N.H.C. １ -C ３ Alkyl, NHC ３ -C ５ Cycloalkyl or N(C １ -C ３ Alkyl) ２ And C １ -C ４ Alkyl, C １ -C ３ Alkyl and C ３ -C ５ Cycloalkyl is halo, OH, OCH ３ , optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine, and CN; R １３ is hydrogen, halo or C １ -C ３ is alkyl, R １４ is hydrogen, halo or C １ -C ３ is alkyl, R ８ , R １０ and R ８Ａ But halo, OH, CN, -OC １ -C ４ Alkyl, -OC ３ -C ５ Cycloalkyl and -Z ４ -R １２ and optionally substituted with one or more substituents independently selected from １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl is halo, OH, OCH ３ , optionally substituted with one or more substituents independently selected from methylamine, N,N-dimethylamine and CN; or a pharma- ceutically acceptable salt thereof.

2. X １ is C and X ２ is N or X １ is N and X ２ or a pharma- ceutically acceptable salt thereof.

3. X １ is N and X ２ or a pharma- ceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein

4. X １ is C and X ２ is N, or a pharma- ceutically acceptable salt thereof.

5. X ３ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is CH.

6. A is R １ and R １Ａ 6. The compound according to claim 1, which is a pyrazole or triazole substituted with:

7. A is R １ and R １Ａ 7. The compound of claim 6, which is a triazole substituted with:

8. R １Ａ is hydrogen or halo, OH and OCH ３ C optionally substituted with one or more substituents independently selected from １ -C ３ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

9. R １Ａ is hydrogen or CH ３ 9. The compound of claim 8, which is: or a pharma- ceutically acceptable salt thereof.

10. R １Ａ 10. The compound of claim 9, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

11. R １ But, CH ３ 11. The compound according to any one of claims 1 to 10, wherein:

12. 12. The compound according to any one of claims 1 to 11, wherein Y is NH or O, or a pharma- ceutically acceptable salt thereof.

13. 13. The compound of claim 12, or a pharma- ceutically acceptable salt thereof, wherein Y is O.

14. R ６ CN, F, Cl, CH ３ , C.F. ３ or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

15. R ６ 15. The compound of claim 14, or a pharma- ceutically acceptable salt thereof, wherein is CN, F, or Cl.

16. R ６ or a pharma- ceutically acceptable salt thereof.

17. R ６ or a pharma- ceutically acceptable salt thereof.

17. The compound of claim 16, wherein:

18. 18. The compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein Z is a bond, cyclobutyl, azetidine, or piperidine.

19. 19. The compound of claim 18, or a pharma- ceutically acceptable salt thereof, wherein Z is a bond, azetidine, or piperidine.

20. 20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof, wherein Z is a bond.

21. Z is CHR ９Ａ And Z １ But, CH ２ and R ９ But, R ９Ａ Condenses with CH ２ 18. The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, which forms:

22. Z １ The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, wherein is a bond.

23. X ４ The compound according to any one of claims 1 to 20, wherein is N, or a pharma- ceutically acceptable salt thereof.

24. X ４ But, C-R ９ and R ９ is hydrogen or CH ３ 21. The compound according to any one of claims 1 to 20, wherein:

25. Y １ is a bond, CHR ７ , C.H. ２ -CHR ７ or CHR ７ -CH ２ and R ７ is hydrogen, F, OH and CH ３ 25. The compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, selected from:

26. Y ２ is a bond, CHR ３ , C.H. ２ -CHR ３ or CHR ３ -CH ２ and R ３ is hydrogen, F, OH and CH ３ 26. The compound according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, selected from:

27. Y ３ But, CR ４ R ５ Or CF ２ and R ４ is hydrogen or CH ３ and R ５ is hydrogen, F, OH or CH ３ 27. The compound according to any one of claims 1 to 26, wherein:

28. Y ３ But, CR ４ R ５ and R ４ is hydrogen, R ５ But one R ３ Condenses with CH ２ , C.H. ２ -CH ２ or CH ２ OCH ２ 27. The compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt thereof, which forms:

29. Y ４ But, CR ３ R ４ and R ４ is hydrogen or CH ３ and R ３ But, R ５ Condenses with CH ２ , C.H. ２ -CH ２ or CH ２ OCH ２ 30. The compound of claim 28, wherein the compound forms:

