Pyrazolo[1,5-a]pyridine and imidazo[1,2-a]pyridine derivatives as FGFR3 inhibitors for the treatment of cancer

Abstract

The present invention provides compounds of the formula as fibroblast growth factor receptor 3 (FGFR3) inhibitors for the treatment of, for example, cancer, systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal skeletal dysplasia, severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), and Muenke syndrome. Preferred compounds are, for example, pyrazolo[1,5-a]pyridine and imidazo[1,2-a]pyridine derivatives. [Formula 1] TIFF2025531794000267.tif29128

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.

[0002] It would be useful to develop new forms of FGFR3 inhibitors to treat cancer. Summary of the Invention

[0003] Provided herein are compounds of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Z, Z1, Z4, Z5, R 2 , and R 6 is as defined herein.

[0004] Provided herein are compounds of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Z', Z4, Z5, R 2 , and R 6 is as defined herein.

[0005] Provided herein are compounds of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Z4, Z5, R 2 , and R 6 is as defined herein.

[0006] Provided herein are compounds of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Z, Z1, Z4, Z6, R 2 , R 6 , and R 13 is as defined herein.

[0007] Provided herein are compounds of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Z', Z4, Z6, R 2 , R 6 , and R 13 is as defined herein.

[0008] Provided herein are compounds of the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Z4, Z6, R 2 , R 6 , and R 13 is as defined herein.

[0009] 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.

[0010] 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 FGFR3-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.

[0011] 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 FGFR3-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 FGFR3-associated cancer.

[0012] explanation Provided herein are compounds that are believed to have clinical use for the treatment of cancer, particularly for the treatment of FGFR3-associated cancers.

[0013] Certain compounds provided herein have superior FGFR3 potency compared to certain previously known FGFR inhibitors. Certain compounds provided herein have superior selectivity for FGFR3 over FGFR1 compared to certain previously known FGFR inhibitors, reducing potential dose-limiting toxicities (e.g., hyperphosphatemia) caused by inhibition of FGFR1.

[0014] The compounds provided herein are compounds of formula (I): [ka] During the ceremony, The Z5, [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 or CHR 7 -CH2, CF2, CH2-CF2 or CF2-CH2, Y2 is a bond, CHR 3 , CH2-CHR 3 or CHR3 -CH2, CF2, CH2-CF2, or CF2-CH2, Y3, CR 4 R 5 or CF2, Y4, CR 3 R 4 or CF2, Y5, CR 5A R 6A or 3- to 6-membered cycloalkyl; 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; Z1, Z 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, is a bond, or Z1 is CHR 9A is CH2 or CH2-CH2, Z2 is a bond, C(O), SO2, or -NR 4 C(O), Z3 is a bond, C(O), SO2, or -NR 4 C(O), Z4 is a bond, Y5-NR 15 , or CH2-Y5-NR 15 and NR 15 N is connected to Z5, Z6 is C=C or C≡C, and C=C is R 14 is optionally replaced by R 2 is C1-C5 alkyl or R8 wherein C1-C5 alkyl is halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z2-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 5A is hydrogen or C1-C3 alkyl, 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 6A is hydrogen or C1-C3 alkyl, 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, C1-C5 alkyl, or R 17wherein C1-C5 alkyl is halo, OH, CN, -OC1-C3 alkyl, NH2, NHC1-C3 alkyl, or N(C1-C3 alkyl)2, R 17 , N.R. 16 R 17 , and -OR 17 wherein the C1-C3 alkyl is optionally substituted with one or more substituents independently selected from halo, OH, OCH3, and CN; R 14 is F, CF3 or CN, R 15 is hydrogen or C1-C3 alkyl, R 16 is hydrogen or C1-C3 alkyl, R 17 is a 3- to 6-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, a 5- to 6-membered heteroaryl, or a 7- to 12-membered spiroheteroalkyl having 1 to 2 ring nitrogen atoms, and the 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl are R 17A and optionally fused to or substituted with R 17A 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 8 , R 10 , R 17 , R 8A and R 17A halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z3-R 12 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; or a pharmaceutically acceptable salt thereof.

[0015] In formulas (II) and (IIA), A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Z4, Z5, Z6, R 2 , R 6 , and R 13 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.

[0016] In formulas (III) and (IIIA), A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Z4, Z6, R 2 , R 6 , and R 13 is as defined above for formula (I), X4 is N or CR 9 and R 9 is hydrogen or C1-C3 alkyl.

[0017] 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.

[0018] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), X1 can be C and X2 can be N, forming: [ka] During the ceremony, *indicates the point of attachment to A in formula (I), (II), (III), (IA), (IIA), or (IIIA).

[0019] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), X1 can be N and X2 can be C, forming: [ka] During the ceremony, * indicates the point of attachment to A in formula (I), (II), (III), (IA), (IIA), or (IIIA).

[0020] 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: [ka] During the ceremony, * indicates the point of attachment to A in formula (I), (II), (III), (IA), (IIA), or (IIIA).

[0021] 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: [ka] During the ceremony, * indicates the point of attachment to A in formula (I), (II), (III), (IA), (IIA), or (IIIA).

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] As used herein, the term "heteroaryl" refers to an aromatic cyclic group having the indicated number of 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, isothiazolyl, oxadiazolyl, and thiadiazolyl. Examples of 6-membered heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0028] As used herein, the term "halogen" or "halo" refers to F (fluoro), Cl (chloro), Br (bromo), and I (iodo).

[0029] As used herein, the term "haloalkyl" refers to -CH3 in which one or more hydrogen atoms have been replaced with independently selected halo.

[0030] As used herein, the term "oxo" refers to the replacement of CH2 with O to form C(O).

[0031] As used herein, the term spiroheteroalkyl refers to a saturated spirocyclic group containing the indicated number of atoms selected from C, N, O, and S. For example, the term "7-12-membered spiroheteroalkyl having 1-2 ring nitrogen atoms" as used herein refers to a saturated spirocyclic ring system having 7, 8, 9, 10, 11, or 12 atoms, two of which are selected from N and the remainder are C. Examples of 7-12-membered spiroheteroalkyl having 1-2 ring nitrogen atoms include, but are not limited to, 2,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.4]octanyl, and 2,7-diazaspiro[3.5]nonanyl.

[0032] 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.

[0033] As used herein, the substituent -NR 4 C(O) is R through N 2 is connected to.

[0034] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A

[0042] The compound may be pyrazole, 1,2,3 triazole, 1,2,4 triazole, 1,2,3 thiadiazole, 1,2,4 thiadiazole, 1,2,5 thiadiazole, 1,3,4 thiadiazole, 1,2,3 oxadiazole, 1,2,4 oxadiazole, 1,2,5 oxadiazole, or 1,3,4 oxadiazole substituted with

[0035] 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

[0036] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A wherein R 1A is hydrogen and R 1 is C1-C3 alkyl.

[0037] 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.

[0038] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [ka] It can be, During the ceremony, * represents the point of attachment to Z, Z′ or X 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 a C1-C3 alkyl.

[0039] In the compound of formula (IIIA), A is [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 a C1-C3 alkyl.

[0040] In the compounds of formula (I), Z is CHR 9A , cyclobutyl, azetidine, pyrrolidine, or piperidine.

[0041] In the compounds of formula (I) or (IA), Z is a bond, [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).

[0042] In the compounds of formula (I) or (IA), Z is a bond, [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).

[0043] In the compounds of formula (I) or (IA), Z is CHR 9AZ1 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] In the compounds of formula (II) or (IIA), Z' is [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).

[0051] In the compounds of formula (II) or (IIA), Z' is [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).

[0052] In compounds of formula (I) or (IA), Z can be a bond.

[0053] In compounds of formula (II) or (IIA), Z' can be a bond.

[0054] In compounds of formula (I), (II), (IA), or (IIA), Z1 can be a bond.

[0055] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y can be NH or O.

[0056] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y can be O.

[0057] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Y is a bond, CHR 7 , CH2-CHR7 , 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.

[0058] 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.

[0059] 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 CH3, forming

[0060] [ka] 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).

[0061] In the compounds of formula (I), (II), (III), (IA), or (IIA), Y is a bond or CHR 7 R 7is hydrogen, F, OH, or CH3, and Y2 is a bond or CHR 3 R 3 is hydrogen, F, OH, or CH3, forming [ka] 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).

[0062] 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 CH3, forming [ka] 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) or (IIIA).

[0063] (IIIA).

[0064] 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, forming [ka] 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) or (IIIA).

[0065] In the 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.

[0066] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1A can be hydrogen or CH3.

[0067] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1A can be hydrogen.

[0068] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1 can be methyl, ethyl, or propyl.

[0069] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 1 can be methyl.

[0070] In the 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 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.

[0071] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 is F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R 10 and may be a C1-C3 alkyl optionally substituted with one or more substituents independently selected from:

[0072] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 teeth, [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).

[0073] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 teeth, [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).

[0074] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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).

[0075] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 2 teeth, [ka] It can be, These are 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).

[0076] 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.

[0077] 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.

[0078] 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 R 4 or CF2, and R 4 is hydrogen or CH3, and R 3 is hydrogen, F, OH, or CH3.

[0079] 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.

[0080] 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 to form: [ka] 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).

[0081] In the compound of formula (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 CH, CH-CH, or CHOCH to form: [ka] 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) or (IIIA).

[0082] In the compounds of formula (I), (II), (III), (IA), or (IIA), X4 is N or CR 9R 9 is hydrogen or CH3.

[0083] 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.

[0084] In compounds of formula (I), (II), (III), (IA), or (IIA), X4 can be N or CH.

[0085] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 can be CN, F, Cl, CH3, CF3, or cyclopropyl.

[0086] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 can be CN, F, Cl, or CF3.

[0087] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 can be CN or Cl.

[0088] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 can be CN.

[0089] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 6 can be Cl.

[0090] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 8 is R 8AThe aryl group may 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:

[0091] In the 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:

[0092] In the 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

[0093] In the 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 fused with

[0094] In the 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 fused with 8A can be phenyl or a 6-membered heteroaryl.

[0095] In the compounds of formula (I), (II), (III), (IA), or (IIA), R 9 can be hydrogen.

[0096] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R10 is R 8A and optionally fused to 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.

[0097] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is R 8A The 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.

[0098] In the 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, oxozolidin-2-onyl, isothiazolidin-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0099] In the 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, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0100] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is R 8A The substituent 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.

[0101] In the 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.

[0102] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 can 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.

[0103] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0104] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0105] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 can be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl.

[0106] In the 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.

[0107] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is R 8AThe group may be fused with or substituted by cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, or pyridinyl.

[0108] In the 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.

[0109] In the 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.

[0110] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 10 is R 8A The group may be cyclopentyl, cyclohexyl, phenyl, or pyridinyl fused with or substituted by.

[0111] In the 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.

[0112] In the 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 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.

[0113] In the 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 tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0114] In the 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 tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolidin-2-onyl, or isothiazolidin-2-onyl.

[0115] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 It may be an optionally substituted C=C.

[0116] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 It may be C=C substituted with

[0117] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 may be C=C substituted with R 14 is F or CN.

[0118] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 can be C=C.

[0119] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0120] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 13 can be hydrogen or C1-C3 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0121] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 can be C≡C, and R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0122] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z4 can be a bond.

[0123] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14and Z4 can be a bond.

[0124] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 and Z4 may be a bond.

[0125] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 may be C=C substituted with R 14 is F or CN, and Z4 can be a bond.

[0126] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 can be C=C and Z4 can be a bond.

[0127] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0128] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 Z4 may be a bond, and R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0129] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R14 Z4 can be a bond; R 13 can be hydrogen or C1-C3 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0130] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 Z4 may be a bond, and R 13 can be hydrogen or C1-C3 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0131] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 is R 14 may be C=C substituted with R 14 is F or CN, Z4 can be a bond, R 13 can be hydrogen or C1-C3 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0132] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 can be C=C, Z4 can be a bond, and R 13 can be hydrogen or C1-C3 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0133] In compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), Z6 can be C≡C, and R 13 can be hydrogen or C1-C5 alkyl, where C1-C5 alkyl is optionally substituted with one or more substituents independently selected from halo, OH, and CN, and Z4 can be a bond.

[0134] In a compound of formula (I) or (IA), when Z and Z1 are both bonds, they together form a single bond.

[0135] 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 and condenses with CH to form: [ka] During the ceremony, * indicates the connection point to A.

[0136] In the compounds of formula (I), (II), (III), (IA), or (IIA), R 5 is one R 3 to form CH-CH, for example to form: [ka] 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).

[0137] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R 5 is one R 3 to form CH-CH, for example to form: [ka] 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).

[0138] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), R8 is R 8A and R 8A may be pyridinyl, for example, forming [ka] During the ceremony, * indicates the connection point to Y.

[0139] 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.

[0140] 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.

[0141] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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.

[0142] In the compound of formula (IIIA), A is [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.

[0143] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A and Y can be O.

[0144] In the compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), A is R 1 and R 1A R may be 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.

[0145] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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.

[0146] In the compound of formula (IIIA), A is [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.

[0147] 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.

[0148] 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 a C1-C3 alkyl, and R 6 can be CN, F, Cl, or CF3.

[0149] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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.

[0150] In the compound of formula (IIIA), A is [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.

[0151] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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.

[0152] In the compound of formula (IIIA), A is [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.

[0153] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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.

[0154] In the compound of formula (IIIA), A is [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 6 can be CN or Cl.

[0155] 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.

[0156] 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 a C1-C3 alkyl, and R 6 can be CN, F, Cl, or CF3, and Y can be NH or O.

[0157] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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.

[0158] In the compound of formula (IIIA), A is [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 NH or O.

[0159] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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.

[0160] In the compound of formula (IIIA), A is [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.

[0161] 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 O.

[0162] 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 a C1-C3 alkyl, and R 6 can be CN, F, Cl, or CF3, and Y can be O.

[0163] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 O.

[0164] In the compound of formula (IIIA), A is [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 O.

[0165] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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.

[0166] In the compound of formula (IIIA), A is [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, and Y can be O.

[0167] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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, and Y can be O.

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

[0169] 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 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.

[0170] 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 F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R 10 and may be a C1-C4 alkyl optionally substituted with one or more substituents independently selected from:

[0171] 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 CF; Y can be NH or O; R 2 teeth, [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).

[0172] 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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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).

[0173] 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 CF; Y can be NH or O; R 2 teeth, [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).

[0174] 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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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).

[0175] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 2is 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.

[0176] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 may be a C1-C4 alkyl optionally substituted with one or more substituents independently selected from:

[0177] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [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).

[0178] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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).

[0179] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [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).

[0180] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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).

[0181] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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).

[0182] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth, [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).

[0183] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth, [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).

[0184] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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; and Z6 is R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0185] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 Z6 can be C1-C4 alkyl optionally substituted with one or more substituents independently selected from R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0186] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These include halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 , and R 10and 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). Z6 represents R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0187] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC cycloalkyl, and R 10 and optionally 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 Z6 represents R 14 Z4 can be a bond; R 13is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0188] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [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). Z6 represents R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0189] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC cycloalkyl, and R 10 and optionally 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 Z6 represents R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0190] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC cycloalkyl, and R 10 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from: * represents the point of attachment to Y in formula (IIIA), and Z6 represents R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0191] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth, [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; * represents the point of attachment to Y in formula (IIIA), and Z6 represents R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0192] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC cycloalkyl, and R 10 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from: * represents the point of attachment to Y in formula (IIIA), and Z6 represents R 14 Z4 can be a bond; R 13 is hydrogen, C1-C5 alkyl, or R 17 C1-C5 alkyl can be selected from halo, OH, CN, and R 17 is optionally substituted with one or more substituents independently selected from

[0193] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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; Z6 can be C≡C; R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0194] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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, CH3, CF3, or cyclopropyl; Y can be NH or O; R 2 is F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl, and R 10 and Z6 can be C≡C; R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0195] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [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; * indicates the point of attachment to Y in formula (I), (II), (III), (IA), or (IIA), Z6 can be C≡C, R 13can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0196] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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), Z6 can be C≡C, R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0197] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be,

[0198] 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; * indicates the point of attachment to Y in formula (I), (II), (III), (IA), or (IIA), Z6 can be C≡C, R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0199] In the compounds of formula (I), (II), (III), (IA), or (IIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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), Z6 can be C≡C, R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0200] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth,

[0201] [ka] Possibly, These are F, OH, CN, oxo, -OCH, -OC 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), Z6 can be C≡C, R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0202] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth, [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), Z6 can be C≡C, R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0203] In the compound of formula (IIIA), A is [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 CF; Y can be NH or O; R 2 teeth, [ka] It can be, These are F, OH, CN, oxo, -OCH, -OC 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), Z6 can be C≡C, R 13 can be hydrogen or C1-C5 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

[0204] In one embodiment, the compound of formula (I) is [ka] [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof; During the ceremony, * The bond at position [ka] It is expressed as:

[0205] For example, for a compound of the formula: [ka] (In the formula, * The bond at position [ka] ), the following compounds: [ka] Form.

[0206] In a further embodiment, the compound of formula (I) is [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof, wherein the bond is [ka] and indicates the E or Z isomer.

[0207] For example, for a compound of the formula: [ka] (wherein the bond is [ka] ), the following compounds: [ka] Form.

