FGFR2 inhibitor compounds

Abstract

The present invention provides compounds of Formula (I): # imgabs0 # or a pharmaceutically acceptable salt thereof wherein A, X1, X2, X3, Y, Z, Z1, Z2, R2 and R6 are as defined herein, which are useful in the treatment of cancer and methods of treating cancer.

Description

Background Art

[0001] Fibroblast growth factor (FGF) has been considered as an important mediator of many physiological processes, such as morphogenesis, fibrosis and angiogenesis during development. The fibroblast growth factor receptor (FGFR) family is composed of five members, of which four members (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 causes FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient to raise and activate specific downstream signaling partners involved in regulating different processes such as cell growth, cell metabolism and cell survival. Therefore, the FGF / FGFR signaling pathway has pleiotropic effects on many biological processes that are crucial to tumor cell proliferation, migration, invasion and angiogenesis. SUMMARY OF THE INVENTION

[0003] Provided herein are compounds of the formula:

[0004]

[0005] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, Y, Z, Z1, Z2, R 2 and R 6 As defined herein.

[0006] Provided herein are compounds of the formula:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, Y, Z', Z2, R 2 and R 6 As defined herein.

[0009] Provided herein are compounds of the formula:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, Y, Z2, R 2 and R 6 As defined herein.

[0012] Provided herein are compounds of the formula:

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Y5, Y6, Z, Z1, R2 and R 6 As defined herein.

[0015] Provided herein are compounds of the formula:

[0016]

[0017] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, X4, Y, Y1, Y2, Y3, Y4, Y5, Y6, Z', R 2 and R 6 As defined herein.

[0018] Provided herein are compounds of the formula:

[0019]

[0020] or a pharmaceutically acceptable salt thereof, wherein A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Y5, Y6, R 2 and R 6 As defined herein.

[0021] The present invention provides pharmaceutical compositions comprising a compound of Formula (I), (II), (III), (IA), (IIA) or (IIIA) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0022] Provided herein are methods for treating proliferative disorders such as cancer, particularly FGFR2-related cancers, using a compound of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof. The methods comprise administering an effective amount of a compound of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0023] Provided herein are compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in treatment. Also provided herein are compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in treating cancer, particularly for treating FGFR2-related cancers. Also provided are uses of compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating cancer, particularly for treating FGFR2-related cancers. Summary of the Invention

[0024] Provided herein are compounds believed to have clinical utility in treating cancer, particularly FGFR2-associated cancers.

[0025] Provided herein is some compound with superior FGFR2 effectiveness compared with some previously known FGFR inhibitors.Compared with some previously known FGFR inhibitors, provided herein is some compound with superior selectivity for FGFR2 relative to FGFR1, reduces the potential dose-limiting toxicity (such as hyperphosphatemia) caused by the inhibition of FGFR1.

[0026] The compounds provided herein are of formula (I):

[0027]

[0028] in

[0029] Z2 is

[0030]

[0031] A is pyrazole, triazole, thiadiazole or oxadiazole, which is replaced by R 1 and R 1A replace;

[0032] R 1 is hydrogen or C1-C3 alkyl;

[0033] R 1A is hydrogen, halo, CN or C1-C3 alkyl, optionally substituted with one or more substituents independently selected from halo, OH, and OCH3;

[0034] X1 and X2 are independently selected from N and C, wherein when one of X1 or X2 is N, the other is C;

[0035] X3 is N or CH;

[0036] X4 is N or CR 9 ;

[0037] Y is NH, O, S or a bond;

[0038] Y1 is a bond, CHR 7 、CH2-CHR 7 、CHR 7 -CH2, CF2, CH2-CF2 or CF2-CH2;

[0039] Y2 is a bond, CHR 3 、CH2-CHR 3 、CHR 3 -CH2, CF2, CH2-CF2 or CF2-CH2;

[0040] Y3 is CR 4 R 5 or CF2;

[0041] Y4 is CR 3 R 4 or CF2;

[0042] Y5 is CR 13 R 14 , CR 13 R 14 CH2 or CH2CR 13 R 14 ;

[0043] Y6 is CR 13 R 14 , CR 13 R 14 CH2 or CH2CR 13 R 14 ;

[0044] Z is a key, CHR 9A , CR 4 R 4A , CR 4 R 4A -CH2, CH2-CR 4 R 4A , cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine;

[0045] When Z is a key, CR 4 R 4A , CR 4 R 4A -CH2, CH2-CR 4 R 4A , cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine, Z1 is a bond, or when Z is CHR 9A When Z1 is CH2 or CH2-CH2;

[0046] Z3 is a bond, C(O), SO2 or -NR 4 C(O);

[0047] Z4 is a bond, C(O), SO2 or -NR 4 C(O);

[0048] R 2 is a C1-C5 alkyl group or R 8, wherein C1-C5 alkyl is optionally substituted by one or more substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 , wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN;

[0049] R 3 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R 3 With R 5 or R 7 Fused to form CH2, CH2-CH2 or CH2OCH2;

[0050] R 4 is hydrogen or C1-C3 alkyl;

[0051] R 4A is hydrogen, halo, OH or C1-C3 alkyl;

[0052] R 5 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or with one R 3 Fused to form CH2, CH2-CH2 or CH2OCH2;

[0053] R 6 is hydrogen, halo, C1-C5 alkyl, CN, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, or 5-6 membered heteroaryl, wherein 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, methyl, halomethyl, OH, or OCH3, and wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from halo, OH, and OCH3;

[0054] R 7 is hydrogen, F, OH, OCH3, C1-C3 alkyl, or with one R 3 Fused to form CH2, CH2-CH2 or CH2OCH2;

[0055] R 8 is a 3-6 membered cycloalkyl, a 4-6 membered heterocycloalkyl, a 5-6 membered aryl or a 5-6 membered heteroaryl, which is optionally 8A Fused or R 8A replace;

[0056] R 8Ais a 3-6 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, a 5-6 membered aryl group or a 5-6 membered heteroaryl group;

[0057] R 9 is hydrogen, C1-C3 alkyl, or R 9A Fused to form CH2 or CH2-CH2;

[0058] R 10 is a 3-6 membered cycloalkyl, a 4-6 membered heterocycloalkyl, a 5-6 membered aryl or a 5-6 membered heteroaryl, which is optionally 8A Fused or R 8A replace;

[0059] R 11 is C1-C4 alkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-C3 alkyl)2, wherein 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;

[0060] R 12 is C1-C4 alkyl, C3-C5 cycloalkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-C3 alkyl)2, wherein 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;

[0061] R 13 is hydrogen, halo or C1-C3 alkyl;

[0062] R 14 is hydrogen, halo or C1-C3 alkyl; and

[0063] R 8 、R 10 and R 8A Optionally substituted with one or more substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z4-R 12 , wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN;

[0064] or a pharmaceutically acceptable salt thereof.

[0065] In formula (II) and (IIA), A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Y5, Y6, R2 and R 6 As defined above for formula (I); and

[0066] X4 is N or CR 9 , where R 9 is hydrogen or C1-C3 alkyl;

[0067] Z' is a key, CR 4 R 4A , CR 4 R 4A -CH2, CH2-CR 4 R 4A , cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine.

[0068] In formula (III), A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Y5, Y6, Z2, R 2 and R 6 As defined above for formula (I); and X4 is N or CR 9 , where R 9 is hydrogen or C1-C3 alkyl.

[0069] In formula (IIIA), A, X1, X2, X3, Y, Y1, Y2, Y3, Y4, Y5, Y6, R 2 and R 6 As defined above for formula (I).

[0070] In the 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.

[0071] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), X1 may be C and X2 may be N, forming:

[0072]

[0073] In formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of connection with A.

[0074] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), X1 may be N and X2 may be C, forming:

[0075]

[0076] In formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of connection with A.

[0077] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), X1 may be C, X2 may be N, and X3 may be CH, forming:

[0078]

[0079] In formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of connection with A.

[0080] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), X1 may be N, X2 may be C, and X3 may be CH, forming:

[0081]

[0082] In formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of connection with A.

[0083] The specific chemical naming conventions used herein are intended to be familiar to those skilled in the chemical art. For greater clarity, some terms are specifically defined.

[0084] As used herein, the term "alkyl" refers to a hydrocarbon chain that can be straight or branched containing a specified number of carbon atoms. For example, as used herein, the term "C1-C5 alkyl" refers to a saturated straight or branched monovalent hydrocarbon group of one, two, three, four, or five carbon atoms. Examples of C1-C5 alkyls include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, and neopentyl. Examples of C1-C4 alkyls include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, and 2-methyl-2-propyl. Examples of C1-C3 alkyls include, but are not limited to, methyl, ethyl, 1-propyl, or isopropyl.

[0085] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group containing the specified number of carbon atoms. For example, as used herein, the term "3-6 membered cycloalkyl" refers to a saturated cyclic hydrocarbon group having three, four, five, or six carbon atoms. Examples of 3-6 membered cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of 3-5 membered cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl.