30. Y ４ But, CR ３ R ４ Or CF ２ and R ４ is hydrogen or CH ３ and R ３ is hydrogen, F, OH or CH ３ 28. The compound according to any one of claims 1 to 27, wherein:

31. Y ３ But, CR ４ R ５ and R ４ is hydrogen or CH ３ and R ５ is hydrogen or CH ３ 27. The compound according to any one of claims 1 to 26, wherein:

32. Y ５ But, CR １３ R １４ , C.R. １３ R １４ -CH ２ or CH ２ -CR １３ R １４ and R １３ and R １４ H and CH ３ and Y is independently selected from ６ But, CR １３ R １４ , C.R. １３ R １４ -CH ２ or CH ２ -CR １３ R １４ and R １３ and R １４ H and CH ３ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, independently selected from:

33. Y ５ But, CH ２ or CH ２ -CH ２ And Y ６ But, CH ２ or CH ２ -CH ２ 33. The compound of claim 32, wherein:

34. Y ５ and Y ６ But, CH ２ 33. The compound of claim 32, wherein:

35. R ２ 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 alkyl, C １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl is halo, OH, OCH ３ , methylamine, N,N-dimethylamine and CN; or a pharma- ceutically acceptable salt thereof.

36. R ２ but, 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 3】 is selected from C １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl is halo, OH, OCH ３ , methylamine, N,N-dimethylamine, and CN, ＊ 35. The compound of any one of claims 1 to 34, or a pharma- ceutically acceptable salt thereof, wherein: represents the point of attachment to Y.

37. R ２ but, 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】 is selected from C １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl is halo, OH, OCH ３ , methylamine, N,N-dimethylamine, and CN, ＊ 37. The compound of claim 36, or a pharma- ceutically acceptable salt thereof, wherein: represents the point of attachment to Y.

38. R １０ But, R ８Ａ 38. The compound of any one of claims 1 to 37, which is a 4- to 6-membered heterocycloalkyl or a 5- to 6-membered heteroaryl, optionally substituted with or fused to:

39. R １０ But, R ８Ａ 40. The compound of claim 38, which is a 5-6 membered heteroaryl optionally substituted with or fused to: or a pharma- ceutically acceptable salt thereof.

40. R １０ But, R ８Ａ 38. The compound of any one of claims 1 to 37, independently selected from cyclopropane, cyclobutane, cyclopropane, pyrrolidine, thiazole, pyrazole, triazole, phenyl, pyridine, pyrazine and pyridazine, optionally substituted with or fused with, or a pharma- ceutically acceptable salt thereof.

41. R １０ and R ８Ａ But halo, OH, CN, -OC １ -C ４ Alkyl, -OC ３ -C ５ Cycloalkyl and -Z ４ -R １２ and optionally substituted with 1, 2 or 3 substituents independently selected from １ -C ４ Alkyl and C ３ -C ５ Cycloalkyl is halo, OH, OCH ３ 41. The compound according to any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2 or 3 substituents independently selected from: N,N-dimethylamine, methylamine, N,N-dimethylamine and CN.

42. R １０ and R ８Ａ But F, Cl, CN, C １ -C ３ Alkyl, CH ２ F, C.H.F. ２ , C.F. ３ , -OCH ３ , -C(O)NH ２ And -S(O) ２ CH ３ 42. The compound of claim 41, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

43. R １０ and R ８Ａ But F, Cl, C １ -C ３ Alkyl, CH ２ F, C.H.F. ２ , C.F. ３ and -OCH ３ 43. The compound of claim 42, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

44. 【Chemical 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 The compound according to claim 1, selected from or a pharma- ceutically acceptable salt thereof.

45. 45. A pharmaceutical composition comprising a compound according to any one of claims 1 to 44, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent or excipient.

46. 45. A method of treating cancer comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 44, or a pharma- ceutically acceptable salt thereof.