[0208] In a further embodiment, the compound of formula (I) is [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0209] In a further embodiment, the compound of formula (I) is [ka] [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0210] In a further embodiment, the compound of formula (I) is [ka] or selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0211] 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 alkyls where one to a maximum number of hydrogens present may be replaced with deuterium. For example, C2D x H 5-x When one to five hydrogens in, for example, C2H5 are replaced with deuterium, ethyl refers to both C2H5 or C2H5.

[0212] 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).

[0213] 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)).

[0214] 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.

[0215] 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.

[0216] The compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, described herein may be components of pharmaceutical compositions for the treatment of cancer, with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally one or more additional therapeutic agents.

[0217] The compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, described herein may be components of pharmaceutical compositions for the treatment of cancer, with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally one or more additional therapeutic agents.

[0218] The compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, provided herein may be combined with one or more other therapeutic agents for simultaneous, separate, or sequential administration.

[0219] 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.

[0220] 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 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.

[0221] Certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR3. For example, certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR3 over another FGFR. For example, certain compounds of formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR3 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 FGFR3 over FGFR1.

[0222] 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 value is expressed as the IC of the same compound against the primary target (e.g., FGFR3). 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.

[0223] 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.

[0224] As used herein, the term "FGFR3-associated cancer" refers to cancers that have dysregulated expression, activity, or levels of the FGFR3 gene, FGFR3 kinase, or any of them. Examples of FGFR3-associated cancers include 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, high-risk non-muscle-invasive bladder cancer, intermediate-risk non-muscle-invasive bladder cancer, Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer, Bacillus These include, but are not limited to, Calmette-Guerin (BCG) recurrent non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), upper urinary tract cancer (e.g., urothelial upper urinary tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., oral cancer), thyroid cancer, kidney cancer (e.g., renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

[0225] As used herein, the term "treating" (or "treatment") refers to inhibiting, slowing, halting, or reversing the progression or severity of an existing symptom, condition, or disorder.

[0226] As used herein, the term "patient" refers to a mammal, particularly a human.

[0227] Provided herein are compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in therapy.

[0228] 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.

[0229] Provided herein is a compound of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, for use in treating an FGFR3-associated cancer, wherein the FGFR3-associated cancer is non-muscle-invasive bladder cancer.

[0230] 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 an FGFR3-associated cancer, wherein the FGFR3-associated cancer is intermediate-risk non-muscle-invasive bladder cancer.

[0231] Provided herein is a compound of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, for use in treating an FGFR3-associated cancer, wherein the FGFR3-associated cancer is Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer or Bacillus Calmette-Guerin (BCG)-recurrent non-muscle-invasive bladder cancer.

[0232] 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 an FGFR3-associated cancer, wherein the FGFR3-associated cancer is high-risk non-muscle-invasive bladder cancer.

[0233] 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 an FGFR3-associated cancer.

[0234] 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 an FGFR3-associated cancer, wherein the FGFR3-associated cancer is non-muscle-invasive bladder cancer.

[0235] 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 an FGFR3-associated cancer, wherein the FGFR3-associated cancer is intermediate-risk non-muscle-invasive bladder cancer.

[0236] 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 an FGFR3-associated cancer, wherein the FGFR3-associated cancer is Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer or Bacillus Calmette-Guerin (BCG)-recurrent non-muscle-invasive bladder cancer.

[0237] 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 an FGFR3-associated cancer, wherein the FGFR3-associated cancer is high-risk non-muscle-invasive bladder cancer.

[0238] 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.

[0239] The cancers provided in the methods and uses herein include stomach cancer. 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, high-risk non-muscle invasive bladder cancer, intermediate-risk non-muscle invasive bladder cancer, Bacillus Calmette-Guerin (BCG)-non-responsive non-muscle-invasive bladder cancer, Bacillus Calmette-Guerin (BCG)-recurrent non-muscle-invasive bladder cancer, muscle-invasive bladder cancer), gastric 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 origin, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), esophagogastric cancer (e.g., esophagogastric junction adenocarcinoma, remnant 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., invasive 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., invasive ductal carcinoma, invasive lobular carcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma), and endometrial cancer (e.g., endometrioid adenocarcinoma).

[0240] The term "NMIBC" or "non-muscle invasive bladder cancer" means bladder cancer staged as T0, Ta, T1, or CIS according to the Tumor, Node, Metastasis Classification (TNM). The term "T0" refers to stage 1 of the disease where there is no evidence of a primary tumor according to the Tumor, Node, Metastasis Classification (TNM). The terms "Ta," "T1," "T2," "T3," and "T4" refer to the size or extent of the primary tumor according to the Tumor, Node, Metastasis Classification (TNM).

[0241] The terms "intermediate-risk non-muscle-invasive bladder cancer," "intermediate-risk NMIBC," or "IR NMIBC" refer to multiple or recurrent low-grade Ta tumors. The following factors to consider are the number of tumors, e.g., more than one; tumor size, e.g., greater than 3 cm; timing, e.g., recurrence within one year; frequency of recurrence, e.g., more than one recurrence per year; and previous treatment.

[0242] The terms "high-risk non-muscle-invasive bladder cancer," "high-risk NMIBC," or "HR NMIBC" refer to recurrent, bacillus Calmette-Guerin (BCG)-unresponsive, high-grade, T1 or CIS tumors, where the recurrence may be after BCG treatment. The following factors to consider are tumor grade, tumor size, such as greater than 3 cm, timing, such as recurrence within one year, frequency of recurrence, such as more than one recurrence per year, and previous treatment.

[0243] The compounds provided herein can be prepared as illustrated in the following preparations and examples.

[0244] Scheme A [ka]

[0245] Scheme A shows two methods for the preparation of (A5), which is further produced in Formula 6. Scheme A also shows the preparation of (A6), which is further produced in Formula 1. In the first method for the preparation of (A5), R 10 is pyridyl, treatment of (A1) with i-PrMgCl, followed by addition of aldehyde (A4), can give alcohol (A5). In a second method for the preparation of (A5), 10

[0047] Treatment of (A1), where A1 is pyridyl, with i-PrMgCl, followed by the addition of 2-(benzyloxy)-N-methoxy-N-methylacetamide (A2) can provide ketone (A3). Reduction of ketone (A3) with sodium borohydride can provide alcohol (A5). In some cases, the enantiomers of alcohol (A5) can be separated by chiral chromatography. Scheme A also shows the preparation of tosylate (A6). Reaction of alcohol (A5) with 4-methylbenzenesulfonyl chloride in the presence of a base can provide tosylate (A6). Alcohol (A5) or tosylate (A6) can be further elaborated to compounds of Formula 1.

[0246] Scheme B [ka]

[0247] Scheme B shows two methods for the preparation of (B6), which is further elaborated in Equations 1, 2, 3, 4, 9, and 10. In the first method, amine (B1) can be treated with 1H-imidazole-1-sulfonyl azide hydrochloride in the presence of base and CuSO₄·HO to provide azide (B2). Reaction of (B2) with ethyl acetoacetate yields ester (B3), which is then hydrolyzed to give carboxylic acid (B4). Treatment of (B4) with bromine under basic conditions can provide bromide (B6). Alternatively, azide (B2) can be reacted with trimethyl(prop-1-yn-1-yl)silane to give trimethylsilyl (B5), which is then treated with NBS in the presence of SiO₂ to give (B6).

[0248] Scheme C [ka]

[0249] Scheme B shows three methods for the preparation of (C10), which is further elaborated in Formula 12. In the first method, deprotection of (B6) under acidic conditions can yield (C1), which can be subjected to reductive amination conditions with an appropriate aldehyde (C2) to afford (C10). In the second method, treatment of compound (C3) with LDA and an appropriate alkylating agent can yield compound (C4). This compound can then be deprotected under acidic conditions to provide (C5). Alkylation of (C5) can be achieved by reaction with triflate (C7) to form (C10). The triflate (C7) used in the alkylation of (C5) can be formed in situ by reacting alcohol (C6) with trifluoromethanesulfonic anhydride. In the third method, reaction of ABr with an appropriate mesylate (C8) can provide (C9). Treatment of (C9) with LDA and an appropriate alkylating agent can provide (C10).

[0250] Scheme D [ka]

[0251] Scheme D shows a method for the preparation of (D6), which is further elaborated in Formula 6. Formation of azide (D2) can be achieved by reacting alcohol (D1) with PPh3 and DEAD, followed by DPPA. Reaction of azide (D2) with ethyl acetoacetate can yield (D3). Hydrolysis of (D3) under basic conditions can yield acid (D4), which can then be subjected to bromination under basic conditions to provide bromide (D5). Removal of the protecting group from (D5) in the presence of FeCl3 can yield alcohol (D6).

[0252] Scheme E [ka]

[0253] Scheme E shows a preparation for a compound of Formula 1. Treatment of (E1) with bis(pinacolato)diboron under palladium catalysis can provide boronic ester (E2). From this intermediate, compounds of Formula 1 can be accessed using two different methods. In the first method, boronic ester (E2) can be reacted with an appropriate bromide (B6) under palladium catalysis to provide (E6). In the second method, boronic ester (E2) can be reacted with (B3) under palladium catalysis to provide (E4), which is then subjected to acidic conditions to remove the protecting group to provide amine (E5). Reaction of amine (E5) with an appropriate ketone under reductive amination conditions can provide (E6). Deprotection of (E6) under acidic conditions can yield amine (E7). From this intermediate, compounds of Formula 1 can be accessed using three methods. In a first method, treatment of amine (E7) with an appropriate alkenyl acid halide can provide a compound of Formula 1. In a second method, a compound of Formula 1 can be synthesized by treating amine (E7) with an appropriate alkynyl carboxylic acid in the presence of a coupling reagent. In a third method, amine (E7) can be reacted with an appropriate aldehyde to provide (E8), which is then deprotected under acidic conditions to give amine (E9). Treatment of amine (E9) with an appropriate alkenyl acid halide can provide a compound of Formula 1. Alternatively, a compound of Formula 1 can be synthesized by treating amine (E9) with an appropriate alkynyl carboxylic acid in the presence of a coupling reagent.

[0254] Scheme F [ka]

[0255] Scheme F shows the preparation for compounds of formula 2. 6Compound (F1) where R =H can be treated with bis(pinacolato)diboron under palladium catalysis to give boronic ester (F2). Reaction of boronic ester (F2) with an appropriate bromide (B6) under palladium catalysis can give (F4). Halogenation of (F4) in the presence of NCS can give (F5), which can then be treated under acidic conditions to remove the protecting group and provide compound (F6). 6 =H, (F4) can be deprotected under acidic conditions to provide (F6). Subsequent treatment of compound (F6) with an appropriate alkenyl acid halide can provide a compound of formula 2. Alternatively, amine (F6) can be subjected to reductive amination conditions using an appropriate aldehyde to provide (F7), which can then be deprotected under acidic conditions to provide amine (F8). Subsequent treatment of amine (F8) with an appropriate alkenyl acid halide can provide a compound of formula 2. Compounds of formula 2 can be synthesized by treating amine (F8) with an appropriate alkynyl carboxylic acid in the presence of a coupling reagent.

[0256] Scheme G [ka]

[0257] Scheme G shows the preparation for compounds of formula 3. Demethylation of compound (E6) with NDM can lead to demethylation of (G1). 2 Reaction with an OH alcohol can give (G2). Alternatively, (G1) can be alkylated with a tosylate (A6). Subsequent removal of the protecting group can be achieved under acidic conditions to give the amine (G3), which can then be treated with an appropriate alkenyl acid halide to provide a compound of formula 3.

[0258] Scheme H [ka]

[0259] Scheme H shows the preparation of a compound of Formula 4. Reaction of (A5) with (H1) under Mitsunobu conditions can provide compound (H2). Treatment of (H2) with bis(pinacolato)diboron under palladium catalysis can provide boronic ester (H3). Reaction of boronic ester (H3) with (D4) under palladium catalysis can provide compound (H4). Treatment of (H4) in the presence of NCS can provide (H5). Reprotection of alcohol (H5) in the presence of TBDMSCl, followed by chiral chromatography to individually isolate the enantiomers, can provide (H6). Removal of the protecting group from (H6) can be achieved by treatment under acidic conditions to provide (H7). Treatment of compound (H7) with trifluoromethanesulfonic anhydride at −78° C., followed by reaction with tert-butyl-1-piperazinecarboxylate, can provide (H8). Removal of the protecting group by treatment with BCl 3 at −78° C. can provide (H9), which can then be reacted with an appropriate alkenyl acid halide to afford compounds of formula 4.

[0260] Scheme J [ka]

[0261] Scheme J shows the preparation of compounds of formula 5. Alkylation of (G1) with an appropriate alpha haloketone can provide (J1). Reaction of (J1) with an appropriate Grignard reagent can result in tertiary alcohol (J2). The tertiary alcohol is then treated under acidic conditions to provide deprotected amine (J3). Subsequent treatment of amine (J3) with an appropriate alkenyl acid halide can provide compounds of formula 5.

[0262] Scheme K [ka]

[0263] Scheme K illustrates an alternative preparation for compounds of Formula 1. Two methods are described for the preparation of (K6). In the first method, (E4) can be subjected to demethylation conditions in the presence of NDM to provide (K1). Reaction of (K1) with an appropriate alcohol using Mitsunobu conditions results in (K2). Removal of the protecting group under acidic conditions can yield amine (K3). Reaction of amine (K3) with an appropriate ketone under reductive amination conditions can yield (K6). In the second method, treatment of (H1) can be alkylated with an appropriate halide to provide (K4). Treatment of (K4) with bis(pinocolato)diboron under palladium catalysis can provide boronic acid (K5), which then reacts with (B6) under palladium catalysis to provide (K6). Deprotection of (K6) under acidic conditions can provide the amine (K7), which then reacts with the appropriate alkenyl acid halide to give compounds of formula 1.

[0264] Scheme L [ka]

[0265] Scheme L shows the preparation for compounds of formula 6. Reaction of (L1) with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of CuI gives R 6 =F to provide (L2). Treatment of (L2) with bis(pinacolato)diboron under palladium catalyzed conditions can provide boronic acid (L3). Palladium catalyzed coupling with an appropriate bromide (B6) and boronic acid (L3) can provide (L4), which can then be demethylated with NDM to provide (L5). Alkylation of (L5) with an appropriate alpha-haloketone can provide ketone (L6), which can then be reduced with NaBH4 to provide (L7). Removal of the protecting group under acidic conditions can provide (L8), which can then be reacted with an appropriate acid halide to provide compounds of formula 6.

[0266] Scheme M [ka]

[0267] Scheme M illustrates the preparation of compounds of Formula 7. Reaction of 4-chloro-6-methoxypyridin-2-amine (M1) with chloroacetaldehyde can provide imidazo[1,2-a]pyridine (M2). Treatment of (M2) with bis(pinocolato)diboron under palladium catalysis can provide boronic acid (M3), which then reacts with (B6) under palladium catalysis to provide (M4). Iodination of (M4) in the presence of NIS can provide iodo (M5), which then reacts with CuCN to provide cyano (M6). Demethylation of (M6) can be achieved by reaction with NDM to provide (M7). Treatment of (M7) with an appropriate alcohol under Mitsunobu conditions can yield (M8). Removal of the protecting group can be achieved by treatment under acidic conditions to provide (M9). Subsequent treatment of amine (M9) with an appropriate alkenyl acid halide can provide compounds of formula 7. Alternatively, treatment of (M9) with an appropriate alkynyl carboxylic acid in the presence of a coupling reagent can provide compounds of formula 7.

[0268] Scheme N [ka]

[0269] Scheme N shows the preparation of compounds of formula 8. Reaction of (E7) with 2-cyanoacetic acid using an appropriate coupling reagent can provide (N1). Compound (N1) is then condensed with an appropriate aldehyde to provide compounds of formula 8.

[0270] Scheme P [ka]

[0271] Scheme P shows the preparation of compounds of formula 9. Palladium-catalyzed coupling of (E2) and (C10) can provide (P2). Deprotection of (B2) under acidic conditions can give (P3), which can then be reacted with an appropriate alkenyl halide to give compounds of formula 9.

[0272] 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. The designations "P1" and "P2" refer to the compounds that elute first and second, respectively, from chromatography under the conditions described herein; if 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).