[0086] As used herein, the term "heterocycloalkyl" refers to a saturated cyclic group containing the specified number of atoms selected from C(O) 0-1 , N, O and S(O) 0-2 For example, as used herein, the term "5-6 membered heterocycloalkyl" refers to a saturated ring system having five or six ring atoms, wherein one, two or three ring atoms are selected from N, O and S(O) 0-2 , the remaining ring atoms are C(O) 0-1 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, tetrahydrothienyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxazolidin-2-onyl, and isothiazolidin-2-onyl. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxazolidin-2-onyl, and isothiazolidin-2-onyl.

[0087] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group having a specified number of carbon atoms. For example, as used herein, the term "5-6 membered aryl" refers to an aromatic cyclic hydrocarbon group having five or six carbon atoms. Examples of 5-6 membered aryl groups include cyclopentadienyl and phenyl.

[0088] As used herein, the term "heteroaryl" refers to an aromatic cyclic group having the specified number of atoms selected from C, N, O, and S. For example, as used herein, the term "5-6 membered heteroaryl" refers to an aromatic cyclic group having five or six ring atoms, one, two, or three of which are selected from N, O, and S, and the rest are C. Examples of 5-6 membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. Examples of 6 membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0089] As used herein, the term "halogen" or "halo" refers to F (fluorine), Cl (chlorine), Br (bromine), and I (iodine).

[0090] As used herein, the term "halomethyl" refers to a -CH3 group in which one or more hydrogen atoms are replaced by independently selected halogens.

[0091] As used herein, the term "oxo" refers to the replacement of CH2 by O to form C(O).

[0092] As used herein, the term "N(C1-C3 alkyl)2" allows for independent selection of each C1-C3 alkyl substituent, for example, N can be substituted with methyl and ethyl.

[0093] As used herein, the substituent -NR 4 C(O) is connected to R through N 2 .

[0094] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole, 1,2,4 triazole, 1,2,3 thiadiazole, 1,2,4 thiadiazole, 1,2,5 thiadiazole, 1,3,4 thiadiazole, 1,2,3 oxadiazole, 1,2,4 oxadiazole, 1,2,5 oxadiazole or 1,3,4 oxadiazole, which is replaced by R 1 and R 1A replace.

[0095] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A replace.

[0096] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Substituted, where R 1A is hydrogen and R 1 It is a C1-C3 alkyl group.

[0097] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Substituted, where R 1A is hydrogen and R 1 It is CH3.

[0098] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0099]

[0100] wherein, in formula (I), (II), (III), (IA) or (IIA), * represents a point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; and R 1 It can be a C1-C3 alkyl group;

[0101] In the compound of formula (IIIA), A can be:

[0102]

[0103] Wherein, in formula (IIIA), * represents the point of attachment to the substituent comprising Y1, and ** represents another point of attachment to A; and R 1 It can be a C1-C3 alkyl group;

[0104] In the compounds of formula (I), Z may be CHR 9A , cyclobutyl, azetidine, pyrrolidine or piperidine.

[0105] In the compounds of formula (I) or (IA), Z can be a bond,

[0106] Wherein, in formula (I) or (IA), * represents the point of connection with Z1, and ** represents the point of connection with A.

[0107] In the compounds of formula (I) or (IA), Z can be a bond,

[0108] Wherein, in formula (I) or (IA), * represents the point of connection with Z1, and ** represents the point of connection with A.

[0109] In the compounds of formula (I) or (IA), Z may be CHR 9A , Z1 may be selected from CH2 or CH2-CH2, and R 9 Can be used with R 9A Fused to form CH2 or CH2-CH2.

[0110] In the compounds of formula (I) or (IA), Z may be CHR 9A , Z1 can be CH2, and R 9 Can be used with R 9A Fused to form CH2 or CH2-CH2.

[0111] In the compounds of formula (I) or (IA), Z may be CHR 9A , Z1 can be CH2-CH2, and R 9 Can be used with R 9A Fused to form CH2 or CH2-CH2.

[0112] In the compounds of formula (I) or (IA), Z may be CHR 9A , Z1 may be selected from CH2 or CH2-CH2, and R 9Can be used with R 9A Fused to form CH2.

[0113] In the compounds of formula (I) or (IA), Z may be CHR 9A , Z1 may be selected from CH2 or CH2-CH2, and R 9 Can be used with R 9A Fused to form CH2-CH2.

[0114] In the compounds of formula (I) or (IA), Z may be CHR 9A , Z1 can be CH2, and R 9 Can be used with R 9A Fused to form CH2.

[0115] In the compounds of formula (I) or (IA), Z may be CHR 9A , Z1 can be CH2-CH2, and R 9 Can be used with R 9A Fused to form CH2-CH2.

[0116] In the compounds of formula (II) or (IIA), Z' may be:

[0117]

[0118] Wherein, in formula (II) or (IIA), ** represents the point of attachment to A, and * represents another point of attachment to Z'.

[0119] In the compounds of formula (II) or (IIA), Z' may be:

[0120]

[0121] Wherein, in formula (II) or (IIA), ** represents the point of attachment to A, and * represents another point of attachment to Z'.

[0122] In the compounds of formula (I) or (IA), Z may be a bond.

[0123] In the compounds of formula (II) or (IIA), Z' may be a bond.

[0124] In the compounds of formula (I), (II), (IA) or (IIA), Z1 may be a bond.

[0125] In the compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), Y may be NH or O.

[0126] In the compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA), Y may be O.

[0127] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y1 can be a bond, CHR 7 、CH2-CHR 7 or CHR 7 -CH2, where R 7 selected from hydrogen, F, OH and CH3; and Y2 can be a bond, CHR 3 、CH2-CHR 3 or CHR 3 -CH2, where R 3 Selected from hydrogen, F, OH and CH3.

[0128] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y1 can be a bond or CHR 7 , where R 7 is hydrogen, F, OH or CH3; and Y2 can be a bond or CHR 3 , where R 3 It is hydrogen, F, OH or CH3.

[0129] In the compounds of formula (I), (II), (III), (IA) or (IIA), Y1 can be a bond, CHR 7 、CH2-CHR 7 or CHR 7 -CH2, where R 7 is hydrogen, F, OH or CH3; and Y2 can be a bond, CHR 3 、CH2-CHR 3 or CHR 3 -CH2, where R 3 is hydrogen, F, OH or CH3, forming:

[0130]

[0131] Wherein, in formula (I) or (IA), * represents the point of connection with Z1; in formula (II) or (IIA), * represents the point of connection with Z'; or in formula (III), * represents the point of connection with A.

[0132] In the compounds of formula (I), (II), (III), (IA) or (IIA), Y1 can be a bond or CHR 7 , where R 7 is hydrogen, F, OH or CH3; and Y2 can be a bond or CHR 3, where R 3 is hydrogen, F, OH or CH3, forming:

[0133]

[0134] Wherein, in formula (I) or (IA), * represents the point of connection with Z1; in formula (II) or (IIA), * represents the point of connection with Z'; or in formula (III), * represents the point of connection with A.

[0135] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y1 can be a bond, CHR 7 、CH2-CHR 7 or CHR 7 -CH2, where R 7 is hydrogen, F, OH or CH3; and Y2 can be a bond, CHR 3 、CH2-CHR 3 or CHR 3 -CH2, where R 3 is hydrogen, F, OH or CH3, forming:

[0136]

[0137] In formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of connection with A.

[0138] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y1 can be a bond or CHR 7 , where R 7 is hydrogen, F, OH or CH3; and Y2 can be a bond or CHR 3 , where R 3 is hydrogen, F, OH or CH3, forming:

[0139]

[0140] wherein, in formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to A, or wherein, in formula (I) or (IA), * represents the point of attachment to Z1; in formula (II) or (IIA), * represents the point of attachment to Z'; or in formula (III) or (IIIA), * represents the point of attachment to A.

[0141] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 1AIt may be hydrogen or C1-C3 alkyl, optionally substituted with one or more substituents independently selected from halo, OH and OCH3.

[0142] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 1A It can be hydrogen or CH3.

[0143] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 1A It may be hydrogen.

[0144] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 1 It can be methyl, ethyl or propyl.

[0145] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 1 It may be methyl.

[0146] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 2 It can be C1-C3 alkyl, which is optionally substituted by one, two, three or four substituents independently selected from 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.

[0147] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 2 It can be C1-C3 alkyl, which is optionally substituted by one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 .

[0148] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 2 It can be:

[0149]

[0150] It is optionally substituted with one, two, three or four substituents independently selected from 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, wherein in Formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to Y.

[0151] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 2 It can be:

[0152]

[0153] It is optionally substituted with one, two, three or four substituents independently selected from 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, wherein in Formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to Y.

[0154] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 2 It can be:

[0155]

[0156] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein in Formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to Y.

[0157] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 2 It can be:

[0158]

[0159] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3 and -OC3 cycloalkyl and R 10 , wherein in Formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to Y.

[0160] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y1 can be a bond, CHR 7 、CH2-CHR 7 or CHR 7 -CH2, where R 7 It can be selected from hydrogen, F, OH and CH3.