47. The cancers include gastric cancer, hepatobiliary cancer, cancer of unknown primary site, gallbladder cancer, gallbladder adenocarcinoma, bile duct cancer, intrahepatic bile duct cancer, extrahepatic bile duct cancer, sarcoma, esophagogastric cancer, esophagogastric junction adenocarcinoma, remnant stomach adenocarcinoma, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, glioma, astrocytoma, oligodendroglioma, ependymoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, gastrointestinal stromal tumor, breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma and small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, gastric cancer 47. The method of claim 46, wherein the cancer is selected from the group consisting of gastric adenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, prostate cancer, prostate adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, colon adenocarcinoma, multiple myeloma, liver cancer, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, skin cancer, squamous cell skin cancer, melanoma, cutaneous melanoma, head and neck cancer, squamous cell carcinoma of the head and neck, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, salivary gland cancer, glioblastoma, endometrial cancer, endometrioid adenocarcinoma, cervical cancer, ovarian cancer, and epithelial ovarian cancer.

48. 47. The method of claim 46, wherein the cancer is selected from the group consisting of hepatobiliary cancer, cancer of unknown primary site, gallbladder cancer, gallbladder adenocarcinoma, cholangiocarcinoma, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, liver cancer, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, skin cancer, squamous cell skin cancer, melanoma, cutaneous melanoma, endometrial cancer, and endometrioid adenocarcinoma.

49. 47. The method of claim 46, wherein the cancer is selected from the group consisting of hepatobiliary cancer, gallbladder cancer, gallbladder adenocarcinoma, cholangiocarcinoma, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, liver cancer, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, endometrial cancer, and endometrioid adenocarcinoma.

50. The method of any one of claims 46 to 49, wherein the cancer is an FGFR2-associated cancer.

51. 45. A compound according to any one of claims 1 to 44, or a pharma- ceutically acceptable salt thereof, for use in therapy.

52. 45. A compound according to any one of claims 1 to 44, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

53. The cancers include gastric cancer, hepatobiliary cancer, cancer of unknown primary site, gallbladder cancer, gallbladder adenocarcinoma, bile duct cancer, intrahepatic bile duct cancer, extrahepatic bile duct cancer, sarcoma, esophagogastric cancer, esophagogastric junction adenocarcinoma, remnant stomach adenocarcinoma, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, glioma, astrocytoma, oligodendroglioma, ependymoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, gastrointestinal stromal tumor, breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma and small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, gastric cancer 53. The compound for use according to claim 52, or a pharmacologic agent selected from the group consisting of gastric adenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, prostate cancer, prostate adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, colon adenocarcinoma, multiple myeloma, liver cancer, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, skin cancer, squamous cell skin cancer, melanoma, cutaneous melanoma, head and neck cancer, squamous cell carcinoma of the head and neck, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, salivary gland cancer, glioblastoma, endometrial cancer, endometrioid adenocarcinoma, cervical cancer, ovarian cancer, and epithelial ovarian cancer, or a pharmacologic agent selected from the group consisting of ovarian cancer, gastric adenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, prostate cancer, prostate adenocarcinoma, colorectal cancer, colon adenocarcinoma, colon adenocarcinoma, multiple myeloma, liver cancer, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, skin cancer, squamous cell skin cancer, melanoma, cutaneous melanoma, head and neck cancer, squamous cell carcinoma of the head and neck, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, salivary gland cancer, glioblastoma, endometrial cancer, endometrioid adenocarcinoma, cervical cancer, ovarian cancer, and epithelial ovarian cancer, or a pharmacologic agent selected from the group consisting of ovarian cancer, gastric adenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma,

54. 53. The compound for use in the treatment of cancer according to claim 52, or a pharmacologic acceptable salt thereof, wherein the cancer is selected from the group consisting of hepatobiliary cancer, cancer of unknown primary site, gallbladder cancer, gallbladder adenocarcinoma, cholangiocarcinoma, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, liver cancer, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, skin cancer, squamous cell skin cancer, melanoma, cutaneous melanoma, endometrial cancer, and endometrioid adenocarcinoma.

55. 53. The compound for use according to claim 52, or a pharmacologic acceptable salt thereof, wherein the cancer is selected from the group consisting of hepatobiliary cancer, gallbladder cancer, gallbladder adenocarcinoma, cholangiocarcinoma, intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, liver cancer, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, endometrial cancer, and endometrioid adenocarcinoma.

56. 56. The compound, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer according to any one of claims 51 to 55, wherein the cancer is an FGFR2-associated cancer.

57. 45. Use of a compound according to any one of claims 1 to 44, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

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