[0273] "AcOH" refers to acetic acid, "ACN" refers to acetonitrile, "aq." refers to aqueous, "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "Pd(DtBPF)Cl2" refers to [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), "TBDMSCl" refers to tert-butyldimethylsilyl chloride, and "XPhos Pd "G2" refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), "DCM" refers to dichloromethane, "DMA" refers to dimethylacetamide, "DMAP" refers to N,N-dimethylpyridin-4-amine, "DPPA" refers to diphenylphosphoryl azide, "NDM" refers to 1-dodecanethiol, "EA" refers to ethyl acetate, "DEAD" refers to diethyl azodicarboxylate, "Et2O" refers to diethyl ether, and "DIAD" refers to diisopropyl azodicarboxylate. azodicarboxylate), "DIPEA" refers to N,N-diisopropylethylamine, and "DMF" refers to N,"NMI" refers to N-dimethylformamide, "FA" refers to formic acid, "hr" refers to hour, "NMI" refers to 1-methyl-1H-imidazole, "IPA" refers to isopropyl alcohol, "iPrMgCl" refers to isopropylmagnesium chloride, "MeMgBr" refers to methylmagnesium bromide, "MeOH" refers to methanol, "NaBH4" refers to sodium borohydride, "NBS" refers to N-bromosuccinimide, "NCS" refers to N-chlorosuccinimide, "M" refers to mole, "mmol" refers to millimole, "mL" refers to milliliter, and "MTBE" refers to methyl tert-butyl ether. tert-butyl ether), "min" refers to minute, "MS" refers to molecular sieve, "NMR" refers to nuclear magnetic resonance, "PdCl2(dppf)" refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), "PE" refers to petroleum ether, "KOAc" refers to potassium acetate, "PPTS" refers to pyridinium p-toluenesulfonate, and "RT" refers to room temperature. temperature), "rxn" refers to reaction, "sat." refers to saturated, "soln" refers to solution, "Pd(PPh3)4" refers to tetrakis(triphenylphosphine)palladium(0), "PPTS" refers to p-toluenesulfonic acid pyridine salt, "NaBH(OAc)3" refers to sodium triacetoxyborohydride, and "TCFH" refers to N,N,N',"NEt3" refers to N'-tetramethylchloroformamidinium hexafluorophosphate, "NEt3" refers to triethylamine, and "PPh3" refers to triphenylphosphine. "T3P" refers to 1-propanephosphonic anhydride, "TFA" refers to 2,2,2-trifluoroacetic acid, and "THF" refers to tetrahydrofuran.

[0274] For compounds where the amine salt was isolated, the formation of monovalent, divalent, or trivalent salts depends on the pKa of the amine and acid used to form the salt. The exact monovalent, divalent, or trivalent salt form for each compound was not identified.

[0275] Preparation 1 2-Benzyloxy-1-[(5-fluoro-2-pyridyl)ethanone [ka]

[0276] To a solution of 2-bromo-5-fluoropyrimidine (50 g, 284 mmol) in toluene (100 mL) was added iPrMgCl (2.0 M solution in THF) (170.47 mL, 341 mmol) dropwise at 0 °C under N. The mixture was stirred at room temperature for 2 h, then 2-(benzyloxy)-N-methoxy-N-methylacetamide (65.4 g, 313 mmol) was added dropwise over 10 min at 0 °C. The reaction was stirred at room temperature for 1 h, cooled to 0 °C, and then quenched with saturated aqueous NH.sub.4Cl (250 mL). The mixture was extracted with EA (3.times.500 mL), and the organic layers were combined, washed with brine (3.times.500 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound (79 g, crude) as a light brown oil that was used directly in the next step. ES / MS m / z 246 [M+H] + .

[0277] Preparation 2 2-benzyloxy-1-(5-fluoro-2-pyridyl)ethanol [ka]

[0278] To a stirred solution of 2-benzyloxy-1-(5-fluoro-2-pyridyl)ethanone (79 g, 322 mmol) in MeOH (273 mL) was added NaBH (6.09 g, 161 mmol) portionwise at 0 °C under N. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by the addition of H O (200 mL) at room temperature and then concentrated. The mixture was extracted with EA (3 × 300 mL). The combined organic layers were dried over Na SO , filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (1:1) to give the title compound (64.6 g, 81%) as a pale yellow solid. ES / MS m / z 248 [M+H] + .

[0279] Preparation 3 2-benzyloxy-1-(5-fluoro-2-pyridyl)ethanol [ka]

[0280] To a solution of 2-bromo-5-fluoropyridine (1.2 g, 6.8 mmol) in toluene (10 mL) was added iPrMgCl (2 M) (1.1 g, 10 mmol) dropwise at 0 °C under N. The mixture was stirred at 0 °C for 30 min. Then, a solution of 2-(benzyloxy)acetaldehyde (1.8 g, 12 mmol) in toluene (2 mL) was added dropwise over 10 min at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then quenched with saturated aqueous NH Cl and extracted with EA (3 × 100 mL). The combined organic layers were dried over Na SO , filtered, and concentrated to an oily residue. The residue was purified by silica gel chromatography eluting with 0% to 100% EA in heptane. The isolated product was re-purified by silica gel chromatography eluting with 10% EA in DCM to give the title compound (0.9 g, 53%) as a colorless oil that solidified on standing. 1H NMR (300MHz,DMSO-d6)δ 3.56 (dd,J = 10.03,6.85Hz,1H),3.71 (dd,J = 10.03Hz,3.91Hz,1H),4.50 (s,2H),4.80 (dt,J = 6.66,4.49Hz,1H),5.69 (d,5.01Hz,1H),7.23-7.29 (m,3H),7.29 - 7.35 (m,2H),7.57 (dd,J = 8.74,4.71Hz,1H),7.71 (td,J = 8.86,2.93Hz,1H),8.48 (d,J = 2.93Hz,1H).

[0281] Preparation 4 2-Benzyloxy-1-(5-fluoro-2-pyridyl)ethanol, Isomer 1 [ka] and Preparation 5 2-Benzyloxy-1-(5-fluoro-2-pyridyl)ethanol, Isomer 2 [ka]

[0282] Separation of 2-benzyloxy-1-(5-fluoro-2-pyridyl)ethanol enantiomers (100 mg) was carried out using the following conditions: SFC; stationary phase: Chiralpak AD-H, 21 × 150 mm, 5 μm; elution with an 80% isocratic solution of CO in MeOH (0.5% DMEA); UV at 265 nm. (R) 2-benzyloxy-1-(5-fluoro-2-pyridyl)ethanol, isomer 1, ES / MS m / z 248 [M+H] in 1.5 min (36.5 mg, %) with 97.4% ee + , and t (R) 2-benzyloxy-1-(5-fluoro-2-pyridyl)ethanol, isomer 2, ES / MS m / z 248 [M+H], 1.84 min (36.8 mg, %) with 97% ee + obtained.

[0283] Preparation 6 [2-benzyloxy-1-(5-fluoro-2-pyridyl)ethyl] 4-methylbenzenesulfonate, isomer 1 [ka]

[0284] To a solution of 2-benzyloxy-1-(5-fluoro-2-pyridyl)ethanol, isomer 1 (3.0 g, 12.13 mmol) in DCM (30 mL) cooled to 0 °C, DMAP (0.15 g, 1.21 mmol) and NEt (2.46 g, 24.26 mmol) were added. The solution was stirred at 0 °C for 5 min, then 4-methylbenzenesulfonyl chloride (3.01 g, 15.77 mmol) was added and stirred for 3 h. The reaction was quenched by the addition of HO, and the organic layer was separated. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 100% EA in heptane to give the title compound (4.37 g, 90%) as an amber oil.

[0285] Preparation 7 [(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-(2-pyridyl)ethyl]4-methylbenzenesulfonate [ka]

[0286] To a solution of (R)-2-((tert-butyldimethylsilyl)oxy)-1-(pyridin-2-yl)ethan-1-ol (25 g, 99 mmol), NEt (20 g, 200 mmol), and DMAP (1.2 g, 9.9 mmol) in DCM (250 mL) cooled to 0 °C was added 4-methylbenzenesulfonyl chloride (24 g, 130 mmol). The mixture was stirred at 0 °C for 8 h and then stored at 4 °C overnight. The solids were filtered off, HO (5 mL) was added to the filtrate, concentrated to dryness, and the crude residue was purified by silica gel chromatography eluting with 0% to 100% EA in heptane to give the title compound (34.9 g, 87%) as a light brown oil that solidified on standing. ES / MS m / z 408 [M+H] + .

[0287] Preparation 8 2-Bromo-N-(2,2-difluoroethyl)-2-methyl-propan-1-imine [ka]

[0288] A solution of 2-bromo-2-methylpropanal (2.00 g, 13.3 mmol) and 2,2-difluoroethanamine (1.07 g, 13.3 mmol) in EtO (30 mL) was treated with 4 Å molecular sieves (100 mg) and stirred at room temperature for 2 h. The resulting mixture was filtered and the solid was washed with EtO (3 × 50 mL). The filtrate was concentrated to give the title compound (2.1 g, 74%) as a white solid. ES / MS m / z ( 79 Br / 81 Br)214 / 216 [M+H] + .

[0289] Preparation 9 N-(2,2-difluoroethyl)-1,1-dimethoxy-2-methyl-propan-2-amine [ka]

[0290] A solution of 2-bromo-N-(2,2-difluoroethyl)-2-methyl-propan-1-imine (2.10 g, 9.8 mmol) in MeOH (20 mL) was stirred at 80° C. for 2 h. After cooling to room temperature, the solution was diluted with HO (10 mL) and the pH was adjusted to 8 with aqueous NaOH (2 M). The mixture was extracted with DCM (3×20 mL). The combined organics were washed with brine (3×50 mL), collected, dried over NaSO, filtered, and concentrated to give the title compound (1.1 g, 57%) as a brown oil. 1 H NMR (300MHz,DMSO-d6)δ 5.89 (tt,J = 56.4,3.8Hz,1H),3.99 (s,1H),3.45 (s,6H),2.95 -2.80 (m,2H),0.93 (s,6H).

[0291] Preparation 10 2-(2,2-difluoroethylamino)-2-methyl-propanal [ka]

[0292] A solution of N-(2,2-difluoroethyl)-1,1-dimethoxy-2-methyl-propan-2-amine (0.50 g, 2.5 mmol) in qHCl (6 M, 15 mL) was stirred for 2 h at 50° C. After cooling to room temperature, the reaction was lyophilized to give the title compound (0.56 g, crude) as a brown oil. 1 H NMR (300MHz,DMSO-d6)δ 9.01 (s,1H),6.33 (tt,J = 54.2,3.8Hz,1H),3.42 - 3.25 (m,2H),1.18 (d,6H).

[0293] Preparation 11 2-Methyl-2-[methyl(oxetan-3-yl)amino]propanal [ka]

[0294] A solution of 2-bromo-2-methylpropanal (250 mg, 1.66 mmol), N-methyloxetan-3-amine (144 mg, 1.66 mmol), and KCO (686 mg, 4.97 mmol) in DMF (5 mL) was stirred at 80 °C for 3 h. Upon cooling to room temperature, HO (10 mL) was added and the mixture was extracted with EA (3 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give the title compound (414 mg, crude) as a pale yellow oil, which was used directly in the next step.

[0295] The following compounds were prepared essentially as described in Preparation 11, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system accordingly.

[0296] [Table 1]

[0297] Preparation 13 tert-Butyl (3S,4R)-4-azido-3-hydroxy-piperidine-1-carboxylate [ka]

[0298] To a mixture of tert-butyl (3S,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (3 g, 13.87 mmol), K2CO3 (0.96 g, 6.94 mmol), and CuSO4·5H2O (0.36 g, 1.39 mmol) in MeOH (30 mL) was added 1H-imidazole-1-sulfonyl azide hydrochloride (3.48 g, 16.65 mmol) at room temperature under N2. The mixture was stirred at room temperature overnight. The reaction was quenched with H2O (100 mL) at room temperature. The mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (4.5 g, crude) as a yellow oil. 1H NMR (400MHz,DMSO-d6)δ 5.39 (s,1H),4.17 -4.03 (m,1H),3.68 - 3.62 (m,1H),3.38 - 3.30 (m,4H),1.80 - 1.69 (m,1H),1.63 - 1.53 (m,1H),1.39 (s,9H).

[0299] Preparation 14 (3-Azidocyclobutoxy)methylbenzene [ka]

[0300] To 3-(benzyloxy)cyclobutan-1-ol (20 g, 112 mmol) and PPh3 (39.7 g, 151 mmol) in THF (50 mL) was added DEAD (27.36 g, 157.100 mmol) dropwise at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h, and then DPPA (37.06 g, 134.7 mmol) was added. The mixture was then stirred at room temperature for 2 h. The mixture was concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (20:1) to give the title compound (21.5 g, 94%) as a pink oil. 1 H NMR (400MHz,CDCl3)δ 7.39 - 7.28 (m,5H),4.41 (s,2H),4.28 - 4.21(m,1H),4.16 - 4.08(m,1H),2.44 - 2.27 (m,4H).

[0301] Preparation 15 Ethyl 1-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-5-methyl-triazole-4-carboxylate [ka]

[0302] A mixture of tert-butyl (3R)-3-azidopyrrolidine-1-carboxylate (45 g, 212 mmol) and K2CO3 (87.90 g, 636 mmol) was treated dropwise with ethyl acetoacetate overnight at 80 °C. The resulting mixture was filtered, and the solid was washed with DCM (3 × 50 mL). The filtrate was concentrated and purified by silica gel chromatography eluting with PE / EA (10:1 to 1:1) to give the title compound (32 g, crude) as a yellow oil. ES / MS m / z 325 [M+H] + .

[0303] The following compounds were prepared essentially as described in Preparation 15, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0304] [Table 2] 1 It was purified by silica gel chromatography eluted with PE / EA (10:1 to 1:1). 2 Workup: Upon cooling to room temperature, the reaction was concentrated. The mixture was diluted with H2O and extracted with EA (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. 3 The residue was purified by silica gel chromatography eluting with 50% EA in PE.

[0305] Preparation 18 tert-Butyl (1R,3r,5S)-3-(4-bromo-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka]

[0306] CsCO (19.20 g, 58.941 mmol) was added portionwise to a stirred room temperature mixture of 4-bromopyrazole (2.89 g, 19.65 mmol) and tert-butyl (1R,3s,5S)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.00 g, 19.65 mmol) in DMF (50 mL), and the mixture was stirred under N at 70 °C overnight. The mixture was concentrated, and the residue was purified by silica gel chromatography eluting with a gradient of PE / EA (10:1 to 5:1) to give the crude product (5.2 g). The crude product was purified by reverse-phase flash chromatography under the following conditions: column, C18, eluted with a gradient of 40% to 80% ACN in HO (0.1% FA) at 220 nm to give the title compound as an off-white solid (3.5 g, 47.5%). ES / MS m / z 341 / 343 [M+H-tBu+ACN] + .

[0307] The following compounds were prepared essentially as described in Preparation 18, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0308] [Table 3] 1 The mixture was concentrated, diluted with H2O and extracted with EA (3 x 200 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound.

[0309] Preparation 20 tert-Butyl 2-(4-bromopyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate [ka]

[0310] CsCO (18.36 g, 56.35 mmol) was added portionwise to a stirred mixture of tert-butyl 2-(methanesulfonyloxy)-7-azaspiro[3.5]nonane-7-carboxylate (6.00 g, 18.78 mmol) and 4-bromopyrazole (2.76 g, 18.78 mmol) in DMF (50 mL) at room temperature under N, and the mixture was stirred at 100 °C under N for 2 h. The mixture was cooled to room temperature, diluted with HO (100 mL), and extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on a C18 column at 220 nm, eluted with a gradient of 40% to 50% ACN in HO (0.1% FA) to give the title compound (5 g). The product was dissolved in DCM (100 mL), washed with brine (2×150 mL), dried over anhydrous NaSO, and the filtrate was concentrated to give the title compound as an off-white solid (4.5 g, 64.7%). 1 H NMR (300MHz,CDCl3)δ 7.50 (s,1H),7.45 (s,1H),4.80 - 4.69 (m,1H),3.47 - 3.38 (m,2H),3.38 - 3.29 (m,2H),2.51 - 2.38 (m,2H),2.38 - 2.25 (m,2H),1.69 - 1.61 (m,4H),1.47 (s,9H).

[0311] Preparation 21 1-(1-tert-butoxycarbonylazetidin-3-yl)-5-methyl-triazole-4-carboxylic acid [ka]

[0312] A mixture of ethyl 1-[1-(tert-butoxycarbonyl)azetidin-3-yl]-5-methyl-1,2,3-triazole-4-carboxylate (20.00 g, 64.44 mmol) and KOH (7.23 g, 128.89 mmol) in HO (100 mL) was stirred at 50 °C under N for 2 h. Upon cooling to room temperature, the mixture was cooled to 0 °C and acidified to pH 4 with 1 M aqueous HCl. The aqueous layer was extracted with EA (3 × 400 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over NaSO, filtered, and concentrated to give the title compound (14 g, crude) as a yellow oil, which was used directly in the next step without purification. ES / MS m / z 283 [M+H] + .

[0313] Preparation 22 1-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-5-methyl-triazole-4-carboxylic acid [ka]

[0314] A solution of KOH (11.07 g, 197.3 mmol) in HO (100 mL) was treated with ethyl 1-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-5-methyl-triazole-4-carboxylate (32 g, crude) at room temperature. The reaction was stirred at 50 °C for 2 h. After cooling, the reaction was extracted with EA (2 × 100 mL). The aqueous layer was acidified to approximately pH 3-4 with aqueous HCl (1 M) at 0 °C to give a white suspension. The solid was collected by filtration, washed with HO (3 × 20 mL), and dried in vacuo to give the product (23 g, 44%) as a white solid. ES / MS m / z 297 [M+H] + .

[0315] The following compounds were prepared essentially as described in Preparation 22, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0316] [Table 4] 1 MeOH was used as a co-solvent. 2 Upon cooling to room temperature, the reaction was used directly in the next step.

[0317] Preparation 25 tert-Butyl (3S,4R)-3-hydroxy-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate [ka]

[0318] A mixture of tert-butyl-(3S,4R)-4-azido-3-hydroxy-piperidine-1-carboxylate (4.5 g) and trimethyl(prop-1-yn-1-yl)silane (2 mL) in toluene (2 mL) was irradiated with microwave radiation at 140° C. for 1 hour. Upon cooling to room temperature, the reaction was concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (4:1) to give the title compound (1.54 g, 23%) as a white solid. ES / MS m / z 355 [M+H] + .