[0161] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y2 can be a bond, CHR 3 、CH2-CHR 3 or CHR 3 -CH2, where R 3 It can be selected from hydrogen, F, OH and CH3.

[0162] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y3 may be CR 4 R 5 or CF2, where R 4 is hydrogen or CH3 and R 5 is hydrogen, F, OH or CH3; and Y4 is CR 3 R 4 or CF2, where R 4 is hydrogen or CH3, and R 3 It is hydrogen, F, OH or CH3.

[0163] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y3 may be CR 4 R 5 , where R 4 is hydrogen and R 5 With an R 3 fused to form CH2, CH2-CH2 or CH2OCH2; and Y4 is CR 3 R 4 , where R 4 is hydrogen, and R 3 With R 5 Fused to form CH2, CH2-CH2 or CH2OCH2.

[0164] In the compounds of formula (I), (II), (III), (IA) or (IIA), Y3 may be CR 4 R 5 , where R 4 is hydrogen and R 5 With an R 3 fused to form CH2, CH2-CH2 or CH2OCH2; and Y4 is CR 3 R 4 , where R 4 is hydrogen, and R 3 With R 5 Fused to form CH2, CH2-CH2 or CH2OCH2, forming:

[0165]

[0166] Wherein, in formula (I) or (IA), * represents the point of connection with Z1; in formula (II) or (IIA), * represents the point of connection with Z'; or in formula (III), * represents the point of connection with A.

[0167] In the compound of formula (IIIA), Y3 can be CR 4 R 5 , where R 4 is hydrogen and R 5 With an R 3 fused to form CH2, CH2-CH2 or CH2OCH2; and Y4 is CR 3 R 4 , where R 4 is hydrogen, and R 3 With R 5 Fused to form CH2, CH2-CH2 or CH2OCH2, forming:

[0168]

[0169] wherein, in formula (IIIA), * represents the point of attachment to A, or wherein, in formula (I) or (IA), * represents the point of attachment to Z1; in formula (II) or (IIA), * represents the point of attachment to Z'; or in formula (III) or (IIIA), * represents the point of attachment to A.

[0170] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), Y5 may be CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13and R 14 are independently selected from H and CH3; and Y6 may be CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0171] In the compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA), Y5 can be CH2 or CH2-CH2 and Y6 can be CH2 or CH2-CH2.

[0172] In the compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA), Y5 and Y6 may be CH2.

[0173] In the compounds of formula (I), (II), (III), (IA) or (IIA), X4 can be N or CR 9 , where R 9 It is hydrogen or CH3.

[0174] In the compounds of formula (I) or (IA), X4 may be CR 9 , where R 9 With R 9A Fused to form CH2 or CH2-CH2; and Z1 is CH2 or CH2-CH2.

[0175] In the compounds of Formula (I), (II), (III), (IA) or (IIA), X4 may be N or CH.

[0176] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 6 It can be CN, F, Cl, CH3, CF3 or cyclopropyl.

[0177] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 6 Can be CN, F or Cl.

[0178] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 6 It can be CN or Cl.

[0179] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 6 It can be CN.

[0180] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 6 It can be Cl.

[0181] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 It can be a 5-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a 5-6 membered aryl or a 5-6 membered heteroaryl, which is optionally 8A Fused or R 8A replace.

[0182] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 It may be a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl, which is optionally 8A Condensed.

[0183] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, which is optionally combined with R 8A Condensed.

[0184] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, which is 8A Condensed.

[0185] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, which is 8A Fused, where R 8A It can be phenyl or a 6-membered heteroaryl.

[0186] In the compounds of formula (I), (II), (III), (IA) or (IIA), R 9 It may be hydrogen.

[0187] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R10 It can be a 3-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a 5-6 membered aryl or a 5-6 membered heteroaryl, which is optionally 8A Condensed.

[0188] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be a 3-6 membered cycloalkyl, a 5-6 membered heterocycloalkyl, a phenyl group or a 5-6 membered heteroaryl group, which is optionally 8A Fused or R 8A replace.

[0189] 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, tetrahydrothienyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxazolidin-2-onyl, isothiazolidin-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, which is optionally substituted with R 8A Fused or R 8A replace.

[0190] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, which is optionally substituted with R 8A Fused or R 8A replace.

[0191] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, which is optionally substituted with R 8A Fused or R 8A replace.

[0192] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10can be cyclopropyl, cyclobutyl, phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, which is optionally combined with R 8A Fused or R 8A replace.

[0193] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxazolidin-2-onyl, isothiazolidin-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

[0194] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

[0195] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

[0196] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It may be cyclopropyl, cyclobutyl, phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl.

[0197] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, which is the same as R 8A Fused or R 8A replace.

[0198] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, which is 8A Fused or R 8A replace.

[0199] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, which is 8A Fused or R 8A replace.

[0200] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, which is 8A Fused or R 8A replace.

[0201] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be cyclopentyl, cyclohexyl, phenyl or pyridyl, which 8A Fused or R 8A replace.

[0202] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be phenyl or pyridyl, which 8A Fused, where R 8A It may be a 5-6 membered heterocycloalkyl group or a 5-6 membered heteroaryl group.

[0203] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be phenyl or pyridyl, which 8A Fused, where R 8A It can be pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxazolidin-2-onyl, isothiazolidin-2-onylfuranyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

[0204] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be phenyl or pyridyl, which 8A Fused, where R 8A It can be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxazolidin-2-onyl, isothiazolidin-2-onyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

[0205] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 10 It can be phenyl or pyridyl, which 8A Fused, where R 8A It may be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxazolidin-2-onyl or isothiazolidin-2-onyl.

[0206] In the compounds of formula (I) or (IA), Z and Z1 are both bonds, which together form a single bond.

[0207] In the compounds of formula (I) or (IA), Z may be CHR 9A , Z1 can be CH2, X4 can be CR 9 , and R 9 Can be used with R 9A Fused to form CH2, forming:

[0208]

[0209] Where * indicates the connection point with A.

[0210] In the compounds of formula (I), (II), (III), (IA) or (IIA), R 5 Can be used with an R 3 Fused to form CH2-CH2, for example:

[0211]

[0212] Wherein, in formula (I) or (IA), * represents the point of connection with Z1; or in formula (II) or (IIA), * represents the point of connection with Z'; or in formula (III), * represents the point of connection with A.

[0213] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 5 Can be used with an R 3Fused to form CH2-CH2, for example:

[0214]

[0215] Wherein, in formula (I) or (IA), * represents the point of connection with Z1; or in formula (II) or (IIA), * represents the point of connection with Z'; or in formula (III) or (IIIA), * represents the point of connection with A.

[0216] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), R 8 It can be a cyclopentyl group, which is 8A Fused, where R 8A It may be pyridyl, for example to form:

[0217]

[0218] Where * indicates the connection point with Y.

[0219] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A substituted; and Y may be NH or O.

[0220] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Substituted, where R 1A is hydrogen and R 1 is C1-C3 alkyl; and Y may be NH or O.

[0221] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0222]

[0223] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 1 can be C1-C3 alkyl; and Y can be NH or O.

[0224] In the compound of formula (IIIA), A can be:

[0225]

[0226] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 1 can be C1-C3 alkyl; and Y can be NH or O.

[0227] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A substituted; and Y may be O.

[0228] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Substituted, where R 1A is hydrogen and R 1 is a C1-C3 alkyl group; and Y may be O.

[0229] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0230]

[0231] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 1 may be a C1-C3 alkyl group; and Y may be O.

[0232] In the compound of formula (IIIA), A can be:

[0233]

[0234] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 1 may be a C1-C3 alkyl group; and Y may be O.

[0235] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Replace; and R 6 It can be CN, F, Cl, CH3, CF3 or cyclopropyl.

[0236] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Substituted, where R 1A is hydrogen and R 1 is a C1-C3 alkyl group; and R 6 It can be CN, F, Cl or CF3.

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

[0238]

[0239] wherein, in formula (I), (II), (III), (IA) or (IIA), * represents a point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; and R 6 It can be CN, F, Cl, CH3, CF3 or cyclopropyl.

[0240] In the compound of formula (IIIA), A can be:

[0241]

[0242] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A, and R 6 It can be CN, F, Cl, CH3, CF3 or cyclopropyl.

[0243] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0244]

[0245] wherein, in formula (I), (II), (III), (IA) or (IIA), * represents a point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; and R 6 It can be CN, F, Cl or CF3.

[0246] In the compound of formula (IIIA), A can be:

[0247]

[0248] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A, and R 6It can be CN, F, Cl, CH3 or CF3.

[0249] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0250]

[0251] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 1 can be a C1-C3 alkyl group; and R 6 It can be CN or Cl.

[0252] In the compound of formula (IIIA), A can be:

[0253]

[0254] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 1 can be a C1-C3 alkyl group; and R 6 It can be CN or Cl.

[0255] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Replacement; R 6 can be CN, F, Cl, CH 3 , CF 3 or cyclopropyl; and Y can be NH or O.

[0256] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Substituted, where R 1A is hydrogen and R 1 is a C1-C3 alkyl group; R 6 can be CN, F, Cl or CF3; and Y can be NH or O.

[0257] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0258]

[0259] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl, CH 3 , CF 3 or cyclopropyl; and Y can be NH or O.

[0260] In the compound of formula (IIIA), A can be:

[0261]

[0262] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl, CH 3 , CF 3 or cyclopropyl; and Y can be NH or O.

[0263] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0264]

[0265] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; and Y can be NH or O.

[0266] In the compound of formula (IIIA), A can be:

[0267]

[0268] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; and Y can be NH or O.

[0269] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Replacement; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be O.

[0270] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R1 and R 1A Substituted, where R 1A is hydrogen and R 1 is a C1-C3 alkyl group; R 6 can be CN, F, Cl or CF3; and Y can be O.

[0271] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0272]

[0273] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be O.

[0274] In the compound of formula (IIIA), A can be:

[0275]

[0276] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; and Y can be O.

[0277] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0278]

[0279] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; and Y can be O.

[0280] In the compound of formula (IIIA), A can be:

[0281]

[0282] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; and Y can be O.

[0283] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0284]

[0285] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 1 It can be a C1-C3 alkyl group; R 6 may be CN or Cl; and Y may be O.

[0286] In the compound of formula (IIIA), A can be:

[0287]

[0288] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; and Y can be O.

[0289] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Replacement; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R 2 It can be C1-C3 alkyl, which is optionally substituted by one, two, three or four substituents independently selected from 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.

[0290] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Replacement; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R 2It can be C1-C4 alkyl, which is optionally substituted by one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 .

[0291] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Replacement; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0292]

[0293] It is optionally substituted with one, two, three or four substituents independently selected from 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, wherein in Formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to Y.

[0294] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Replacement; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0295]

[0296] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein in Formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to Y.

[0297] In the compounds of formula (I), (II), (III), (IA), (IIA) or (IIIA), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R1 and R 1A Replacement; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0298]

[0299] It is optionally substituted with one, two, three or four substituents independently selected from 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, wherein in Formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to Y.

[0300] In the compound of formula (I), A can be pyrazole, 1,2,3 triazole or 1,2,4 triazole, which is replaced by R 1 and R 1A Replacement; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0301]

[0302] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein in Formula (I), (II), (III), (IA), (IIA) or (IIIA), * represents the point of attachment to Y.

[0303] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0304]

[0305] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R 2It can be C1-C3 alkyl, which is optionally substituted by one, two, three or four substituents independently selected from 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.

[0306] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0307]

[0308] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R 2 It can be C1-C4 alkyl, which is optionally substituted by one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 .

[0309] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0310]

[0311] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0312]

[0313] It is optionally substituted with one, two, three or four substituents independently selected from 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, wherein, in Formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Y.

[0314] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0315]

[0316] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0317]

[0318] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of connection with Y.

[0319] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0320]

[0321] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0322]

[0323] It is optionally substituted with one, two, three or four substituents independently selected from 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, wherein, in Formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Y.

[0324] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0325]

[0326] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0327]

[0328] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of connection with Y.

[0329] In the compound of formula (IIIA), A can be:

[0330]

[0331] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0332]

[0333] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein in formula (IIIA), * represents the point of connection with Y.

[0334] In the compound of formula (IIIA), A can be:

[0335]

[0336] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0337]

[0338] It is optionally substituted with one, two, three or four substituents independently selected from 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 by one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein in formula (IIIA), * represents the point of connection to Y.

[0339] In the compound of formula (IIIA), A can be:

[0340]

[0341] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0342]

[0343] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein in formula (IIIA), * represents the point of connection with Y.

[0344] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0345]

[0346] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R 2It can be C1-C3 alkyl, which is optionally substituted by one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 , wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0347] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0348]

[0349] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl, CH3, CF3 or cyclopropyl; Y can be NH or O; and R 2 It can be C1-C4 alkyl, which is optionally substituted by one or more substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 ;Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14-CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0350] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0351]

[0352] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0353]

[0354] It is optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 , wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Y; Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0355] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0356]

[0357] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0358]

[0359] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Y; Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0360] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0361]

[0362] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0363]

[0364] It is optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R11 and R 10 , wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Y; Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0365] In the compounds of formula (I), (II), (III), (IA) or (IIA), A may be:

[0366]

[0367] Wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Z, Z' or Z2, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0368]

[0369] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein, in formula (I), (II), (III), (IA) or (IIA), * represents the point of attachment to Y; Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0370] In the compound of formula (IIIA), A can be:

[0371]

[0372] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0373]

[0374] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein in formula (IIIA), * represents the point of attachment to Y; Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0375] In the compound of formula (IIIA), A can be:

[0376]

[0377] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0378]

[0379] It is optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 , wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein in formula (IIIA), * represents the point of attachment to Y; Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0380] In the compound of formula (IIIA), A can be:

[0381]

[0382] Wherein, in formula (IIIA), * represents the point of attachment to the substituent containing Y1, and ** represents another point of attachment to A; R 6 can be CN, F, Cl or CF3; Y can be NH or O; and R 2 It can be:

[0383]

[0384] It is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, -OCH3, -OC3 cycloalkyl and R 10 , wherein in formula (IIIA), * represents the point of attachment to Y; Y5 is CR 13 R 14 , CR13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

[0385] In one embodiment, the compound of formula (I) is selected from:

[0386]

[0387]

[0388] or a pharmaceutically acceptable salt thereof,

[0389] The key at the * position is as follows shown.

[0390] For example, for the compound of the following formula:

[0391]

[0392] The key at the * position is as follows As shown, the compound is formed:

[0393]

[0394] In another embodiment, the compound of formula (I) is selected from:

[0395]

[0396]

[0397] or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is as shown.

[0398] In another embodiment, the compound of formula (I) is selected from:

[0399]

[0400]

[0401] or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is as shown.

[0402] In another embodiment, the compound of formula (I) is selected from:

[0403]

[0404]

[0405] or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is as shown.

[0406] In another embodiment, the compound of formula (I) is selected from:

[0407]

[0408]

[0409]

[0410] or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is as shown.

[0411] In another embodiment, the compound of formula (I) is selected from:

[0412]

[0413] or a pharmaceutically acceptable salt thereof.

[0414] In another embodiment, the compound of formula (I) is selected from:

[0415]

[0416]

[0417]

[0418] or a pharmaceutically acceptable salt thereof.

[0419] In another embodiment, the compound of formula (I) is selected from:

[0420]

[0421]

[0422] or a pharmaceutically acceptable salt thereof.

[0423] In another embodiment, the compound of formula (I) is selected from:

[0424]

[0425]

[0426]

[0427]

[0428]

[0429] or a pharmaceutically acceptable salt thereof.

[0430] In another embodiment, the compound of formula (I) is selected from:

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438] or a pharmaceutically acceptable salt thereof.

[0439] In the compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or pharmaceutically acceptable salts thereof, any or all hydrogen atoms present in the compounds or in specific groups or moieties present in the compounds may be replaced by deuterium or tritium. Thus, a description of an alkyl group includes deuterated alkyl groups in which from one to the maximum number of hydrogen atoms present may be replaced by deuterium. For example, ethyl refers to C2H5 or C2H5 in which from one to five hydrogen atoms are replaced by deuterium, such as C2D x H 5-x .

[0440] The compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA) provided herein can form pharmaceutically acceptable salts. The examples provided herein can form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts are intended to be included. Pharmaceutically acceptable salts and conventional methods for preparing them are well known in the art (see, for example, P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011); S.M. Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

[0441] The compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA) provided herein, or pharmaceutically acceptable salts thereof, can be mixed with one or more pharmaceutically acceptable carriers, diluents or excipients. More particularly, the compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA) provided herein, or pharmaceutically acceptable salts thereof, can be formulated into pharmaceutical compositions. Such pharmaceutical compositions and methods for their preparation 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)).

[0442] 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 a variety of routes. Such routes of administration include oral and intravenous.

[0443] 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 additional therapeutic agents.

[0444] The compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, provided herein, can be components of pharmaceutical compositions for treating cancer, with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or more additional therapeutic agents.

[0445] The compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, provided herein, can be components of pharmaceutical compositions for treating cancer, with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or more additional therapeutic agents.

[0446] The compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA) provided herein, or pharmaceutically acceptable salts thereof, may be combined with one or more other therapeutic agents for simultaneous, separate, or sequential administration.

[0447] The 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.

[0448] The compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA) provided herein, or pharmaceutically acceptable salts thereof, are generally effective over a wide dosage range. For example, daily dosages are generally in the range of about 0.5 to about 100 mg / kg body weight. In some cases, dosage levels below the lower limit of the above range may be sufficient, while in other cases, larger doses may be used without causing any harmful side effects, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. It should be understood that the amount of compound actually administered will be determined by the physician based on the relevant circumstances, including the condition to be treated, the route of administration selected, the one or more compounds actually administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms.