[0319] Preparation 26 tert-Butyl (3S,4R)-4-(4-bromo-5-methyl-triazol-1-yl)-3-hydroxy-piperidine-1-carboxylate [ka]

[0320] To a solution of tert-butyl (3S,4R)-3-hydroxy-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate (1.54 g, 4.34 mmol) in ACN (50 mL) was added SiO (0.52 g, 8.69 mmol) and NBS (1.16 g, 6.52 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C for 2 h. Upon cooling to room temperature, the reaction was concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (4:1) to give the title compound (1.2 g, 76%) as a white solid. ES / MS m / z ( 79 Br / 81 Br)361 / 363 [M+H] + .

[0321] Preparation 27 tert-Butyl 3-(4-bromo-5-methyl-triazol-1-yl)azetidine-1-carboxylate [ka]

[0322] To a solution of 1-(1-tert-butoxycarbonylazetidin-3-yl)-5-methyl-triazole-4-carboxylic acid (14.00 g, 49.59 mmol) and KOH (6.96 g, 123.98 mmol) in HO (150 mL) was added Br (10.30 g, 64.47 mmol) dropwise at 0 °C under N. The mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (2 × 400 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over NaSO, filtered, and concentrated to give the title compound (14 g, crude) as a yellow solid, which was used in the next step without purification. ES / MS m / z ( 79 Br / 81 Br)317 / 319 [M+H] + .

[0323] The following compounds were prepared essentially as described in Preparation 27, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0324] [Table 5] a1 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). 1 Purification was by C18 reverse flash chromatography, eluting with 505-80% ACN in H2O (0.1% FA).

[0325] Preparation 31 [ka]

[0326] A solution of tert-butyl (3R)-3-(4-bromopyrazol-1-yl)pyrrolidine-1-carboxylate (2.00 g, 6.33 mmol) and CHI (2.69 g, 18.98 mmol) in THF (50 mL) was treated dropwise with LDA (18.98 mL, 37.95 mmol) at −5° C. under N. The mixture was stirred at −5° C. for 3 h. The reaction was then quenched with saturated aqueous NHCl (100 mL) and then extracted with EA (3×100 mL). The combined organic layers were washed with brine (2×50 mL) and dried over NaSO. After filtration, the filtrate was concentrated to give the title compound (2.3 g) as a brown oil, which was used directly in the next step without further purification. 1H NMR (300MHz,DMSO-d6)δ 7.53 (s,1H),5.00 (d,1H),3.67 (d,1H),3.50 - 3.42 (m,2H),2.27 (s,3H),2.24 - 2.10 (m,2H),1.40 (d,9H).

[0327] The following compounds were prepared essentially as described in Preparation 31, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0328] [Table 6] 1 Purification was carried out by silica gel chromatography eluting with PE followed by PE / EA (1:10). 21 H NMR (400 MHz, DMSO-d6). 3 It was purified by silica gel chromatography and eluted with PE / EA (5 / 1 to 4 / 1). 41 H NMR (300 MHz, DMSO-d6). 5 The product was purified by silica gel chromatography and eluted with PE / EA (15:1 to 12:1). 6 The product was purified by silica gel chromatography and eluted with PE / EA (9:1 to 5:1). a ES / MS m / z ( 79 Br / 81 Br)370 / 372 [M+H] + . b ES / MS m / z ( 79 Br / 81 Br)344 / 346 [M+H] + .

[0329] Preparation 39 3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutanol [ka]

[0330] A mixture of 1-(3-benzyloxycyclobutyl)-4-bromo-5-methyl-triazole (8.5 g, 26.38 mmol) and FeCl (8.56 g, 52.76 mmol) in DCM (100 mL) was stirred at 50 °C under N for 2 h and then allowed to cool 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 concentrated to give the title compound (8 g, crude) as a brown solid. 1 H NMR (400MHz,DMSOd6)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).

[0331] Preparation 40 4-(4-Bromo-5-methyl-pyrazol-1-yl)piperidine hydrochloride [ka]

[0332] A solution of tert-butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate (1.50 g, 4.4 mmol) in DCM (10 mL) was treated portionwise with HCl in 1,4-dioxane (4 M, 10 mL) at room temperature. After stirring at room temperature for 12 hours, the reaction was concentrated and the resulting solid was triturated with EtO (15 mL). The solid was collected by filtration and washed with EtO (3 × 20 mL) to give the title compound (1.2 g, 98%) as an off-white solid. 1H NMR (300MHz,DMSO-d6)δ 9.20 (brs,1H),8.85 (brs,1H),7.54 (s,1H),4.61 - 4.47 (m,1H),3.42 - 3.37 (m,2H),3.11 - 3.00 (m,2H),2.28 (s,3H),2.19 - 2.09 (m,2H),2.05 - 1.95 (m,2H).

[0333] Preparation 41 1-(azetidin-3-yl)-4-bromo-5-methyl-pyrazole, 2,2,2-trifluoroacetic acid [ka]

[0334] A solution of tert-butyl 3-(4-bromo-5-methyl-pyrazol-1-yl)azetidine-1-carboxylate (3.00 g, 9.5 mmol) in DCM (20 mL) was treated with TFA (10 mL) and stirred at room temperature for 2 hours. The reaction was concentrated to give the title compound (4 g, crude) as a brown oil, which was used without purification. 1 H NMR (300MHz, CDCl3)δ 7.50 (s,1H),5.16 - 5.06 (m,1H),4.30 (t,2H),3.88 (t,2H),2.25 (s,3H).

[0335] Preparation 42 tert-Butyl (3S)-3-[3-(4-bromo-5-methyl-pyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate [ka]

[0336] A solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (2.00 g, 10.7 mmol) and DIPEA (4.14 g, 32 mmol) in DCM (30 mL) at −40° C. was treated with trifluoromethanesulfonic anhydride (3.62 g, 12.8 mmol) and then stirred at −40° C. for 2 hours. The resulting mixture was added dropwise to a −40° C. solution of 1-(azetidin-3-yl)-4-bromo-5-methyl-pyrazole, 2,2,2-trifluoroacetic acid (4 g, crude) in DCM (30 mL) basified to approximately pH 10 with DIPEA (3 mL). The reaction was stirred at −40° C. for 1 hour and then at room temperature overnight. The reaction was purified by C18 reverse phase chromatography, eluting with 20% to 30% ACN in HO (0.1% FA) to give the title compound (0.50 g, 12%) as a pale yellow solid. ES / MS m / z ( 79 Br / 81 Br)385 / 387 [M+H] + .

[0337] The following compounds were prepared essentially as described in Preparation 42, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0338] [Table 7] 1 It was purified by C18 reversed-phase flash chromatography eluting with 30%-50% ACN in H2O (0.1% FA).

[0339] Preparation 44 tert-Butyl N-[2-[4-(4-bromo-5-methyl-pyrazol-1-yl)-1-piperidyl]-1,1-dimethyl-ethyl]carbamate [ka]

[0340] A solution of 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine hydrochloride (1.20 g, 4.9 mmol) and tert-butyl N-(1,1-dimethyl-2-oxo-ethyl)carbamate (1.38 g, 7.4 mmol) in MeOH (10 mL) was treated with AcOH (14.76 mg, 0.25 mmol) and the reaction was stirred at room temperature for 30 min. The reaction was treated portionwise with NaBHCN (617.77 mg, 9.8 mmol) at room temperature and then stirred at 50 °C for 12 h. After cooling to room temperature, the reaction was quenched with aqueous NH Cl (20 mL) and extracted with EA (3 × 50 mL). The combined organics were washed with brine (2 × 100 mL), collected, dried over Na SO , filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (6:1 to 5:1) to give the title compound (0.40 g, 20%) as an off-white solid. 1 H NMR (300MHz,CDCl3)δ 7.45 (s,1H),4.84 (brs,1H),4.06 - 3.88 (m,1H),3.02 - 2.98 (m,2H),2.54 - 2.38 (m,4H),2.29 - 2.21 (m,5H),1.82 - 1.77 (m,2H),1.45 (s,9H),1.27 (s,6H).

[0341] Preparation 45 7-chloro-5-methoxyimidazo[1,2-a]pyridine [ka]

[0342] 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-butanol (140 mL) was divided into 14 batches and stirred in sealed tubes at 65 °C overnight. The solution was cooled to room temperature, diluted with HO (200 mL), and extracted with EA (3 × 200 mL). The organic extracts were dried over NaSO and concentrated. 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] + .

[0343] Preparation 46 6-Bromo-3-fluoro-4-methoxy-pyrazolo[1,5-a]pyridine [ka]

[0344] A solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5 g, 22 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (7.04 g, 22 mmol) in ACN (50 mL) was stirred overnight at room temperature under N. The mixture was diluted with HO (50 mL) and then extracted with EA (3 × 100 mL). The combined organic layers were 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, 30% to 40% ACN in HO (0.1% FA) over 10 min 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).

[0345] Preparation 47 6-Bromo-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine [ka]

[0346] 6-Bromo-4-methoxypyrazolo[1,5-a]pyridine (0.41 g, 1.8 mmol) and NIS (609 mg, 2.7 mmol) were dissolved in ACN (8 mL) and stirred at room temperature for 1 h. The suspension was filtered and the filtrate was concentrated. 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%). ES / MS m / z ( 79 Br / 81 Br)353 / 355 [M+H] + .

[0347] Preparation 48 6-Bromo-4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine [ka]

[0348] A mixture of 6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine (3.0 g, 8 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.0 g, 0.1 mol), and CuI (2.0 g, 0.1 mol) in DMF (36 mL) was heated at 80 °C for 2 h. The mixture was diluted with EA, filtered through DE, and placed in a separatory funnel. Additional EA (250 mL) was added, washed with 10% aqueous LiCl (20 mL × 3), saturated aqueous NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated, SiO2 was added, and the solid was loaded onto a silica gel column. The column was eluted with 0% to 30% EA in heptane. The title compound (0.76 g, 2.57 mmol) was obtained as a white amorphous solid. ES / MS m / z ( 79 Br / 81Br)295 / 297 [M+H] + .

[0349] Preparation 49 6-Bromo-4-isopropoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0350] To a solution of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (5.00 g, 21.01 mmol) and 2-iodopropane (7.14 g, 42.01 mmol) in DMF (100 mL) was added K2CO3 (8.71 g, 63.01 mmol) at room temperature under N2. The mixture was stirred at 80 °C for 1 h. The mixture was diluted with H2O (150 mL) and extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (3 × 300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (6:1 to 5:1) to give the title compound (5.0 g, 85%) as an off-white solid. ES / MS m / z ( 79 Br / 81 Br)280 / 282 [M+H] + .

[0351] Preparation 50 4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]-6-bromo-pyrazolo[1,5-a]pyridine [ka]

[0352] To a mixture of PPh3 (22.16 g, 84.5 mmol) in THF (25 mL) was added dropwise DIAD (15.38 g, 76 mmol) under N2 at 0 °C. The mixture was stirred for 0.5 h, then 2-benzyloxy-1-(5-fluoro-2-pyridyl)ethanol (12.54 g, 50.7 mmol) was added along with 6-bromopyrazolo[1,5-a]pyridin-4-ol (9 g, 42.2 mmol) in THF (25 mL). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was purified by C18 reverse flash chromatography, eluting with 65%-70% ACN in HO to give the title compound (14 g, 75%) as a white solid. ES / MS m / z ( 79 Br / 81 Br)440 / 442 [M+H] + .

[0353] The following compounds were prepared essentially as described in Preparation 50, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0354] [Table 8] 1 It was purified by silica gel chromatography eluting with PE / EA (4:1 to 1:2). 2 Instead of DIAD, DEAD was used. 3 Purification was carried out by silica gel chromatography eluting with PE / EA (3:1).

[0355] Preparation 53 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine [ka]

[0356] To 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5.00 g, 22 mmol) and bis(pinacolato)diboron (6.71 g, 26.4 mmol) in dioxane (10 mL) was added KOAc (6.48 g, 66.1 mmol) and Pd(dppf)Cl (0.32 g, 0.44 mmol) at room temperature under N. The resulting mixture was stirred at 80 °C under N for 2 h. The mixture was carried forward without purification. ES / MS m / z 275 [M+H] + . The following compounds were prepared essentially as described in Preparation 53, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0357] [Table 9] 1 Workup: The reaction was filtered and the filter cake was washed with 1,4-dioxane. 2 Pd(dppf)Cl2·CH2Cl2 was used as the catalyst. 3 Work-up: The reaction was filtered and the filter cake was washed with EA. The filtrate was concentrated to give the title compound.

[0358] Preparation 58 [4-Methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]boronic acid [ka]

[0359] A mixture of 6-bromo-4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine (1.69 g, 5.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.74 g, 6.9 mmol), KOAc (1.69 g, 17.2 mmol), and PdCl(dppf) (0.42 g, 0.6 mmol) in 1,4-dioxane (15 mL) was sparged with argon (15 min). The mixture was heated at 80 °C for 16 h. The mixture was cooled to room temperature, diluted with EA, washed with HO (100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 50% EA in heptane to give the title compound (1.55 g, 104%). The title compound was used directly in the next step without further purification. ES / MS m / z 261 [M+H] + .

[0360] Preparation 59 5-Methoxyimidazo[1,2-a]pyridin-7-ylboronic acid [ka]

[0361] A stirred mixture of 7-chloro-5-methoxyimidazo[1,2-a]pyridine (1.00 g, 5.5 mmol) and bis(pinacolato)diboron (1.67 g, 6.6 mmol) in 1,4-dioxane was treated with KOAc (1.61 g, 16.4 mmol) and Xphos Pd G4 (0.05 g, 0.06 mmol) at room temperature under N2 and stirred at 80 °C for 8 h. The mixture was diluted with HO (100 mL), acidified to pH 4 with 1 N aqueous HCl, and extracted with i-PrOH / CHCl3 (3:1) (3 × 200 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the title compound as a pale pink solid (1.4 g, crude). ES / MS m / z 193 [M+H] + .

[0362] Preparation 60 (1r,3r)-3-[4-[4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]cyclobutanol [ka]

[0363] To a stirred mixture of 4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]-6-bromo-pyrazolo[1,5-a]pyridine (14 g, 27.1 mmol), bis(pinacolato)diboron (8.27 g, 32.6 mmol), and KOAc (7.99 g, 81.4 mmol) in 1,4-dioxane (120 mL) was added Pd(dppf)Cl.CH.Cl. (0.99 g, 1.4 mmol) at room temperature under N. The mixture was stirred at 100 °C for 2 h. The reaction was used directly in the next step without further workup. To the above mixture were added K2CO3 (11.25 g, 81.4 mmol), (1r,3r)-3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanol (8.14 g, 35.3 mmol), and Pd(PPh3)4 (1.56 g, 1.4 mmol), and HO (30 mL). The mixture was stirred under N2 at 100 °C for 2 h. Upon cooling to room temperature, the reaction was quenched with HO. The mixture was extracted with EA (3 × 800 mL). The combined organic layers were washed with brine (3 × 800 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with CHCl2 / MeOH (50:1 to 20:1) to give the title compound (12 g, 82%) as a white solid. ES / MS m / z 515 [M+H] + .

[0364] Preparation 61 tert-Butyl 4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate [ka]

[0365] A mixture of tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (200 mg, 0.51 mmol), 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine (239.4 mg, 1 mmol), and Pd(PPh) (124 mg, 0.1 mmol) in aqueous KCO (2 M, 0.5 mL) and 1,4-dioxane (3 mL) was heated to 125 °C in a microwave and maintained at that temperature for 3 h. The reaction was loaded onto a reverse-phase cartridge and eluted with 5% to 100% ACN (0.1% TFA) in HO (0.1% TFA) to give the title compound (182 mg, 87%). ES / MS m / z 412 [M+H] + .

[0366] Preparation 62 tert-Butyl 4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl)piperidine-1-carboxylate [ka]

[0367] To 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (5 g, 18.2 mmol) and tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (6.93 g, 20.1 mmol) in 1,4-dioxane (80 mL) and HO (20 mL) was added KCO (7.56 g, 54.7 mmol) and Pd(DtBPF)Cl (0.24 g, 0.36 mmol) at room temperature under N. The reaction was stirred at 80 °C overnight. Upon cooling to room temperature, 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 x 80 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 30% to 60% EA in PE to give the title compound as a light brown solid (4.5 g, 60%). ES / MS m / z 413 [M+H] + .

[0368] The following compounds were prepared essentially as described in Preparation 62, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0369] [Table 10] 1 KOAc was used as the base. 2 It was purified by silica gel chromatography eluting with PE / EA (2:1 to 1:1).

[0370] Preparation 64 tert-Butyl 4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate [ka]

[0371] A mixture of tert-butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate (2 g, 5.8 mmol), 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (2.61 g, 8.7 mmol), 2 M aqueous NaCO solution (6.1 mL, 12.2 mmol), and Pd(PPh) (0.67 g, 0.58 mmol) in 1,4-dioxane (19.4 mL) was heated to 90 °C overnight. Upon cooling to room temperature, the reaction was treated with DCM and HO, and the layers were separated. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 10% to 90% EA in hex to give the title compound (738 mg, 29% yield). ES / MS m / z 437 [M+H] + .

[0372] Preparation 65 tert-Butyl 3-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]azetidine-1-carboxylate [ka]

[0373] To a solution of tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylate (2.50 g, 7.9 mmol) and 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (2.37 g, 7.9 mmol) in 1,4-dioxane (80 mL) and HO (20 mL) was added KCO (3.28 g, 23.7 mmol) and Pd(PPh) (0.09 g, 0.08 mmol) at room temperature under N. The mixture was stirred at 100 °C overnight. Upon cooling to room temperature, the reaction was quenched with HO (100 mL) and extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (10:1 to 1:1) to give the title compound (1.88 g, 58%) as a white solid. 1 H NMR (300MHz,DMSO-d6)δ 8.61 - 8.51 (m,2H),7.95 (s,1H),7.09 (d,1H),5.41 - 5.26 (m,1H),4.37 - 4.26 (m,2H),4.18 (d,2H),4.06 (s,3H),2.41 (s,3H),1.43 (s,9H).

[0374] The following compounds were prepared essentially as described in Preparation 65, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0375] [Table 11-1] [Table 11-2] [Table 11-3] 1 It was purified by silica gel chromatography eluting with PE / EA (5:1 to 1:1). 2 Purification was by C18 reverse flash chromatography, eluting with 60%-63% ACN in H2O (0.1% NH4HCO3). 3 The product was purified by silica gel chromatography and eluted with PE / EA (5:1 to 1:1). 4 Pd(dppf)Cl2 was used as the catalyst. 5 Purification was by C18 reverse flash chromatography, eluting with 60%-70% ACN in H2O. 6 Purification was carried out by silica gel chromatography, eluting with PE / EA (1:2). 7 The product was purified by silica gel chromatography and eluted with PE / EA (3:1 to 1:1). 8 The product was purified by silica gel chromatography and eluted with PE / EA (4:1 to 3:1). 9 The product was purified by silica gel chromatography and eluted with PE / EA (3:1 to 2:1). 10 Purified by preparative TLC eluting with PE / EA (1:1). 11 Pd(OAc) and PCy were used as catalysts, with KPO used as base and toluene / HO used as solvent. Purification was performed by silica gel chromatography, eluting with PE / EA (5:1). 12 Pd(OAc) and PCy were used as catalysts, with KPO as the base and toluene / HO as the solvent. Purification was performed by silica gel chromatography, eluting with PE / EA (10:1 to 8:1). 13 KF was used as the base. Purification was performed by C18 reverse-phase chromatography, eluting with 35%-45% ACN in H2O (0.1% NH3H2O). 14KF was used as the base. Purification was carried out by silica gel chromatography, eluting with PE / EA (3:1 to 1:1). 15 Purification was by C18 reverse-phase flash chromatography, eluting with 30%-50% ACN in H2O (0.1% FA). 16 Purification was by C18 reverse-phase flash chromatography, eluting with 44%-49% ACN in H2O (0.1% NH4HCO3).

[0376] Preparation 85 tert-Butyl (3S,4R)-3-hydroxy-4-[4-[4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate [ka]

[0377] To a solution of [4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]boronic acid (178 mg, 0.68 mmol) and tert-butyl (3S,4R)-4-(4-bromo-5-methyl-triazol-1-yl)-3-hydroxy-piperidine-1-carboxylate (225 mg, 0.62 mmol) in DMF (2.5 mL) was added KPO (4 M, 528 mg, 2.5 mmol) in HO. The mixture was sparged with N, and then Xphos Pd G was added (24 mg, 0.03 mmol). The mixture was resparged with N and then heated at 65 °C for 3 h. The reaction was diluted with HO (100 mL), extracted with EA, dried over NaSO, filtered, and concentrated. The residue was purified by reverse phase chromatography eluting with ACN in H2O to give the title compound (214 mg, 69%) as a pale green solid. ES / MS m / z 497 [M+H] + . Preparation 86 tert-Butyl 4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl)piperidine-1-carboxylate [ka]

[0378] A solution of tert-butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (16.1 g, 39 mmol) in CHCl3 (50 mL) was treated with PPTS (981 mg, 3.9 mmol) followed by NCS (5.21 g, 39 mmol). The reaction was stirred at 40 °C for 95 minutes. Upon cooling to room temperature, the reaction was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0% to 100% EA in heptane to afford the title compound (17.7 g, 101%) as a colorless solid. ES / MS m / z 391 [M+2H-tBu] + .

[0379] Preparation 87 3-[4-[4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]cyclobutanol [ka]

[0380] A solution of 3-[4-[4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]cyclobutanol (12 g, 23.3 mmol) in DCM (120 mL) was treated with NCS (2.96 g, 22.2 mmol) at room temperature. The mixture was stirred under N at room temperature for 2 hours. The mixture was then diluted with HO (500 mL) and extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over NaSO, filtered, and concentrated. The residue was purified by C reverse flash chromatography eluting with 50%-60% ACN in HO to give the title compound (12 g, 94%) as a white solid. ES / MS m / z 549 [M+H] + .

[0381] Preparation 88 4-(2-(benzyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(1-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-chloropyrazolo[1,5-a]pyridine, isomer 1 and Preparation 89 4-(2-(benzyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(1-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-chloropyrazolo[1,5-a]pyridine, isomer 2 [ka]

[0382] To a mixture of (1r,3r)-3-[4-[4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]cyclobutanol (12 g, 21.86 mmol) and imidazole (2.98 g, 43.72 mmol) in DCM (120 mL) was added TBDMSCl (3.95 g, 26.23 mmol) at room temperature under N. The mixture was stirred for 1 h. The reaction was quenched with HO and extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (4:1) to give the racemic title compound (9.5 g, 66%) as a white solid. ES / MS m / z 663 [M+H] + .

[0383] The enantiomers were isolated by preparative chiral HPLC using the following conditions: Column: NB_ASA CHIRALPAK IG_2, 5 x 30 cm, 10 μm, eluted with 35% MeOH / DCM (1:1) (0.1% DEA) in CO2. (R) 6.31 min (4.0 g, 42%), ee 98%, 4-(2-(benzyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(1-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-chloropyrazolo[1,5-a]pyridine, Isomer 1, ES / MS m / z 663 [M+H] + , and t (R) 8.02 min (4.3 g, 45%), ee 98%, 4-(2-(benzyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(1-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-chloropyrazolo[1,5-a]pyridine, isomer 2, ES / MS m / z 663, [M+H] + obtained.

[0384] Preparation 90 (1r,3r)-3-[4-[4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]cyclobutanol, isomer 1 [ka]

[0385] To a solution of 4-(2-(benzyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(1-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-chloropyrazolo[1,5-a]pyridine, isomer 1 (4.0 g, 6.03 mmol) in MeOH (40 mL) was added HCl (2.97 g, 30.16 mmol, 37%) at room temperature under N. The mixture was stirred for 2 h. The reaction was quenched with saturated aqueous NaHCO (30 mL). The crude product was recrystallized from HO / PE (1:1, 400 mL) to give the title compound (2.07 g, 63%) as a white solid. ES / MS m / z 549 [M+H] + .

[0386] Preparation 91 tert-Butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate [ka]

[0387] A stirred room temperature solution of tert-butyl 4-(4-[5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (500 mg, 1.2 mmol) in DCM (6 mL) was treated with NIS (300 mg, 1.3 mmol) and stirred at room temperature for 8 h. The mixture was diluted with EA (100 mL) and washed with HO (20 mL) and brine (20 mL). The combined organic extracts were dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give the title compound (820 mg, crude), which was used directly without further purification. ES / MS m / z 539 [M+H] + .

[0388] Preparation 92 tert-Butyl 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate [ka]

[0389] A solution of tert-butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (800 mg, crude), DMF (8 mL), and CuCN (173.01 mg, 1.9 mmol) was stirred at 100 °C under N for 2 h. The mixture was diluted with DCM (100 mL) and washed with HO (20 mL), followed by brine (20 mL). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18; elution with a gradient of 50% to 70% ACN in HO (0.1% FA) to give the title compound (450 mg, 46%). ES / MS m / z 438 [M+H] + .

[0390] Preparation 93 tert-Butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl)piperidine-1-carboxylate [ka]

[0391] A solution of tert-butyl 4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (10.24 g, 22.9 mmol) and NDM (23.19 g, 114.6 mmol) in DMA (40 mL) was treated with NaOH (4.58 g, 114.6 mmol). The reaction was stirred at 80 °C overnight. Upon cooling to room temperature, HO (300 mL) was added and the pH was adjusted to 5-6 by the addition of FA. The mixture was stirred for 30 min and then filtered through a cotton plug to collect the solid. The solid was dissolved in DCM, transferred to a separatory funnel, and the phases were separated. The organic layer was filtered through NaSO, diluted with heptane, and concentrated to remove DCM. The residue was triturated with heptane and filtered to collect a pale yellow solid that was dissolved in CHCl. The solution was purified by silica gel chromatography eluting with 0% to 10% MeOH in DCM to give the title compound (7.53 g, 76%) as a pale yellow solid. ES / MS m / z 377 [M+2H-tBu] + .

[0392] The following compounds were prepared essentially as described in Preparation 93, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0393] [Table 12] 1 The pH of the mixture was acidified to 4 with FA. The mixture was stirred at room temperature under N for 3 h. The resulting precipitate was collected by filtration and then washed with HO (3 x 10 mL) and PE (3 x 10 mL). 2 Workup: The reaction was diluted with H2O and PE. The mixture was acidified with FA to pH 4. The precipitated solid was collected by filtration.

[0394] Preparation 96 tert-Butyl (3S,4R)-3-hydroxy-4-[4-[4-hydroxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate [ka]

[0395] To a solution of tert-butyl (3S,4R)-3-hydroxy-4-[4-[4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (214 mg, 0.43 mmol) in DMA (2 mL) was added a freshly prepared solution of NaOH (178 mg, 4.3 mmol) (50% in HO) and NDM (437 mg, 2.2 mmol) at room temperature under N. The mixture was stirred at 85 °C for 5 h. Upon cooling to room temperature, the mixture was diluted with HO (5 mL) and acidified to pH 4 with FA. The resulting precipitated solid was collected by filtration and washed with HO (3 × 10 mL) followed by heptane (3 × 10 mL). The precipitate was dried under vacuum to give the title compound (200 mg, 96%) as a yellow solid. ES / MS m / z 483 [M+H] + .

[0396] The following compounds were prepared essentially as described in Preparation 96, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0397] [Table 13] 1 Acidified to pH 4 with FA and the solid was collected by filtration.

[0398] Preparation 99 tert-Butyl (3S,4R)-4-[4-[4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-hydroxy-piperidine-1-carboxylate [ka]

[0399] To a solution of tert-butyl (3S,4R)-3-hydroxy-4-[4-[4-hydroxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (130 mg, 0.27 mmol) and CsCO (185 mg, 0.57 mmol) in ACN (4 mL) at room temperature was added slowly a solution of 2-bromo-1-(5-fluoropyridin-2-yl)ethan-1-one (76 mg, 0.30 mmol) in ACN (2 mL). After stirring for 2 h, the reaction was diluted with EA, filtered, and the filtrate was concentrated. The residue was purified by C18 reverse-phase chromatography, eluting with 10% to 100% ACN in HO to give the title compound (62 mg, 37%) as a yellow solid ES / MS m / z 620 [M+H]. + was obtained as.

[0400] The following compounds were prepared essentially as described in Preparation 99, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0401] [Table 14]

[0402] Preparation 101 tert-Butyl 4-[4-[4-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-(2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate [ka]

[0403] To [(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-(2-pyridyl)ethyl] 4-methylbenzenesulfonate (1.44 g, 3.5 mmol) in DMF (8.0 mL) at room temperature was added tert-butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1.68 g, 3.9 mmol) and CsCO (1.15 g, 3.5 mmol). The mixture was heated at 55 °C for 4 h. Upon cooling to room temperature, the reaction was diluted with HO (25 mL) and extracted with DCM (3 × 25 mL). The combined organic layers were concentrated and then purified by silica gel chromatography eluting with 0% to 100% EA in heptane to give the title compound (1.40 g, 59%) as a white foam. ES / MS m / z 668 [M+H] + .

[0404] Preparation 102 tert-Butyl 4-[4-[3-chloro-4-[(1R)-1-(1-methylpyrazol-3-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate [ka]

[0405] A mixture of PPh3 (364 mg, 1.4 mmol) and DIAD (234 mg, 1.2 mmol) in THF (4.0 mL) was stirred at 0 °C for 30 min. Next, a mixture of tert-butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (200 mg, 0.46 mmol) and (S)-1-(1-methyl-1H-pyrazol-3-yl)ethan-1-ol (69.9 mg, 0.55 mmol) in THF (1 mL) was added, and the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography, eluting with 0% to 100% ACN in HO to give the title compound (205 mg, 82%). ES / MS m / z 541 [M+H] + .

[0406] The following compounds were prepared essentially as described in Preparation 102, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0407] [Table 15] 1 Fractions containing the title compound from the reverse-phase chromatography were combined and concentrated to remove ACN. The aqueous solution was extracted with DCM (3x) and the combined organic layers were concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 10% MeOH in DCM. 2 Purification was by C18 reverse flash chromatography, eluting with 505-70% ACN in H2O (0.1% NH4HCO3). 3 Purification was performed by reverse phase chromatography using the following conditions: column, C18, eluted with 50%-60% ACN in H2O (0.1% FA). 4 The product was purified by silica gel chromatography and eluted with PE / EA (2:1 to 0:1).

[0408] Preparation 109 tert-Butyl (3S,4R)-4-[4-[4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-hydroxy-piperidine-1-carboxylate [ka]

[0409] To a solution of tert-butyl (3S,4R)-4-[4-[4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-hydroxy-piperidine-1-carboxylate (62 mg, 0.10 mmol) in MeOH (2 mL) at room temperature was added NaBH (4.5 mg, 0.12 mmol). After 10 min, the reaction was concentrated. The residue was treated with EA and HO, the phases were separated, and the aqueous layer was extracted with EA (2 × 20 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give the title compound (58 mg, 94%) as a pale yellow solid. ES / MS m / z 622 [M+H] + .

[0410] Preparation 110 tert-Butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-propoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate [ka]

[0411] To a solution of tert-butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (180 mg, 0.33 mmol) in THF (8 mL) at room temperature, MeMgBr (3 M solution) (58.2 mg, 0.49 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NH4Cl, extracted into EA (2x), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 100% EA in heptane, to give the title compound (90 mg, 49%) as a white solid. ES / MS, m / z 570 [M+H] + .

[0412] Preparation 111 tert-Butyl 4-[4-[4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate, isomer 1 [ka]

[0413] To tert-butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (300 mg, 0.69 mmol) was added [2-benzyloxy-1-(5-fluoro-2-pyridyl)ethyl] 4-methylbenzenesulfonate, Isomer 1 (320 mg, 0.80 mmol) and CsCO (339 mg, 1.04 mmol) in DMF (3 mL). The mixture was flushed with N and stirred at 60 °C for 2.5 h. The reaction was allowed to cool to room temperature, diluted with HO, extracted with EA, and washed with a 10% aqueous solution of LiCl. The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0% to 100% EA in heptane to give the title compound (0.43 g, 93%). ES / MS, m / z 662 [M+H] + .

[0414] Preparation 112 4-Methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0415] tert-Butyl 4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (738 mg, 1.7 mmol) was stirred in TFA (5 mL) and DCM (5.6 mL) at room temperature for 30 minutes and then concentrated. To the reaction was added DCM and saturated aqueous NaHCO3. The layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (0.56 g, 98%). ES / MS m / z 337 [M+H] + .

[0416] The following compounds were prepared essentially as described in Preparation 112, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0417] [Table 16] 1 After concentration, the reaction was basified with Na2CO3 and extracted with EA to give the product. 2 After concentration, the solid was triturated with Et2O and collected by filtration to give the product. 3 The reaction was concentrated and the residue was taken without purification.

[0418] Preparation 117 6-[1-(azetidin-3-yl)-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0419] A solution of tert-butyl 3-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]azetidine-1-carboxylate (480 mg, 1.18 mmol) and TFA (20 mL) in DCM (20 mL) was stirred at room temperature under N for 30 minutes. The mixture was concentrated, and the residue was basified to pH 8 with saturated aqueous NaHCO. The resulting mixture was extracted with DCM / IPA (3:1) (3 × 100 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by C reverse flash chromatography, eluting with 0% to 30% ACN in HO (0.1% FA) to afford the title compound (210 mg, 57%) as a white solid. ES / MS m / z 309 [M+H] + .

[0420] Preparation 118 tert-Butyl (3R)-3-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate [ka]

[0421] A solution of tert-butyl (3S)-3-(methanesulfonyloxy)pyrrolidine-1-carboxylate (400 mg, 1.5 mmol), 4-methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (101 mg, 0.30 mmol), and KCO (125 mg, 0.91 mmol) in toluene (8 mL) was stirred at 150 °C for 12 h. Upon cooling to room temperature, the reaction was concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (1:1 to 3:7) to afford the title compound (95 mg, 62%) as a yellow solid. ES / MS m / z 506 [M+H] + .

[0422] The following compounds were prepared essentially as described in Preparation 118, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0423] [Table 17] 1 Purification was performed by C18 reverse flash chromatography eluting with 50%-60% ACN in H2O (0.1% NH3H2O).