[0449] Certain compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR2. For example, certain compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR2 relative to another FGFR. For example, certain compounds of Formula (I), (II), (III), (IA), (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, selectively target FGFR2 relative to 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 more selective for FGFR2 than for FGFR1 (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).

[0450] As used herein, the term "selectivity" of a compound means that the compound is more active against a first target than against a second target. Fold selectivity can be calculated by any method known in the art. For example, the fold selectivity can be calculated by dividing the IC of the compound against a second target (e.g., FGFR1) by the IC of the compound against the second target (e.g., FGFR1). 50 The value is divided by the IC value of the same compound for the first target (e.g. FGFR2). 50 IC 50 The value can be determined by any method known in the art. For example, IC 50 The value can be determined by the following measurement method.

[0451] As used herein, the term "cancer" refers to or describes the physiological condition in a patient that is typically characterized by unregulated cell proliferation. This definition includes benign and malignant cancers, primary and metastatic cancers.

[0452] As used herein, the term "FGFR2-related cancer" refers to a cancer that is associated with or has an expression or activity or level disorder of the FGFR2 gene, FGFR2 kinase protein, or any one thereof. Non-limiting examples of FGFR2-related cancers are described herein. As used herein, "FGFR2-related cancer" includes, but is not limited to, gastric cancer, hepatobiliary cancer, cancer of unknown primary, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), sarcoma, esophagogastric cancer (e.g., gastroesophageal junction adenocarcinoma, gastric remnant adenocarcinoma), esophageal cancer (e.g., esophageal duct cancer ... 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, squamous cell lung cancer, and small cell lung cancer), urothelial carcinoma, bladder cancer (e.g., urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), gastric cancer (e.g., gastric adenocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer (e.g., colorectal adenocarcinoma, colon adenocarcinoma), multiple myeloma, liver cancer (e.g., hepatocellular carcinoma, fibrolamellar hepatocyte 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 cancer, salivary gland cancer), glioblastoma, endometrial cancer (e.g., endometrial endometrioid adenocarcinoma), cervical cancer, and ovarian cancer (e.g., epithelial ovarian cancer).

[0453] As used herein, the term "treat," "treat," "treat," or "treating" means to inhibit, slow, halt, or reverse the progression or severity of an existing symptom, condition, or disorder.

[0454] As used herein, the term "patient" refers to a mammal, particularly a human.

[0455] Provided herein are compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in therapy.

[0456] Provided herein are compounds of Formula (I), (II), (III), (IA), (IIA), or (IIIA), or pharmaceutically acceptable salts thereof, for use in treating cancer.

[0457] 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 preparation of a medicament for treating cancer.

[0458] Provided herein are methods 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.

[0459] In the methods and uses provided herein, the cancer is selected from gastric cancer, hepatobiliary cancer, cancer of unknown primary, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), sarcoma, esophagogastric cancer (e.g., gastroesophageal 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, squamous cell lung cancer, and small cell lung cancer), urothelial carcinoma, bladder cancer, bladder cancer (e.g., urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), stomach 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 carcinoma), melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., squamous cell carcinoma of the head and neck, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, salivary gland cancer), glioblastoma, endometrial cancer (e.g., endometrial endometrioid adenocarcinoma), cervical cancer, and ovarian cancer (e.g., epithelial ovarian cancer). In particular, the cancer is selected from gastric cancer, hepatobiliary cancer, cancer of unknown primary, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), esophagogastric cancer (e.g., gastroesophageal 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, squamous cell lung cancer, and small cell lung cancer). Examples of the present invention include: ovarian cancer (e.g., squamous cell carcinoma, leukemia), gastric 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., squamous cell carcinoma of the head and neck, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, salivary gland cancer), glioblastoma, endometrial cancer (e.g., endometrial endometrioid adenocarcinoma), and ovarian cancer (e.g., epithelial ovarian cancer). More particularly, the cancer is selected from hepatobiliary cancer, cancer of unknown primary, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrolamellar hepatic carcinoma), skin cancer (e.g., squamous cell skin carcinoma), melanoma (e.g., cutaneous melanoma), and endometrial cancer (e.g., endometrial endometrioid adenocarcinoma).Most particularly, the cancer is selected from hepatobiliary cancer, gallbladder cancer (e.g., gallbladder adenocarcinoma), bile duct cancer (e.g., intrahepatic bile duct cancer, extrahepatic bile duct cancer), breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma), liver cancer (e.g., hepatocellular carcinoma, fibrolamellar hepatic carcinoma), and endometrial cancer (e.g., endometrioid adenocarcinoma of the endometrium).

[0460] The compounds provided herein can be prepared as shown in the following Preparations and Examples.

[0461] Plan A

[0462]

[0463] Scheme A describes the preparation of compound (A8), wherein R1′ is defined as a C1-C3 alkyl group, by various synthetic routes to obtain compound (A11), which is further refined to Formula 1. Alcohol (A1) can be reacted with methanesulfonyl chloride or toluenesulfonyl chloride to obtain compound (A2a) or (A2b), which can be further reacted with (A3a) to obtain (A4). Compound (A4) can be treated with LDA and an appropriate alkylating agent to obtain compound (A8). Alternatively, compound A8 can be synthesized directly by alkylating compound A3b with mesylate A2a or toluenesulfonate A2b to obtain compound A8.

[0464] Compound (A8) can also be synthesized via an alternative route shown in Scheme 1. Alcohol (A1) can be reacted under Mitsunobu conditions to form azide (A5). Azide (A5) can be condensed with a β-ketoester to give triazole ester (A6), which can be saponified to give carboxylic acid (7). Carboxylic acid (A7) can be treated with bromine in the presence of a base to give compound (A8).

[0465] Scheme 1 further describes the preparation process of compound (A11). Compound (A8) can be deprotected to give compound (A9). Compound (A9) reacts with an appropriate ketone (A10) under reductive amination conditions to give compound (A11). 1’ It is defined as a C1-C3 alkyl group.

[0466] Plan A1

[0467]

[0468] Scheme A1 describes an alternative route to compound (A8). Reaction of (A5) in the presence of trimethyl(prop-1-yn-1-yl)silane under microwave conditions affords the trimethylsilyl analog of (A5a). Treatment of (A5a) with NBS in the presence of SiO2 affords compound (A8).

[0469] Option A2

[0470]

[0471] Scheme A2 describes the preparation of compound (A2i'), wherein R1' is defined as a C1-C3 alkyl group, which is further elaborated to Formula 1. O-protected cyclobutane-1-one (A2a') can be reacted in the presence of NaBH4 to produce alcohol (A2b'). Formation of the azide (A2c') can be accomplished by reacting the alcohol (A2b') with PPh3 and DIAD, followed by reaction with DPPA. Reaction of the azide (A2c') with ethyl acetoacetate can produce the ester (A2d'). Hydrolysis of (A2d') under alkaline conditions can produce the acid (A2e'), which can then be brominated under alkaline conditions to produce the bromide (A2f'). Removal of the protecting group from (A2f') can produce the alcohol (A2g'). Oxidation of the alcohol (A2g') can produce the ketone (A2h'), which can then react under reductive amination conditions to produce (A2i').

[0472] Plan A3

[0473]

[0474] Scheme A3 describes the preparation of compound (A3h'), which is further elaborated to Formula 1. A solution of (A3a') can be reacted with N-diazo-1,1,1-trifluoromethanesulfonamide in the presence of copper sulfate and NaHCO3 to provide the azide (A3b'). Treatment of the azide in the presence of trimethyl(prop-1-yn-1-yl)silane under microwave conditions can provide (A3c'). Formation of the bromide (A3d') can be accomplished by treating (A3c') with NBS in the presence of SiO2. Reaction of (A3d') with p-nitrobenzoic acid under Mitsunobu conditions can produce the ester (A3f'). Hydrolysis of the ester (A3e') under basic conditions can provide the alcohol (A3f'). When the alcohol (A3f') is treated with (trifluoromethane)sulfonyl triflate in the presence of a base, the triflate (A3g') can be generated. Displacement of the triflate (A3g') with an appropriate amine can provide (A3h').

[0475] Plan B

[0476]

[0477] Scheme B describes the preparation of compounds B6, B8, B9, and B10, which are further elaborated to Formula 1. Compounds (B10) and (B10a) can be further elaborated to Formula 2, Formula 3, Formula 4, or Formula 4a.

[0478] Compound (B2) can be synthesized starting from halide (B1a) or (B1b) by reacting either halide with tributyl(1-ethoxyvinyl)stannane under palladium catalysis. Hydrolysis of the ethoxyvinyl group (B2) can yield ketone (B5). Ketone (B5) can be reduced to alcohol (B6), which can then react with MsCl to yield mesylate (B8) or chloride (B9).

[0479] Alternatively, compound (B6) can be synthesized by reacting aldehyde (B7) with a suitable Grignard reagent to give alcohol (B6). A third alternative route to compound (B6) can be accomplished by treating halide (B1b) with lithium dibutyl (methyl) magnesite followed by addition of acetaldehyde to give alcohol (B6).