[0424] Preparation 120 tert-Butyl N-[1-[[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]methyl]cyclopropyl]carbamate [ka]

[0425] A mixture of 4-methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.30 mmol), ACN (4 mL), tert-butyl N-[1-(bromomethyl)cyclopropyl]carbamate (148 mg, 0.60 mmol), K2CO3 (102 mg, 0.74 mmol), and KI (74 mg, 0.45 mmol) was stirred at 80 °C for 5 h. Upon cooling to room temperature, EA (100 mL) was added and the mixture was washed with HO (3 × 30 mL). The layers were separated, and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (4:1 to 2:1) to give the title compound (65 mg, 43%) as a white solid. ES / MS m / z 506 [M+H] + .

[0426] The following compounds were prepared essentially as described in Preparation 120, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0427] [Table 18] 1 The product was purified by silica gel chromatography and eluted with PE / EA (1:1 to 1:3).

[0428] Preparation 122 tert-Butyl 4-((1s,3s)-3-(4-(4-(2-(benzyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutyl)piperazine-1-carboxylate, isomer 1 [ka]

[0429] A solution of 3-[4-[4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]cyclobutanol, Isomer 1 (150 mg, 0.27 mmol) and DIPEA (177 mg, 0.23 mmol) in DCM (2 mL) was cooled to −78° C. and then treated with trifluoromethanesulfonic anhydride (1.16 g, 0.41 mmol). The reaction was stirred at −78° C. for 15 minutes. The reaction was then treated with a mixture of DIPEA (177 mg, 1.4 mmol) and tert-butyl-1-piperazinecarboxylate (56.0 mg, 0.30 mmol) in DCM (2 mL). The mixture was heated at 40° C. overnight. The mixture was purified by silica gel chromatography eluting with 0% to 100% EA in DCM (12 cv) followed by 0% to 30% MeOH in DCM (8 cv) to give the title compound (196 mg, 100%) as a brown residue. ES / MS m / z 717 [M+H] + .

[0430] Preparation 123 tert-Butyl N-[3-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]cyclobutyl]carbamate, P1 [ka] and Preparation 124 tert-Butyl N-[3-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]cyclobutyl]carbamate, P2 [ka]

[0431] NaBH(OAc)3 (76 mg, 0.36 mmol) was added to tert-butyl N-(3-oxocyclobutyl)carbamate (22 mg, 0.12 mmol) and 4-methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (40 mg, 0.12 mmol) in DCM (0.7 mL) at room temperature and stirred overnight. The mixture was loaded onto a silica gel column and eluted with 1% to 10% MeOH in DCM (containing 1% NH4OH) to give trans-tert-butyl N-[3-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]cyclobutyl]carbamate, P1 (25 mg, 42%), 1%. 1 H NMR (400MHz,CDCl3)δ ppm 1.44 (s,9 H)1.65 - 1.75 (m,2 H)1.87 - 1.99 (m,4 H)2.19 - 2.38 (m,2 H)2.38 - 2.47 (m,4 H),2.56 (m,1 H),3.03 (m,2 H),3.82 - 3.95 (m,1 H),4.05 (m,4 H),4.59 - 4.71 (m,1 H),6.67 (s,1 H),7.61 (s,1 H),8.12 (s,1 H),8.16 (s,1H), and tert-butyl N-[3-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]cyclobutyl]carbamate, P2 (23 mg, 38%), 1 H NMR (400MHz,CDCl3)δ ppm 1.38 - 1.51 (s,9H),1.87 - 1.99 (m,4 H),2.02 (m,2 H),2.24 - 2.38 (m,4 H),2.41 (s,3 H),2.93 - 3.02 (m,1 H),3.06 (m,2 H),4.05 (m,4 H),4.63 - 4.84 (m,1 H),6.68 (s,1 H),7.61 (s,1 H),8.12 (s,1 H),8.16 (s,1 H) were obtained.

[0432] The following compounds were prepared essentially as described in Preparations 123 and 124, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting the purification system accordingly.

[0433] [Table 19] 1 1 H NMR (400MHz,CDCl3)δ ppm 1.45 (s,9 H),1.62 (m,2 H),1.91 (m,2 H),2.0-2.1 (m,2H)2.11 - 2.19 (m,1 H),2.34 (m,3 H),2.41 (s,3 H),2.44 - 2.55 (m,1 H),2.83 (m,1 H),3.32 (m,2 H),4.05 (m,4 H),4.20 (m,1 H),5.15 (m,1 H),6.66 (s,1H),7.60 (s,1 H),8.10 - 8.18 (m,2 H). 2 1 H NMR(400MHz,CDCl3)δ ppm 1.45 (s,9 H),1.54 - 1.72 (m,2 H),1.78 (m,1 H),1.98 - 2.05 (m,4 H),2.10 - 2.19 (m,1 H),2.27 - 2.38 (m,4 H),2.40 - 2.44 (m,3 H),3.02 (m,1 H),3.25 (m,2 H),4.05 (m,4 H,)4.14 (m,1 H),6.67 (s,1 H),7.61 (s,1 H),8.10 - 8.17 (m,2 H). 3 1H NMR (400MHz,CDCl3)δ ppm 1.45 (s,9 H),1.59 - 1.73 (m,1 H),1.73 - 1.84 (m,1 H),1.95 - 2.06 (m,4 H),2.13 - 2.23 (m,1 H),2.24 - 2.45 (m,7 H),3.04 (m,1 H),3.26 (m,2 H),4.05 (m,4 H),4.11 - 4.21 (m,1 H),4.49 - 4.67 (m,1 H),6.66 (s,1 H),7.61 (s,1 H),8.08 - 8.17 (m,2 H). 4 1 H NMR (400MHz,CDCl3)δ ppm 1.45 (s,9 H),1.59 - 1.73 (m,2 H),1.85 - 1.98 (m,3 H),2.0 - 2.1 (m,1H),2.15 - 2.22 (m,1 H),2.35 (s,3H),2.39 - 2.45 (m,3 H),2.60 (m,1 H),2.91 (m,1 H),3.36 (m,2 H),4.05 (m,4 H),4.24 (m,1 H),5.28 (m,1 H),6.66 (s,1 H),7.60 (s,1 H),8.09- 8.19 (m,2 H).

[0434] Preparation 130 tert-Butyl 4-[3-[4-[3-cyano-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]azetidin-1-yl]piperidine-1-carboxylate [ka]

[0435] To a solution of 6-[1-(azetidin-3-yl)-5-methyl-triazol-4-yl]-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid (363 mg) and tert-butyl 4-oxopiperidine-1-carboxylate (722 mg, 3.63 mmol) in MeOH (5 mL) was added AcOH (54 mg, 0.91 mmol) at room temperature under N. The mixture was stirred at 50° C. for 30 minutes. Upon cooling to room temperature, NaBHCN (85 mg, 1.4 mmol) was added. The reaction was stirred at 50° C. for 3 hours. Upon cooling to room temperature, the reaction was quenched with saturated aqueous NaHCO (30 mL). The mixture was extracted with CHCl3 / i-PrOH (3:1) (3 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by C18 reverse-phase flash chromatography eluting with 58%-65% ACN in HO (0.1% FA) to give the title compound (297 mg, 56%) as a pale yellow solid. ES / MS m / z 584 [M+H] + .

[0436] The following compounds were prepared essentially as described in Preparation 130, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting the purification system accordingly.

[0437] [Table 20] 1 Workup: The reaction was quenched with H2O and extracted with EA (3x), the organic layers were combined, dried over Na2SO4, filtered and concentrated. 2 Workup: The reaction was quenched with HO and extracted with EA (3x), the organic layers were combined, dried over NaSO, filtered and concentrated, and the residue was purified by C reverse-phase flash chromatography eluting with 45% ACN in HO (0.1% NHHCO). 3The completed reaction was basified with Na2CO3, concentrated and purified by preparative TLC eluting with PE / EA (1:1).

[0438] Preparation 134 6-[1-[1-(3-aminocyclobutyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid, P1 [ka]

[0439] Trans-tert-butyl N-[3-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]cyclobutyl]carbamate (23 mg, 0.05 mmol) was stirred in TFA (0.13 mL, 1.8 mmol) and DCM (5.6 mL) at room temperature for 30 minutes, then concentrated to give the title compound (18 mg, 76%). ES / MS m / z 406 [M+H] + .

[0440] The following compounds were prepared essentially as described in Preparation 134, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting the purification system accordingly.

[0441] [Table 21-1]

[0442] [Table 21-2]

[0443] [Table 21-3] 1The reaction was concentrated and diluted with DCM and saturated aqueous NaHCO3 The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. 2 The reaction was concentrated and diluted with CHCl3 / IPA (3:1) and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. 3 Purification was carried out by C18 reverse flash chromatography, eluting with 25%-30% ACN in H2O (0.1% TFA). The residue was neutralized to pH 10 with saturated aqueous Na2CO3 and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. 4 Purification was by C18 reverse-phase flash chromatography, eluting with 60%-70% ACN in H2O (0.1% NH4HCO3). 5 The product was recrystallized from EA / PE. 6 Purification was by C18 reverse-phase flash chromatography, eluting with 20%-30% ACN in H2O (0.1% NH4HCO3). 7 Purification was by C18 reverse-phase flash chromatography, eluting with 10% to 30% ACN in H2O (0.1% TFA). 8 The reaction was concentrated, the pH adjusted to 9 with saturated aqueous Na2CO3, extracted with EA (3 x 200 mL), and concentrated. The residue was purified by C18 reverse-phase flash chromatography, eluting with 40% to 60% ACN in H2O (0.1% NH3H2O). 9 The reaction was concentrated, the pH adjusted to 9 with saturated aqueous NaCO, extracted with EA (3 x 30 mL), and concentrated. The residue was purified by C reverse-phase flash chromatography, eluting with 50%-70% ACN in HO (0.1% FA). 10Purification was performed by preparative HPLC. Column: Xbridge Shield RP18 OBD, 19 x 150 mm, 5 mm; eluted with 20%-35% ACN in H2O (10 mmol / L NH4HCO3). 11 Purification was performed by preparative HPLC. Column: Xbridge Shield RP18 OBD, 19 x 150 mm, 5 mm; eluted with 18% to 33% ACN in H2O (10 mmol / L NH4HCO3).

[0444] Preparation 154 (3S,4R)-4-[4-[4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidin-3-ol dihydrochloride [ka]

[0445] To tert-butyl (3S,4R)-4-[4-[4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]-3-(trifluoro-methyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-hydroxy-piperidine-1-carboxylate (58 mg, 0.09 mmol) was added DCM (1 mL) followed by a solution of HCl in 1,4-dioxane (13.7 mg, 0.38 mmol, 4 M) at room temperature. After stirring for 30 minutes, the reaction was concentrated to give the title compound (52 mg, 100%) ES / MS m / z 522 [M+H]. + obtained.

[0446] The following compounds were prepared essentially as described in Preparation 154, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting the purification system accordingly.

[0447] [Table 22-1]

[0448] [Table 22-2]

[0449] [Table 22-3] 1 After the addition of HCl, the reaction was stirred for 1 h, cooled to 0° C., and MTBE was added. The precipitate was collected by filtration and dried under a blanket of N2 until the solid reached ambient temperature. 2 The reaction was concentrated and the residue was purified by reverse phase chromatography, eluting with 0% to 100% ACN in H2O. 3 The residue was washed with EA (3x). 4 The reaction was concentrated and the residue was purified by reverse phase chromatography: Column: Xbridge Prep C18 OBD, 19 x 150 mm, 5 μm; eluted with 20% to 58% ACN in H2O (0.05% NH3H2O). 5 Purification was performed by preparative HPLC. Column: Gemini-NXC18 AXAI, 21.2 × 150 mm, 5 μm; elution was performed with 18% to 37% ACN in H2O (10 mmol / L NH4HCO3). 6 1,4-Dioxane was used as the solvent. 7 Work-up: The suspension was filtered and the filter cake was washed with EA to give the title compound. 8 The crude product was recrystallized from EA. 9 Purification was by reverse phase chromatography on a C18 column, eluting with 20%-30% ACN in H2O (0.1% HCl). 10 Purification was performed by preparative HPLC. Column: Xbridge Shield RP18 OBD, 19 x 150 mm, 5 mm; elution was performed with 5% to 25% ACN in H2O (0.1% FA). 11 The reaction was concentrated to give the title compound, which was used without purification. 12 The reaction was concentrated and the residue was purified by reverse phase chromatography: Column: Xbridge Shield RP18 OBD, 19 x 150 mm, 5 mm; eluted with 5% to 25% ACN in H2O (0.1% formic acid). 13 The crude product was recrystallized from MeOH / EA (4 mL:80 mL).

[0450] Preparation 174 2-[3-chloro-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol, hydrochloride, isomer 1 [ka]

[0451] tert-Butyl 4-[4-[4-[2-benzyloxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate, isomer 1 (1.7 g, 2.6 mmol) was dissolved in DCM (20 mL) and cooled to −78 °C. After 20 min, a solution of BCl (1 M in DCM) (0.90 g, 7.7 mmol) was added over 5 min, and the temperature was maintained at −78 °C for 5 h. At this point, additional BCl (1 M in DCM) (0.90 g, 7.7 mmol) was added. After stirring for an additional 1 h, the reaction was slowly quenched with DCM / MeOH (1:1, 30 mL). The reaction was allowed to warm to room temperature, and then the reaction was concentrated in vacuo. The residue was dissolved in a small amount of MeOH and purified by C18 reverse phase chromatography to give the title compound (1.2 g, 92%) as a white solid.

[0452] Preparation 175 4-(2-(benzyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloro-6-(5-methyl-1-(3-(piperazin-1-yl)cyclobutyl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine, isomer 1 [ka]

[0453] A solution of tert-butyl 4-(3-(4-(4-(2-(benzyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutyl)piperazine-1-carboxylate, P1 (196 mg, 0.27 mmol) in DCM (2 mL) was cooled to −78° C., then treated with BCl3 (96 mg, 0.82 mmol) and allowed to warm to room temperature with stirring for 3 h. The reaction was quenched with MeOH and concentrated to give the title compound (144 mg, 100%) as an off-white solid. ES / MS m / z 527 [M+H] + .

[0454] Preparation 176 6-[1-[1-(2-cyanoacetyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0455] DIPEA (0.68 mL, 3.89 mmol) was added to 4-methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (654 mg, 1.9 mmol), 2-cyanoacetic acid (182 mg, 2.1 mmol), and HATU (813 mg, 2.1 mmol) in DCM (13 mL) and stirred overnight at room temperature. The mixture was concentrated. The residue was purified by silica gel chromatography eluting with 1% to 10% MeOH in DCM to give the title compound (775 mg, 98%). ES / MS m / z 404 [M+H] + .

[0456] Preparation 177 tert-Butyl 2-[3-cyano-4-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]-1,1-dimethyl-4-oxo-but-2-enyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka]

[0457] To a solution of 6-[1-[1-(2-cyanoacetyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.25 mmol), tert-butyl 2-(1,1-dimethyl-2-oxo-ethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (220 mg, 0.74 mmol) in DCM (3 mL) was added pyrrolidine (88 mg, 1.2 mmol), and TMSCl (134 mg, 1.2 mmol). The solution was stirred at room temperature for 1 hour and then concentrated. HO (10 mL) was added, and the mixture was extracted with EA (3 × 20 mL). The combined organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with DCM / IPA (13:1 to 10:1) to give the title compound (60 mg, 35%) as a yellow solid. ES / MS m / z 682 [M+H] + .

[0458] Preparation 178 6-[1-[1-[4-[tert-butyl(dimethyl)silyl]oxy-2-cyano-4-methyl-pent-2-enoyl]-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0459] To a solution of 6-[1-[1-(2-cyanoacetyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (80 mg, 0.2 mmol) and 2-[(tert-butyldimethylsilyl)oxy]-2-methylpropanal (60 mg, 0.3 mmol) in DCM (5 mL) was added TMSCl (107 mg, 0.99 mmol), pyrrolidine (71 mg, 0.99 mmol), and 4Å MS (100 mg) at room temperature under N2. The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by preparative TLC eluting with 50% EA in PE to give the title compound (90 mg, 77%) as a white solid. ES / MS m / z 588 [M+H] + .

[0460] Example 1 N-[3-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]cyclobutyl]prop-2-enamide, P1 [ka]

[0461] DIPEA (0.03 mL, 0.17 mmol) was added to a solution of trans-6-[1-[1-(3-aminocyclobutyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid (18 mg, 0.03 mmol) and acryloyl chloride (0.003 mL, 0.04 mmol) in DCM (0.35 mL) at room temperature. After stirring at room temperature for 2 hours, the reaction was concentrated. The residue was purified on a C18 column and eluted with 5% to 95% ACN in HO (1% TFA). The fractions containing the title compound were combined, concentrated, and then treated with DCM and saturated aqueous Na2CO3 and separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (3.1 mg, 18%). ES / MS m / z 460 [M+H] + .

[0462] Example 2 4-Methoxy-6-[5-methyl-1-(1-prop-2-enoyl-4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0463] Acryloyl chloride (0.01 mL, 0.1 mmol) was added to 4-methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (27 mg, 0.08 mmol) and DIPEA (0.02 mL, 0.1 mmol) in DCM (0.8 mL) at room temperature. After 30 minutes, the mixture was concentrated. The residue was purified by silica gel chromatography eluting with 1% to 10% MeOH in DCM to give the title compound (8.9 mg, 28%). ES / MS m / z 391 [M+H] + .