[0480] Treatment of ketone (B5) with phenyltrimethylammonium bromide can yield α-bromoketone (B10). Alternatively, α-bromoketone (B10) can be formed by reacting ethoxyvinyl (B2) in aqueous THF in the presence of NBS.

[0481] Plan B1

[0482]

[0483] Scheme B1 describes an alternative route to prepare α-haloketones (B10a), which are further elaborated to give Formula 1. Treatment of (B1b) with i-PrMgCl followed by addition of chloro-N-methoxy-N-methylacetamide affords (B10a), which is further elaborated to give compounds of Formula 1.

[0484] Plan C

[0485]

[0486] Scheme C describes the preparation of compound (C5), which is further elaborated into Formula 1. Treatment of compound (C1) with i-PrMgCl followed by addition of aldehyde (C2) affords alcohol (C3). Alcohol (C3) is reacted in the presence of methyl iodide by addition of potassium tert-butoxide to afford compound (C4), which is then deprotected to afford alcohol (C5).

[0487] Plan C1

[0488]

[0489] Scheme C1 describes the preparation of compound (C1e), which can be further elaborated to Formula 1. The vinyl group (C1a) reacts in the presence of K2OsO4 and NMO to provide the diol (C1b). The primary alcohol of (C1a) can be protected by treatment with SEM-Cl in the presence of a base to provide (C1b). The secondary alcohol of (C1b) can be alkylated with methyl iodide under silver catalysis to provide the ether (C1d). Removal of the protecting group of (C1d) under acidic conditions yields the primary alcohol (C1e).

[0490] Plan D

[0491]

[0492] Scheme D describes the preparation of compound (D7), which is further elaborated to Formula 1. Treatment of methyl 3,3-difluorocyclobutane-1-carboxylate with KHMDS in the presence of fluorine (D1), where X = Br, provides the ester (D2). Ester (D2) can be reduced to alcohol (D4) by treatment with LiBH4. Protection of alcohol (D4) with DHP and a catalytic amount of TsOH provides tetrahydropyran (D5). Reaction of tetrahydropyran (D5) with n-BuLi followed by addition of NFSI provides (D6). Removal of the protecting group under acidic conditions provides the alcohol (D7).

[0493] Plan E

[0494]

[0495] Scheme E describes the preparation of compounds (E1) and (E6), which are further refined to Formula 1. Compound (E6) can be synthesized by reacting (E2) with POCl3 to yield the halo (E3). Treatment of (E3) with tributyl(1-ethoxyvinyl)stannane under palladium catalysis yields the ethoxyvinyl (E4). Reaction of (E4) with benzylamine yields the N-benzyl-protected (E5). Deprotection of (E5) yields the amine (F6).

[0496] Compound (E1) can be synthesized by treating (B5) with NH4OAc.

[0497] Plan F

[0498]

[0499] Scheme F describes the preparation of compound (F5), which is further elaborated to Formula 1. (F1) reacts with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of CuI to afford (F2). Treatment of (F2) with bis(pinacolato)diboron under palladium catalysis affords the boronate ester (F3). Palladium-catalyzed coupling of the appropriate bromide with the boronate ester (F3) affords (F4), which is then demethylated with NDM to afford (F5).

[0500] Plan G

[0501]

[0502] Scheme G describes the preparation of compound (G5), which is further elaborated into Formula 1. (G1) reacts with 1-chloromethyl-4-fluoro-1,4-diazoniumbicyclo[2.2.2]octane bis(tetrafluoroborate) to provide (G2), where R6 is defined as R6 = F. Treatment of (G2) with bis(pinacolato)diboron under palladium catalysis provides the boronate ester (F3). Coupling of the boronate ester (F3) with an appropriate bromide in the presence of a palladium catalyst provides (G4). Demethylation of (G4) with NDM provides (G5).

[0503] Plan H

[0504]

[0505] Scheme H describes various methods for preparing compounds (H4) and (H6), which will be further elaborated into compounds of Formula 1 (G1), wherein Hal is defined as Hal = halogen, which can be reacted with bis(pinacolato)diboron under palladium catalysis to provide the boronate (H1). In the presence of a palladium catalyst, the boronate (H1) is coupled with an appropriate bromide to provide (H2). Chlorination of (H2) with NSC can provide (H3), wherein R6 is defined as R6 = Cl, which is then demethylated with NDM to provide (H4). Deprotection of (H4) under acidic conditions can produce (H5), which can then be reacted with an appropriate ketone under reductive amination conditions to provide (H6). Alternatively, the boronate (H1), wherein R6 is defined as R6 = H, can be coupled with an appropriate bromide to provide (H7). Chlorination of (H7) can be accomplished by treatment with NCS to provide (H8), wherein R6 is defined as R6 = Cl. Demethylation of (H8) with NDM can provide (H6).

[0506] Scheme H also describes various methods for preparing compounds (H4) and (H6), wherein R6 is defined as R6=CN and Hal is defined as Hal=Br, which are further refined to Formula (I). Compound (G1) can be reacted with bis(pinacolato)diboron under palladium catalysis to provide the boronate ester (H1). In the presence of a palladium catalyst, the boronate ester (H1) is coupled with an appropriate bromide to provide (H2). Treatment of (H2) with NDM can provide the demethylated (H4). Deprotection of (H4) under acidic conditions can produce (H5), which can then be reacted with an appropriate ketone under reductive amination conditions to provide (H6). Alternatively, the boronate ester (H1) can be coupled with an appropriate bromide to provide (H7). Demethylation of (H7) with NDM can provide (H6).

[0507] Plan J

[0508]

[0509] Scheme J describes the preparation of compounds of Formula 1. (J1) can be alkylated with a halogen of (B8), (B10), (B10a), or with a mesylate of (B9) to yield (K2). Alternatively, reaction of an alcohol of (C1e), (C5), or (D7) under Mitsunobu conditions can also yield (J2). Deprotection of (J2) under acidic conditions yields (J3), which is then reacted with an appropriate ketone under reductive amination conditions to yield the compound of Formula 1. Alternatively, the compound of Formula 1 can be synthesized by alkylating (J4) with a halogen of (B8), (B10), (B10a), or a mesylate of (B9), or with an alcohol of (C1e), (C5), or (D7) under Mitsunobu conditions. One skilled in the art will recognize that compound (J1) can be interchanged with compound (G5) or (H4). Additionally, one skilled in the art will recognize that compound (J4) can be interchanged with compound (F5) or (H6).

[0510] Plan K

[0511]

[0512] Scheme K describes the preparation of compounds of Formula 1. The reaction of (K1) where Hal is defined as Hal=Br can be alkylated with a halide of (B8), (B10), (B10a) or with a mesylate of (B9) to provide (L2). Treatment of (K2) with bis(pinacolato)diboron under palladium catalysis can provide the boronate (K3). Palladium-catalyzed coupling of (K3) with an appropriate bromide, (A2i′) or (A3h′) can provide compounds of Formula (I). Alternatively, compounds of Formula (I) can be synthesized by palladium-catalyzed coupling of (K3) with an appropriate bromide to produce (K4). Deprotection of (K4) under acidic conditions can provide (K5), which can be reacted with an appropriate ketone under reductive amination conditions to provide the compound of Formula 1.

[0513] Plan K1

[0514]

[0515] Scheme K1 describes an alternative preparation method for compound (K3), which can be used for 1. Reaction of (K1) under Mitsunobu conditions can provide ketone (K1a). Reduction of ketone (K1a) can provide alcohol (K1b), which can be alkylated with an appropriate alkylating agent to provide ether (K1c). Treatment of (K1b) or (K1c) with bis(pinacolato)diboron under palladium catalysis can provide (K3). Alternatively, (K1a) can be reacted with an appropriate Grignard reagent to provide (K1d). Treatment of (K1d) with bis(pinacolato)diboron under palladium catalysis can provide (K3).

[0516] Plan L

[0517]

[0518] Scheme L describes two methods for preparing compounds of Formula 1. In the first method, (L1) is treated with NIS to give (L2), which is then reacted with CuCN to give (L3). (L3) is reacted with an amine (F4) in the presence of an organic base to give (L4). (L4) is treated with bis(pinacolato)diboron under palladium catalysis to give the boronate ester (L5). Palladium-catalyzed coupling of (L5) with an appropriate bromide gives the compound of Formula 1. Alternatively, in the second method, the compound of Formula 1 can be synthesized by palladium-catalyzed coupling of (L5) with an appropriate bromide to produce (L7). Deprotection of (L7) under acidic conditions gives (L8), which is reacted with an appropriate ketone under reductive amination conditions to give the compound of Formula 1. For compounds of Formula 1, enantiomers can be separated by chiral chromatography.

[0519] Scheme L also describes a method for preparing compounds of Formula 1. Treatment of (L3) with an amine (F4) or (F5) under palladium catalysis can provide (L4). Reaction of (L4) with bis(pinacolato)diboron under palladium catalysis can provide the boronate ester (L5). Palladium-catalyzed coupling of (L5) with an appropriate bromide can provide compounds of Formula 1. For compounds of Formula 1, enantiomers can be separated by chiral chromatography.