[0464] The following compounds were prepared essentially as described in Example 2, using the appropriate reagents, adjusting the temperature and reaction time to determine reaction completion, and adjusting the purification system accordingly.

[0465] [Table 23-1]

[0466] [Table 23-2]

[0467] [Table 23-3]

[0468] [Table 23-4]

[0469] [Table 23-5] 1 Purification was by C18 reverse-phase flash chromatography, eluting with 10% to 50% ACN in H2O (0.1% NH4HCO3). 2 NEt3 was used as the base. 3 Purification was by preparative HPLC using the following conditions: Column: YMC-Actus Triart C18, 20 x 250 mm, 5 μm, eluted with 34%-53% ACN in H2O. 4 Purification was by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD, 19 x 150 mm, 5 μm, eluted with 15%-42% ACN in H2O (0.1% FA). 5 Purified by prep-HPLC using the following conditions: Column: Phenomenx Luna, 5 μm C18 100A LC; 250×21.2 mm, eluted with 10%-100% ACN in H2O. 6 Purification was performed by C18 reverse flash chromatography, eluting with 20%-30% ACN in H2O (0.1% FA). 7 Purification was performed by preparative HPLC using the following conditions: Column: Gemini-NX C18 AXAI, 21.2 x 150 mm, 5 μm, eluted with 24%-38% ACN in H2O (0.05% FA). 8 Purification was by C18 reverse phase flash chromatography, eluting with 45%-50% ACN in H2O. 9 Purification was by C18 reverse-phase flash chromatography, eluting with 30%-60% ACN in H2O (0.1% FA). 10Purified by preparative HPLC using the following conditions: Column: SunFire Prep C18 OBD, 19 x 150 mm, 5 μm, eluted with 32%-46% ACN in H2O. 11 Purification was by C18 reverse phase flash chromatography, eluting with 30%-50% ACN in H2O. 12 Purification was by C18 reverse-phase flash chromatography, eluting with 40%-60% ACN in H2O (0.1% NH3-H2O). 13 Purification was by C18 reverse-phase flash chromatography, eluting with 40%-50% ACN in H2O (0.1% NH4HCO3). 14 Purification was performed by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD, 19 x 150 mm, 5 mm, eluted with 28%-31% ACN in H2O (10 mmol / L NH4HCO3). 15 Purification was by C18 reverse phase chromatography, eluting with 0% to 100% ACN in H2O (0.1% FA). 16 Purification was performed by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD, 19 x 150 mm, 5 mm, eluted with 26%-40% ACN in H2O (10 mmol / L NH4HCO3). 17 Purification was performed by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD, 19 x 150 mm, 5 mm, eluted with 31%-46% ACN in H2O (10 mmol / L NH4HCO3). 18 It was purified by silica gel chromatography eluting with MeOH / DCM (25:1 to 20:1) and then recrystallized from hexane / DCM (200:1). 19 Purification was by C18 reverse-phase flash chromatography, eluting with 30%-40% ACN in H2O (0.1% NH3-H2O). 20Purification was performed by preparative HPLC using the following conditions: Column: XBridge Prep C18 OBD, 19 x 150 mm, 5 mm, eluted with 23%-34% ACN in H2O (10 mmol / L NH4HCO3). 21 Purification was by reverse-phase C18 flash chromatography, eluting with 30%-50% ACN in H2O (0.1% NH4HCO3). 22 Purification was performed by C18 reverse-phase chromatography, eluting with 5% to 95% ACN in H2O (1% TFA). The fractions were concentrated, and the residue was treated with DCM and washed with saturated aqueous Na2CO3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. 23 The reaction was diluted with DCM / IPA (3:1) and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in ACN / H2O (2% TFA) (1:1) and purified on a C18 column. The product was eluted with 5% to 95% ACN in H2O. Fractions containing the title compound were combined, and the pH was adjusted to approximately 8.0 with saturated aqueous NaHCO3. The solution was extracted with CHCl3 / IPA (3:1). The organic layer was washed with H2O, brine, dried over Na2SO4, filtered, and concentrated to give the title compound. 24 Purification was by C18 reverse-phase flash chromatography, eluting with 30%-40% ACN in H2O (0.1% NH4HCO3). 25 Purified by preparative HPLC: Column: SunFire Prep C18 OBD column, 19 x 150 mm 5 μm, eluted with 12%-22% ACN in H2O (0.1% FA). 26 Purification was by C18 reverse-phase flash chromatography, eluting with 15%-30% ACN in H2O (0.1% FA). 27 Purified by silica gel chromatography eluting with 0% to 10% MeOH in DCM. 28It was purified by C18 reversed-phase flash chromatography eluting with 25%-40% ACN in H2O (0.1% FA).

[0470] Example 36 1-[4-[4-[3-chloro-4-[(1R)-1-(1-methylpyrazol-3-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidyl]prop-2-en-1-one [ka]

[0471] To a mixture of 3-chloro-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]-4-[(1R)-1-(1-methylpyrazol-3-yl)ethoxy]pyrazolo[1,5-a]pyridine hydrochloride (77 mg, 0.17 mmol) and DIPEA (0.11 g, 0.87 mmol) in DCM (3 mL) was added acrylic anhydride (24 mg, 0.19 mmol), and the mixture was stirred for 20 minutes. Volatiles were removed under reduced pressure. The residue was purified by reverse-phase chromatography, eluting with 0% to 100% ACN in HO to give the title compound (29 mg, 34%). ES / MS m / z 495 [M+H] + .

[0472] The following compounds were prepared essentially as described in Example 36, using the appropriate reagents, adjusting reaction times to determine reaction completion, and adjusting the purification system accordingly.

[0473] [Table 24] 1 Purification was performed by reverse phase chromatography, eluting with 10% to 100% ACN in H2O (0.1% FA). 2 Purification was carried out by reverse phase chromatography, eluting with 10% to 100% ACN in H2O.

[0474] Example 42 1-[4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]prop-2-en-1-one [ka]

[0475] A solution of 4-methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine; 2,2,2-trifluoroacetic acid (44.27 mg, 0.14 mmol) and acrylic acid (38.2 mg, 0.53 mmol) in DMF (2 mL) was treated with HATU (83.5 mg, 0.22 mmol) and DIPEA (0.1 mL, 0.57 mmol) and stirred at room temperature for 1 h. The reaction was filtered and loaded onto a reverse-phase cartridge eluting with 10% to 100% ACN in HO to give an off-white solid. This solid was dissolved in 50% MeOH in DCM (3 mL) and loaded onto a bicarbonate cartridge (Agilent StratoSphere SPE). The cartridge was washed with 50% MeOH in DCM (3 mL) followed by 100% MeOH to give the title compound (18.3 mg, 33%). ES / MS m / z 366 [M+H] + .

[0476] Example 43 1-[4-[4-[3-chloro-4-[(1S)-2-hydroxy-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidyl]-2-fluoro-prop-2-en-1-one [ka]

[0477] (2S)-2-[3-chloro-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-2-(2-pyridyl)ethanol; dihydrochloride (55 mg, 0.10 mmol) and 2-fluoroacrylic acid (9.2 mg, 0.10 mmol) were added to a vial and then diluted with DCM (1 mL). DIPEA (53 mg, 0.41 mmol) was added, and the mixture immediately became homogeneous. T3P (0.13 g, 0.2 mmol) was added to the mixture, and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo. The residue was purified by C18 reverse-phase chromatography, eluting with 10% to 100% ACN in HO to give the title compound (38 mg, 71%). ES / MS m / z 526 [M+H] + .

[0478] Example 44 1-[(3S,4R)-4-[4-[4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-3-hydroxy-1-piperidyl]prop-2-en-1-one [ka]

[0479] (3S,4R)-4-[4-[4-[2-(5-Fluoro-2-pyridyl)-2-hydroxy-ethoxy]-3-(trifluoromethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidin-3-ol; dihydrochloride (52 mg, 0.09 mmol) was suspended in DCM (2 mL) and then DIPEA (114 mg, 0.88 mmol) was added. After stirring for 5 minutes, perfluorophenyl acrylate (20 mg, 0.08 mmol) was added. The reaction was stirred for an additional 5 minutes and concentrated. The residue was purified by C18 reverse-phase chromatography, eluting with 10% to 100% ACN in HO to give (14 mg, 28%) as a white powder. ES / MS m / z 576 [M+H]+ .

[0480] Example 45 6-[1-(1-but-2-ynoyl-4-piperidyl)-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0481] To a solution of 4-methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.3 mmol), 2-butynoic acid (38 mg, 0.45 mmol), and NMI (74 mg, 0.9 mmol) in ACN (5 mL) was added TCFH (127 mg, 0.45 mmol), and the mixture was stirred at 50 °C under N for 2 h. The solution was purified by C reverse-phase flash chromatography, eluting with 30% to 50% ACN in HO (0.1% NHHCO) to give the title compound (50 mg, 42%) as a white solid. ES / MS m / z 403 [M+H] + .

[0482] Example 46 7-[1-(1-but-2-ynoyl-4-piperidyl)-5-methyl-triazol-4-yl]-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile [ka]

[0483] To a solution of 5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile; hydrochloride (310 mg, 0.7 mmol) and 2-butynoic acid (88 mg, 1 mmol) in DCM (5 mL), HATU (1.32 g, 3.5 mmol) and DIPEA (269 mg, 2.1 mmol) were added portionwise at room temperature under N. The resulting mixture was stirred for 2 hours. The mixture was diluted with HO (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by C18 reverse-phase flash chromatography eluting with 60% to 70% ACN in H2O (0.1% NH4HCO3) to give the title compound (103 mg, 28%) as a white solid. ES / MS m / z 513 [M+H] + .

[0484] Example 47 6-[1-[1-(1-but-2-ynoyl-4-piperidyl)azetidin-3-yl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0485] To a mixture of 4-methoxy-6-[5-methyl-1-[1-(4-piperidyl)azetidin-3-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid (80 mg, 0.16 mmol), 2-butynoic acid (17 mg, 0.20 mmol), and DIPEA (61 mg, 0.47 mmol) in DCM (2 mL) was added T3P (50% in EA, 298 mg, 0.47 mmol) at room temperature under N2. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated. The residue was purified by reverse-phase flash chromatography eluting with 10% to 40% ACN in HO (0.1% NH3HO) to give the title compound (33 mg, 45%) as a pale green solid. ES / MS m / z 458 [M+H] + .

[0486] The following compounds were prepared essentially as described in Example 47, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0487] [Table 25] 1 It was purified by reverse-phase flash chromatography eluting with 0% to 70% ACN in H2O (0.1% FA).

[0488] Example 49 6-[1-[1-[2-cyano-4-methyl-pent-2-enoyl]-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0489] To a solution of 6-[1-[1-(2-cyanoacetyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (80 mg, 0.2 mmol) and piperidine acetate (29 mg, 0.2 mmol) in IPA (3 mL) was added isobutyraldehyde (14 mg, 0.20 mmol). The solution was stirred at 80 °C under N for approximately 2 h. Upon cooling to room temperature, the reaction was concentrated. The residue was purified by reverse-phase flash chromatography: C18 column, eluting with 20% to 40% ACN in HO (0.1% FA) to give the title compound (9.8 mg, 11%) as a red solid. ES / MS m / z 458 [M+H] + . 1 H NMR (400MHz,DMSO-d6)δ 8.58 (s,1H),8.54 (s,1H),7.83 (s,1H),7.09 (s,1H),6.95 (d,1H),4.68 - 4.58 (m,1H),4.52 - 4.30 (m,1H),4.14 - 3.93 (m,4H),3.58 - 3.43 (m,1H),3.11 - 2.92 (m,1H),2.89 - 2.75 (m,1H),2.49 (s,3H),2.09 - 1.82 (m,4H),1.12 (d,6H).

[0490] The following compounds were prepared essentially as described in Example 49, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0491] [Table 26] 1 NEt3 was used instead of piperidine acetate. 2 Purification was performed by C18 reverse-phase flash chromatography: column, C18, eluted with 25%-35% ACN in H2O (0.1% FA). 31H NMR (300MHz,CDCl3)δ 8.19 (s,1H),8.15 (d,1H),7.64 (s,1H),7.26 (q,1H),6.68 (s,1H),4.80 - 4.30 (m,3H),4.08 (s,3H),3.43 - 3.02 (m,2H),2.46 (s,3H),2.39 - 2.26 (m,2H),2.22 (d,3H),2.14 - 2.03 (m,2H).

[0492] Example 51 6-[1-[1-[2-cyano-3-(1-methylpyrazol-4-yl)prop-2-enoyl]-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0493] A solution of 6-[1-[1-(2-cyanoacetyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.10 mmol) in MeOH (6.2 mL) was treated with 1-methylpyrazole-4-carbaldehyde (23 mg, 0.21 mmol), followed by piperidine (0.02 mL, 0.21 mmol). The reaction was heated in a sealed tube at 50° C. overnight. Upon cooling to room temperature, the reaction was diluted with DCM / IPA (4:1) and the layers were separated. The organic layer was washed with HO, brine, dried over NaSO, filtered, and concentrated to give a yellow oil. The oil was dissolved in DCM. The solution was purified by silica gel chromatography, eluting with 0% to 20% MeOH in DCM. Fractions containing the title compound were combined and concentrated. The solid was dissolved in DMSO and HO was added dropwise with stirring until cloudiness persisted. The mixture was stirred for 30 min and then filtered to give the title compound (23 mg, 43% yield) as an off-white solid ES / MS m / z 496 [M+H] + was collected as.

[0494] The following compounds were prepared essentially as described in Example 51, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0495] [Table 27] 1 Workup: Concentrated. The residue was purified by reverse phase chromatography eluting with 5% to 95% ACN in H2O (1% TFA).

[0496] Example 53 6-[1-[1-[2-cyano-4-(2,2-difluoroethylamino)-4-methyl-pent-2-enoyl]-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0497] A solution of 2-(2,2-difluoroethylamino)-2-methyl-propanal (0.10 g, 0.66 mmol) and 6-[1-[1-(2-cyanoacetyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (0.13 g, 0.33 mmol) in iPrOH (15 mL) was treated with piperidine (0.17 g, 2 mmol) and stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was concentrated and the residue was dissolved in ACN (5 mL). The solution was loaded onto a C18 column and eluted with 10% to 50% ACN in HO (0.1% NH4HCO3) to give the title compound (28.4 mg, 10%) as an off-white solid. ES / MS m / z 537 [M+H] + .

[0498] Example 54 6-[1-[1-[2-cyano-3-isothiazol-4-yl-prop-2-enoyl]-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0499] A solution of 6-[1-[1-(2-cyanoacetyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (50 mg, 0.1 mmol) in MeOH (6.3 mL) was treated with isothiazole-4-carbaldehyde (23 mg, 0.2 mmol) followed by piperidine (0.02 mL, 0.2 mmol). The reaction was heated in a sealed tube at 50 °C overnight. Upon cooling to room temperature, the reaction was diluted with DCM / IPA (4:1) and the layers were separated. The organic layer was washed with HO, brine, dried over NaSO, filtered, and concentrated to give a yellow oil. The oil was dissolved in ACN / HO (2% TFA) (1:1) and loaded onto a C18 column. The material was eluted with 10% to 95% ACN in HO (0.1% FA). Fractions containing the title compound were combined and extracted with DCM / IPA (4:1). The organic layers were combined, washed with HO, brine, dried over NaSO, filtered, and concentrated to give a yellow oil. The oil was dissolved in DCM and purified by silica gel chromatography, eluting with 20% to 100% EA in DCM to give the title compound (25 mg, 49%). ES / MS m / z 499 [M+H] + .

[0500] Example 55 6-[1-[1-[2-cyano-4,4-dimethyl-5-morpholino-pent-2-enoyl]-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile [ka]

[0501] A solution of 6-[1-[1-(2-cyanoacetyl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.24 mmol), 2,2-dimethyl-3-(morpholin-4-yl)propanal (127 mg, 0.74 mmol), TMSCl (135 mg, 1.24 mmol), and pyrrolidine (88 mg, 1.24 mmol) in DCM (5 mL) was stirred at 50 °C for 1 h under N. The resulting mixture was cooled to room temperature and diluted with HO (50 mL). The mixture was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by reverse-phase flash chromatography: column, C18, eluted with 30%-50% ACN in H2O (0.05% NH3 H2O) to give the compound (17 mg, 13%) as a white solid. ES / MS m / z 557 [M+H] + . 1 H NMR (400MHz,CDCl3)δ 8.19 (s,1H),8.15 (s,1H),7.64 (s,1H),7.03 (s,1H),6.68 (s,1H),4.72 - 4.49 (m,1H),4.40 - 4.32 (m,2H),4.08 (s,3H),3.72 (t,4H),3.47 - 2.99 (m,2H),2.57 (t,4H),2.48 - 2.24 (m,5H),2.39 - 2.24 (m,2H),2.12 - 2.05 (m,2H),1.34 (s,6H).

[0502] The following compounds were prepared essentially as described in Example 55, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0503] [Table 28] 1Purified by reverse phase flash chromatography: column, C18, eluted with 30%-50% ACN in H2O (0.1% NH4HCO3). 21 H NMR (300MHz,DMSO-d6)δ 8.58 (s,1H),8.54 (d,1H),7.83 (s,1H),7.09 (d,1H),6.84 (d,1H),4.66 - 4.30 (m,6H),4.15 - 4.03 (m,4H),4.00 - 3.86 (m,1H),3.50 - 3.39 (m,1H),3.10 - 2.92 (m,1H),2.49 (s,3H),2.33 (s,3H),2.08 - 1.90 (m,4H),1.18 (s,6H).

[0504] Example 57 6-[1-[1-[2-cyano-4-(2,7-diazaspiro[3.5]nonan-2-yl)-4-methyl-pent-2-enoyl]-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile; 2,2,2-trifluoroacetic acid [ka]

[0505] To a stirred solution of tert-butyl 2-[(E)-3-cyano-4-[4-[4-(3-cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-pyrazol-1-yl]-1-piperidyl]-1,1-dimethyl-4-oxo-but-2-enyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (100 mg, 0.17 mmol) in DCM (5 mL) was added TFA (1 mL) dropwise at room temperature under N. The mixture was stirred at room temperature for 0.5 h and then concentrated. EtO (5 mL) was added and the organic phase was separated. ACN (3 mL) and H2O (5 mL) were added and the mixture was lyophilized to give the title compound (56 mg, 53%) as a white solid. ES / MS m / z 582 [M+H] + . 1H NMR (300MHz,DMSO-d6)δ 8.49 (s,1H),8.44 (s,1H),7.80 (s,1H),7.01 (s,1H),6.96 (s,1H),4.66 - 4.52 (m,1H),4.47 - 4.31 (m,1H),4.12 - 3.95 (m,8H),3.45 - 3.30 (m,1H),3.11 - 2.91 (m,5H),2.44 (s,3H),2.11 - 1.85 (m,8H),1.59 (s,6H).

[0506] The following compounds were prepared essentially as described in Example 57, using the appropriate reagents, adjusting the temperature, adjusting the reaction time to determine reaction completion, and adjusting the purification system as appropriate.

[0507] [Table 29] 11 H NMR (300MHz,DMSO-d6)δ 11.11(brs,1H),8.59 (s,1H),8.55 (s,1H),8.24 (s,1H),7.84 (s,1H),7.09 (s,1H),4.73 - 4.51 (m,2H),4.08 (s,3H),4.07 - 3.93 (m,1H),3.31 - 3.18 (m,1H),3.11 - 2.97 (m,1H),2.50 (s,3H),2.25 - 2.11 (m,1H),2.05 - 1.88 (m,3H),1.65 (s,6H).

[0508] Biological assays The following assays demonstrate that the compounds provided herein are FGFR3 inhibitors. The following assays demonstrate that certain compounds provided herein selectively target FGFR3.

[0509] FGFR3 and FGFR1 Enzyme Assay 1 FGFR3 protein was purchased from Reaction Biology (catalog no. 1068), and FGFR1 protein was purchased from ThermoFisher Scientific (catalog no. PV4105). Enzyme activity was monitored using the KinEASE™-TK Assay Kit (CisBio, catalog no. 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 (Greiner, catalog no. 784075-25).

[0510] Incubations were performed with FGFR3 or FGFR1 protein, 125.0 nM TK-biotin substrate (CisBio), 7.81 nM streptavidin-XL665 (CisBio), and 0.25× anti-phosphorylated TK-biotin-cryptate (CisBio). The final enzyme concentration was 0.25 nM in a 10 μL reaction. Compound titration was performed in a half-logarithmic manner in 100% dimethyl sulfoxide (DMSO) starting at 1 μM. Before initiating the reaction with adenosine triphosphate (ATP), FGFR1 protein and compounds were preincubated at room temperature for 15 minutes, and FGFR3 protein and compounds were preincubated on ice for 15 minutes. The reaction proceeded at 30°C for 30 minutes. The plates were quenched by the addition of an anti-TK cryptate antibody / streptavidin-XL665 mixture. After 1 hour in the stop solution, the plates were read on an Envision plate reader (Perkin Elmer) (Ex. Filter. 320 nm and Em1 665 nm / Em2 615 nm).

[0511] FGFR3 and FGFR1 Enzyme Assay 2 FGFR3 protein was purchased from Reaction Biology (catalog number 1068), and FGFR1 protein was purchased from ThermoFisher Scientific (catalog number PR4660A). 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 (Corning, catalog number 3825).

[0512] Incubations were performed with FGFR3 or FGFR1 protein, 125.0 nM TK-biotin substrate (CisBio), 15.62 nM streptavidin-XL665 (CisBio), and 0.25x anti-phosphorylated TK-biotin-cryptate (CisBio). Final enzyme concentrations varied by construct and lot, ranging from 0.07 to 0.5 nM in 10 μL reactions (FGFR1 0.5 nM, FGFR3 0.07 nM). Compound titration was performed using 2.5-fold dilutions in 100% dimethyl sulfoxide (DMSO) starting at 20 μM. Before initiating the reaction with adenosine triphosphate (ATP), FGFR1 protein and compounds were preincubated at room temperature for 15 min, and FGFR3 protein and compounds were preincubated on ice for 15 min. The reaction was allowed to proceed for 30 minutes at 25°C. The plate was quenched by the addition of an anti-TK cryptate antibody / streptavidin-XL665 mixture. After 1 hour in stop solution, the plate was read on a Pherastar plate reader ((BMG) (Ex. Filter. 320 nm and Em1 665 nm / Em2 615 nm)).

[0513] For enzyme assays 1 and 2, the ratios were converted to percent of control (POC) using the specific emission coefficient. 100 POC was measured without test compound and 0 POC was measured in the presence of 1 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.

[0514] In Enzyme Assay 1, the compounds of Examples 1, 3 to 24, 29 to 34, and 45 to 58 had an IC of less than 350 nM against FGFR3. 50 The values ​​were shown.

[0515] In Enzyme Assay 1, the compounds of Examples 1, 3 to 13, 15 to 17, 19 to 21, 24, 29 to 34, 45, 46 and 48 to 58 had an IC of less than 100 nM against FGFR3. 50 values ​​and are at least three-fold selective for FGFR3 over FGFR1.

[0516] In Enzyme Assay 1, the compounds of Examples 1, 6-8, 10, 11, 24, 29, 32, 46, 49, 50-52, 54-56 and 58 had an IC of less than 50 nM against FGFR3. 50 values ​​and are at least 10-fold selective for FGFR3 over FGFR1.

[0517] In enzyme assay 2, the compounds of Examples 36, 37, 39-41, 43 and 44 had an IC of less than 350 nM against FGFR3. 50 The values ​​were shown.

[0518] In enzyme assay 2, the compounds of Examples 36, 37, 39-41, 43 and 44 had an IC of less than 100 nM against FGFR3. 50 values ​​and are at least three-fold selective for FGFR3 over FGFR1.

[0519] In enzyme assay 2, the compounds of Examples 36, 39-41, 43 and 44 had an IC of less than 50 nM against FGFR3. 50 values ​​and are at least 10-fold selective for FGFR3 over FGFR1.

Claims

1. A compound of the formula: 【Chemical 1】 During the ceremony, Z ５ 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 or 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 or 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 ５Ａ R ６Ａ or 3- to 6-membered cycloalkyl; 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 １ But Z is 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, is a bond; or Z １ Z is CHR ９Ａ If CH ２ or CH ２ -CH ２ and Z ２ is a bond, C(O), SO ２ , or -NR ４ C(O), Z ３ is a bond, C(O), SO ２ , or -NR ４ C(O), Z ４ is the bond, Y ５ -NR １５ , or CH ２ -Y ５ -NR １５ and NR １５ N is Z ５ is connected to Z ６ is C═C or C≡C, and C═C is R １４ is optionally replaced by 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 ２ -R １１ , and R １０ and optionally substituted with one or more substituents independently selected from C １ ~C ４ Alkyl and C ３ ~C ５ Cycloalkyl is halo, OH, OCH ３ , methylamine, N,N-dimethylamine, and CN; R ３ But 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 But 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 ５Ａ is hydrogen or C １ ~C ３ is alkyl, 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 C １ ~C ５ Alkyl is halo, OH, and OCH ３ and optionally substituted with one or more substituents independently selected from R ６Ａ is hydrogen or C １ ~C ３ is alkyl, R ７ But 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 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 But hydrogen, C １ ~C ３ alkyl or R ９Ａ Condenses with CH ２ or CH ２ -CH ２ Forming 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 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 , 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 , methylamine, N,N-dimethylamine, and CN; R １３ But hydrogen, C １ ~C ５ alkyl, or R １７ and C １ ~C ５ Alkyl is halo, OH, CN, -OC １ ~C ３ Alkyl, NH ２ , N.H.C. １ ~C ３ Alkyl, or N(C １ ~C ３ alkyl) ２ , R １７ , N.R. １６ R １７ , and -OR １７ and optionally substituted with one or more substituents independently selected from C １ ~C ３ Alkyl is halo, OH, OCH ３ and CN; R １４ But F, CF ３ , or CN, R １５ is hydrogen or C １ ~C ３ is alkyl, R １６ is hydrogen or C １ ~C ３ It is an alkyl R １７ is a 3- to 6-membered cycloalkyl, a 4- to 6-membered heterocycloalkyl, a 5- to 6-membered aryl, a 5- to 6-membered heteroaryl, or a 7- to 12-membered spiroheteroalkyl having 1 to 2 ring nitrogen atoms, and the 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl are R １７Ａ and optionally fused to or substituted with R １７Ａ 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 ８ , R １０ , R １７ , R ８Ａ , and R １７Ａ Halo, OH, CN, -OC １ ~C ４ Alkyl, —OC ３ ~C ５ cycloalkyl, and -Z ３ -R １２ and optionally substituted with one or more substituents independently selected from C 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 pharmaceutically acceptable salt thereof.

2. Z ６ 2. The compound of claim 1, wherein is C=C, or a pharmaceutically acceptable salt thereof.

3. Z ６ But, R １４ C═C substituted with R １４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is F or CN.

4. R １３ But hydrogen, C １ ~C ５ alkyl, or R １７ and C １ ~C ５ Alkyl is selected from halo, OH, CN, and R １７ 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, optionally substituted with one or more substituents independently selected from:

5. R １３ is hydrogen or C １ ~C ３ alkyl, C １ ~C ３ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

6. Z ６ But, C≡C and R １３ is hydrogen or C １ ~C ５ alkyl, C １ ~C ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one or more substituents independently selected from halo, OH, and CN.

7. Z ４ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is a bond.

8. X １ is N and X ２ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein

9. X １ is C and X ２ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is N.

10. X ３ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is CH.

11. A is R １ and R １Ａ 11. The compound of any one of claims 1 to 10, which is a pyrazole or triazole substituted with:

12. R １Ａ is hydrogen, or halo, OH, and OCH ３ C optionally substituted with one or more substituents independently selected from １ ~C ３ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is alkyl.

13. R １Ａ is hydrogen or CH ３ 13. The compound of claim 12, wherein:

14. R １Ａ 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

15. R １ But CH ３ 15. The compound according to any one of claims 1 to 14, wherein:

16. 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Y is O.

17. R ６ is CN, F, Cl, or CF ３ 17. The compound according to any one of claims 1 to 16, wherein:

18. R ６ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein is CN.

19. R ６ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein is Cl.

20. 20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein Z is a bond, cyclobutyl, azetidine, or piperidine.

21. 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein Z is a bond, azetidine, or piperidine.

22. 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

23. Z is CHR ９Ａ and Z １ But CH ２ and R ９ But, R ９Ａ Condenses with CH ２ 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, which forms:

24. Z １ The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein is a bond.

25. X ４ The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein

26. X ４ But, C-R ９ and R ９ is hydrogen or CH ３ 23. The compound according to any one of claims 1 to 22, wherein:

27. 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 27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, selected from:

28. 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 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, selected from:

29. 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 29. The compound according to any one of claims 1 to 28, wherein:

30. Y ３ But, CR ４ R ５ and R ４ is hydrogen or CH ３ and R ５ is hydrogen or CH ３ 30. The compound of claim 29, wherein:

31. 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 31. The compound according to any one of claims 1 to 30, wherein:

32. Y ３ But, CR ４ R ５ and R ４ is hydrogen, and R ５ But one R ３ Condenses with CH ２ , C.H. ２ -CH ２ , or CH ２ OCH ２ 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, which forms:

33. 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 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, which forms:

34. 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 pharmaceutically acceptable salt thereof.

35. R ２ but, 【Chemistry 3】 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 1, 2, 3, or 4 substituents independently selected from C １ ~C ４ Alkyl and C ３ ~C ５ Cycloalkyl is halo, OH, OCH ３ , methylamine, N,N-dimethylamine, and CN, wherein ＊ 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein: represents the point of attachment to Y.

36. R ２ but, 【Chemistry 4】 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 1, 2, 3, or 4 substituents independently selected from C １ ~C ４ Alkyl and C ３ ~C ５ Cycloalkyl is halo, OH, OCH ３ , methylamine, N,N-dimethylamine, and CN, wherein ＊ 36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein represents the point of attachment to Y.

37. R １０ But, R ８Ａ 37. The compound of any one of claims 1 to 36, wherein R is a 4- to 6-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with or fused to R, or a pharmaceutically acceptable salt thereof.

38. R １０ But, R ８Ａ 38. The compound of claim 37, which is a 5-6 membered heteroaryl optionally substituted with or fused to: or a pharmaceutically acceptable salt thereof.

39. R １０ But, R ８Ａ 37. The compound of any one of claims 1 to 36, wherein each of the groups is independently selected from cyclopropane, cyclobutane, pyrrolidine, thiazole, pyrazole, triazole, phenyl, pyridine, pyrazine, and pyridazine, optionally substituted with or fused with, or a pharmaceutically acceptable salt thereof.

40. R １０ and R ８Ａ 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 C １ ~C ４ Alkyl and C ３ ~C ５ Cycloalkyl is halo, OH, OCH ３ 40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, or 3 substituents independently selected from , methylamine, N,N-dimethylamine, and CN.

41. R １０ and R ８Ａ But F, Cl, CN, C １ ~C ３ Alkyl, CH ２ F, CHF ２ , C.F. ３ , -OCH ３ , —C(O)NH ２ , and -S(O) ２ CH ３ 41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

42. R １０ and R ８Ａ However, F, Cl, C １ ~C ３ Alkyl, CH ２ F, CHF ２ , C.F. ３ , and -OCH ３ 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from:

43. 【Chemical 5】 【Chemistry 6】 【Chemistry 7】 The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

44. 44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

45. 44. A method of treating systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal skeletal dysplasia, severe achondroplasia with developmental retardation and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer, comprising administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof.

46. The treatment is cancer, and the cancer is selected from the group consisting of breast cancer, invasive ductal carcinoma, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, squamous cell lung carcinoma, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, high-risk non-muscle invasive bladder cancer, intermediate-risk non-muscle invasive bladder cancer, Bacillus Calmette-Guerin (BCG) non-responsive non-muscle invasive bladder cancer, and Bacillus 46. ​​The method of claim 45, wherein the cancer is selected from the group consisting of Calmette-Guerin (BCG)-recurrent non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

47. 47. The method of claim 46, wherein the treatment is cancer, and the cancer is selected from the group consisting of breast cancer, invasive ductal carcinoma, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, high-risk non-muscle invasive bladder cancer, intermediate-risk non-muscle invasive bladder cancer, Bacillus Calmette-Guerin (BCG) non-responsive non-muscle invasive bladder cancer, Bacillus Calmette-Guerin (BCG) recurrent non-muscle invasive bladder cancer, muscle invasive bladder cancer upper urinary tract cancer, urothelial upper urinary tract cancer, and glioblastoma.

48. 48. The method of claim 47, wherein the cancer is selected from the group consisting of bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, and muscle-invasive bladder cancer.

49. The method of any one of claims 45 to 48, wherein the cancer is an FGFR3-associated cancer.

50. 44. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, for use in therapy.

51. 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, lethal skeletal dysplasia, severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), Muenke syndrome, or cancer.

52. The cancer is selected from the group consisting of breast cancer, invasive ductal carcinoma, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, high-risk non-muscle invasive bladder cancer, intermediate-risk non-muscle invasive bladder cancer, Bacillus Calmette-Guerin (BCG) non-responsive non-muscle invasive bladder cancer, Bacillus 52. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 51 , wherein the compound is selected from the group consisting of Calmette-Guerin (BCG) recurrent non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, kidney cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

53. 53. The compound, or a pharmaceutically acceptable salt thereof, for use in treating cancer according to claim 52, wherein the cancer is selected from the group consisting of breast cancer, invasive ductal carcinoma, invasive lobular breast cancer, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, small cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, high-risk non-muscle-invasive bladder cancer, intermediate-risk non-muscle-invasive bladder cancer, Bacillus Calmette-Guerin (BCG) non-responsive non-muscle-invasive bladder cancer, Bacillus Calmette-Guerin (BCG) recurrent non-muscle-invasive bladder cancer, muscle-invasive bladder cancer, upper urinary tract cancer, urothelial upper urinary tract cancer, and glioblastoma.

54. 54. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 53, wherein the cancer is selected from the group consisting of bladder cancer, urothelial bladder cancer, non-muscle-invasive bladder cancer, and muscle-invasive bladder cancer.

55. 55. The compound, or a pharmaceutically acceptable salt thereof, for use in treating cancer according to any one of claims 51 to 54, wherein the cancer is an FGFR3-associated cancer.

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