[0520] Plan M

[0521]

[0522] Scheme M describes the preparation of compounds of Formula 1, wherein R6 is defined as R6 = Cl and X1, X2, and X3 are defined as X2 = N, X1, and X3 = C. Treatment of (M1), wherein Hal is defined as Cl and Y is defined as O, with chloroacetaldehyde in the presence of a base provides (M2). Reaction of (M2) with bis(pinacolato)diboron under palladium catalysis provides the boronic acid (M3). Palladium-catalyzed coupling of (M3) with an appropriate bromide provides (M4). Demethylation of (M4) with NDM provides (M5), which can then be reacted with an alcohol of (C1e) or (C5) under Mitsunobu conditions to provide (M6). Deprotection of (M6) under acidic conditions provides (M7), which can then be reacted with an appropriate ketone under reductive amination conditions to provide the compound of Formula 1. For compounds of Formula 1, enantiomers can be separated by chiral chromatography.

[0523] Plan N

[0524]

[0525] Scheme N describes two methods for preparing compounds of Formula 2. In the first method, (N1) can be alkylated with α-bromoketone (B10) or (B10a) to provide (N2). Subsequent deprotection of (N2) under acidic conditions can provide (N3), which can then be reacted with an appropriate ketone to provide the compound of Formula 2. In the second method, (N6) can be alkylated with α-bromoketone (B10) or (B10a). For compounds of Formula 2, enantiomers can be separated by chiral chromatography.

[0526] Compounds of Formula 3 can be synthesized by treating compounds of Formula 2 with an appropriate Grignard reagent to provide compounds of Formula 3. For compounds of Formula 3, enantiomers can be separated by chiral chromatography.

[0527] Compounds of Formula 4 can be synthesized via two routes. In the first route, reduction of the ketone in the compound of Formula 2 can be accomplished by treatment with NaBH4 to yield the compound of Formula 4. In the second route, the ketone (N2) can be reduced with NaBH4 to yield (N4), which can be deprotected under acidic conditions to yield (N5). Treatment of (N5) with an appropriate ketone under reductive amination conditions yields the compound of Formula 4. For compounds of Formula 4, enantiomers can be separated by chiral chromatography.

[0528] Those skilled in the art will recognize that compound (N1) can be interchanged with compound (G5) or (H4). In addition, those skilled in the art will recognize that compound (N6) can be interchanged with compound (F5).

[0529] The compound of formula (4a) can be synthesized by reacting trimethylsulfoxonium iodide in the presence of a base, followed by adding the compound of formula 4.

[0530] Plan N1

[0531]

[0532] Scheme N1 describes the asymmetric synthesis of compounds of Formula 4b and 4c. Asymmetric reduction of the ketone (N2) can be achieved by treatment with ruthenium(II) chloride (n-[(1R,2R)-2-[(S)-[2-[[1,2,3,4,5,6-η)-4-methylphenyl]methoxy]ethyl]amino]-1,2-diphenylethylmethanesulfonamidato) to afford the alcohol (N4a). Deprotection of (N4a) under acidic conditions affords the amine (N5a). Reductive amination of (N5a) with an appropriate ketone affords the compound of Formula 4b.

[0533] Alkylation of the alcohol (N4a) with an appropriate alkylating agent can yield an alkyl ether (N4b). Subsequent deprotection of (N4b) under acidic conditions can yield an amine (N4c). Reductive amination of (N4c) with an appropriate ketone can yield a compound of formula 4c.

[0534] Plan N2

[0535]

[0536] Scheme N2 illustrates an alternative method for preparing compounds of Formula 3. Ketones (N2) can react with Grignard reagents to yield tertiary alcohols (N2a). Removal of the protecting group (N2a) under acidic conditions yields amines (N2b). Compounds of Formula 3 can be obtained by reacting (N2b) with an appropriate ketone under reductive amination conditions.

[0537] In the case where (N2a) has R6 = H, treatment with NCS can provide compounds where (N2b') has R6 = Cl. Subsequent treatment of (N2b') under acidic conditions can provide the amine (N2b).

[0538] Plan N3

[0539]

[0540] Scheme N3 depicts an alternative route for the synthesis of compounds of Formula 4c. Alkylation of the alcohol (N4) with an appropriate alkylating agent can provide an alkyl ether (N4a'). Deprotection of (N4a') under acidic conditions can provide an amine (N4b'), which can then be reacted with an appropriate ketone under reductive amination conditions to provide compounds of Formula 4c.

[0541] Plan P

[0542]

[0543] Scheme P describes the preparation of compounds of Formula 6 or Formula 7. For the preparation of compounds of Formula 6, compounds of Formula 4 can be reacted with NaH, followed by treatment with an appropriate alkylating agent to provide compounds of Formula 6. For the preparation of compounds of Formula 6, compounds of Formula 4 can be reacted with MsCl to provide (P1). (P1) is then treated with an appropriate amine to provide compounds of Formula 7.

[0544] Plan P1

[0545]

[0546] Scheme P1 illustrates an alternative method for preparing compounds of Formula 7. Mesylates (P1a) can be prepared by reacting (N4) with methanesulfonyl chloride. Substitution of mesylate (P1a) with an amine provides an alkylamino group (P1b). Deprotection of (P1b) under acidic conditions provides an amine (P1c), which reacts with an appropriate ketone under reductive amination conditions to provide compounds of Formula 7.

[0547] For the sake of clarity, certain stereochemical centers are not specified in the following schemes, and certain substituents have been eliminated, but this is not meant to limit the teaching of the schemes in any way. In addition, one of ordinary skill in the art can separate or split individual isomers, enantiomers, and diastereomers at any convenient point in the synthesis of the compounds of the invention by methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and SH. Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The names "isomer 1" and "isomer 2" refer to the compounds eluted from chiral chromatography for the first and second time, respectively, under the conditions described herein, and if chiral chromatography is started early in the synthesis, the same names apply to subsequent intermediates and embodiments. In addition, the variable protecting groups may be the same or different at each occurrence, depending on the specific reaction conditions and the specific transformation to be 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”, 4th edition, by Peter GM Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0548] When a ketone has been asymmetrically reduced using a ruthenium catalyst as described herein, the name "isomer 1" is also used. The same name applies to subsequent intermediates and examples, unless the examples have been subjected to chiral chromatography. The asymmetric reduction of ketones to secondary alcohols using ruthenium catalysts is known in the literature (see, for example, J. Am. Chem. Soc. 2011, 133, 14960–14963).

[0549] "AcOH" refers to acetic acid; "AcCN" refers to acetonitrile; "NH4OAc" refers to ammonium acetate; "NH4OH" refers to ammonium hydroxide; "aq" refers to aqueous; "BPR" refers to backpressure regulator; "NBS" refers to N-bromosuccinimide; "nBuOH" refers to 1-butanol; "n-BuLi" refers to n-butyllithium; "DCDMH" refers to 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione; "NCS" refers to N-chlorosuccinimide; "conc" refers to concentrated; "cHex" refers to cyclohexane; "DE" refers to diatomaceous earth; "DHP" refers to 3,4-dihydropyran; "DIAD" refers to diisopropyl azodicarboxylate; "DDQ" refers to ethanol; " refers to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; "DCE" refers to 1,2-dichloroethane; "DCM" refers to dichloromethane; "DEA" refers to diethylamine; "Et2O" refers to diethyl ether; "DIPEA" refers to diisopropylethylamine; "DIEA" refers to diisopropylethylamine; "ex" refers to example; "DMA" refers to dimethylacetamide; "DME" refers to 1,2-dimethoxyethane; "HATU" refers to N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide; "NDM" refers to 1-dodecanethiol; "DMEA" refers to dimethylethylamine; "NMO" refers to N-methylmorpholine N-oxide; "Et2O" refers to diethyl ether; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to dimethyl sulfoxide; "dppf" refers to 1'-bis(diphenylphosphino)ferrocene; "DPPA" refers to diphenylphosphoryl azide; "EtOH" refers to ethanol; "EA" refers to ethyl acetate; "EtMgBr" refers to ethylmagnesium bromide; "NFSI" refers to N-fluorobenzenesulfonimide; "FA" refers to formic acid; "h" refers to hours; "hal" refers to halogen; "NIS" refers to N-iodosuccinimide; "IPA" refers to isopropyl alcohol; "IPAm" refers to isopropylamine; "i-PrMgCl" refers to isopropylmagnesium chloride ; "L" means liter; "LDA" means lithium diisopropylamide; "MsCl" means methanesulfonyl chloride; "MeMgBr" means methylmagnesium bromide; "MTBE" means methyl tert-butyl ether; "MeTHF" means 2-methyltetrahydrofuran; "ml" means milliliter; "min" means minute; 'M' means mole; "PdCl2(DtBPF)" means [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride; "KHMDS" means potassium bis(trimethylsilyl)amide; "Pd(PPh3)4" means tetrakis(triphenylphosphine)palladium(0); "Pd(dppf)Cl2" means (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride;“Pd2(dba)3” refers to tris(dibenzylideneacetone)dipalladium(0); “PE” refers to petroleum ether; “POCl3” refers to phosphorus oxychloride; “KOAc” refers to potassium acetate; “t-BuOK” refers to potassium tert-butoxide; “RT” refers to room temperature; “t; R " refers to retention time; "sat" refers to saturated; "NaOMe" refers to sodium methoxide; "Na(OAc)3BH" refers to sodium triacetoxyborohydride; "sat." refers to saturated; "soln" refers to solution; "SFC" refers to supercritical fluid chromatography; "THF' refers to tetrahydrofuran; "SOCl2" refers to thionyl chloride; "TsOH" refers to p-toluenesulfonic acid; "NEt3" and "Et3N" refer to triethylamine; "Et3Si" refers to triethylsilane; "TFA" refers to trifluoroacetic acid; "SEM-Cl" refers to 2-(trimethylsilyl)ethoxymethyl chloride; "PPh3" refers to triphenylphosphine; "Dess-Martin" refers to 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benzidoyl-3-(1H)-one; "Xphos Palladacycle Gen" refers to "4" refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II); "XPhos Pd G4" refers to dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphonium; methanesulfonic acid; N-methyl-2-phenylaniline; palladium; "ACN" refers to acetonitrile; "CAN" refers to acetonitrile; and "NSC" refers to N-chlorosuccinimide.

[0550] Table A: Analytical chiral chromatography.

[0551]

[0552]

[0553] Preparation Example 1

[0554] tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate

[0555]

[0556] A solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (3.6 g, 17 mmol) in MeOH (50 ml) was cooled to 0°C and treated with NaBH4 (1.0 g, 26 mmol) in batches. The reaction was stirred overnight and slowly warmed to room temperature. The reaction was diluted with EA (100 ml) and washed with saturated aqueous NaHCO3 (2 x 100 ml) and brine (100 ml). The organic layer was collected, dried over MgSO4, filtered and concentrated to give the title compound (3.1 g, 85%) as a white solid. MS ES+ m / z 158 [MH- t Bu] + .

[0557] The following compounds were prepared in a manner substantially similar to the method of Preparation 1, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0558] Table 1

[0559]

[0560] Preparation Example 4

[0561] tert-Butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate

[0562]

[0563] A solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (3.1 g, 15 mmol) in DCM (35 ml) was cooled to 0°C and treated with Et3N (3.6 ml, 26 mmol), followed by the dropwise addition of methanesulfonyl chloride (1.5 ml, 19 mmol). The reaction was stirred at 0°C and slowly warmed to room temperature. After stirring for 1 hour, the reaction was diluted with EA (75 ml), washed with 50% brine (100 ml), collected, dried over MgSO4, filtered and concentrated to give the title compound (4.3 g, 87%) as a white solid which was used without purification. MS ES+ m / z 236 [MH- t Bu] + .

[0564] The following compounds were prepared in a manner substantially similar to the method of Preparation 4, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0565] Table 2

[0566]

[0567] Preparation Example 8

[0568] Benzyloxycyclobutanol

[0569]

[0570] A mixture of 3-(benzyloxy)cyclobutane-1-one (20 g, 113.5 mmol) and NaBH (4.29 g, 113.5 mmol) in MeOH (50 ml) was stirred at room temperature under N for 2 h. The reaction was quenched with H O at 0°C, extracted with EA (3 x 100 ml), washed with brine (2 x 100 ml), dried over Na SO, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (20 g, 99%) as a light yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.42-7.21(m,5H),4.45(s,2H),3.93-3.85(m,1H),3.71-3.62(m,1H),2.82-2.63(m,2H),1.97-1.92(m,2H).

[0571] Preparation Example 9

[0572] tert-Butyl (1R,5S)-3-azido-8-azabicyclo[3.2.1]octane-8-carboxylate

[0573]

[0574] A mixture of tert-butyl (1R,5S)-3-(p-tolylsulfonyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (4.5 g, 12 mmol) in DMSO (79 ml) was sonicated to help dissolve the solids and then treated with NaN3 (4M in H2O, 4.1 ml, 17 mmol). 80 mL of this solution was then passed through a Uniqsis Flowsyn system consisting of a 14 ml Teflon reactor (1 / 16") with a residence time of 40 min, a temperature of 135°C, and a BPR of 10 bar. The reaction was diluted with H2O (200 mL) and extracted with EA (2 x 100 ml). The combined organics were dried over MgSO4, filtered, and concentrated to give the title compound as a solution in DMSO which was used in the next synthetic step without purification and assumed to be 100% conversion.

[0575] Preparation Example 10

[0576] (4R)-4-Azido-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester

[0577]

[0578] A solution of (4R)-4-amino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (2 g, 8.47 mmol) and KCO (1.99 g, 14.39 mmol) in MeOH (20 ml) was treated with CuSO 5H O (0.21 g, 0.85 mmol) and 1H-imidazole-1-sulfonyl azide hydrochloride (2.13 g, 10.16 mmol) at room temperature under N and stirred overnight. The reaction was diluted with H O (50 ml) and extracted with EA (2 x 100 ml). The combined organic layers were washed with brine (2 x 50 ml), dried over Na SO , filtered and concentrated to give the title compound as a yellow oil (3.4 g, crude). 1 H NMR(300MHz, CDCl3)δ(ppm):4.25-4.14(m,1H),4.08-3.90(m,1H),3.76-3.71(m,1H) ,3.59-3.37(m,1H),3.20(d,1H),2.04-1.91(m,1H),1.69-1.54(m,1H),1.41(s,9H).

[0579] The following compounds were prepared in a manner substantially similar to the method of Preparation 10, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0580] Table 3

[0581]

[0582]

[0583] Preparation Example 12

[0584] N-diazo-1,1,1-trifluoro-methanesulfonamide

[0585]

[0586] To a solution of NaN (9.22 g, 142 mmol) and tetra(butyl-1-yl)ammonium hydrogen sulfate (0.48 g, 1.42 mmol) in distilled H O (30 mL) cooled to 0° C. was slowly added a solution of (CF SO) O (8.00 g, 28.4 mmol) in heptane (25 mL). The reaction was stirred at 0° C. for 1-2 hours. Heptane (25 ml) was added to the reactants and the layers were separated. The aqueous layer was extracted with heptane (3 x 10 ml). The combined organic layers were dried over NaOH pellets. The organic layer was decanted and the solution was immediately used for subsequent reactions.

[0587] Preparation Example 13

[0588] (1r,3r)-3-Azidocyclobutanol

[0589]

[0590] A solution of (1r,3r)-3-aminocyclobutane-1-ol (1.23 g, 14.2 mmol), NaHCO₃ (4.05 g, 48.2 mmol), and CuSO₄ 5H₂O (1.77 g, 7.08 mmol) in MeOH (15 ml) and H₂O (15 ml) (v / v) was treated with a freshly prepared stock solution of N-diazo-1,1,1-trifluoro-methanesulfonamide in heptane (4.96 g, 28.3 mmol). Additional MeOH was added to the reaction in 5 mL increments until a homogeneous mixture was obtained (a total of 20 mL was added). The reaction was stirred at room temperature overnight. EA was added and the layers were separated. The aqueous layer was extracted with EA (3x). The combined organic layers were concentrated in vacuo to give a dark green solution (1.60 g, 100%, assuming quantitative yield). 1 H NMR (400MHz, DMSO-d6) δ2.05-2.31(m,4H)4.07-4.18(m,1H)4.29(br s,1H)5.14-5.32(m,1H).

[0591] Preparation Example 14

[0592] (3R,4R)-4-Azido-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester

[0593]

[0594] To a solution of tert-butyl (3R, 4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (4 g, 18.24 mmol) and PPh (6.22 g, 23.72 mmol) in THF (40 ml) at 0°C under N2 was added DIAD (5.53 g, 27.37 mmol) followed by DPPA (5.52 g, 20.07 mmol). The reaction was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give the title compound (1.7 g, 38%) as a light yellow solid. 1 H NMR (300MHz, DMSO-d6) δ4.63-4.24(m,1H),4.09-3.83(m,2H),3.80-3.55(m,1H),3.20-2.84(m,2H),2.06-1.78(m,1H),1.42-1.36(m,10H).

[0595] The following compounds were prepared in a manner substantially similar to the method of Preparation 14, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0596] Table 4

[0597]

[0598] 1 Purify by reverse phase chromatography; C18 column; eluting with 40% to 50% ACN in H2O.

[0599] 2 1 H NMR (300 MHz, DMSOd6).

[0600] 3 Purify by silica gel chromatography eluting with PE / EA (20:1).

[0601] 4 Purify by silica gel chromatography eluting with PE / EA (15:1).

[0602] 5 1 H NMR (400 MHz, DMSOd6).

[0603] Preparation Example 19

[0604] tert-Butyl 4-methyl-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate

[0605]

[0606] A mixture of tert-butyl 4-azido-4-methyl-piperidine-1-carboxylate (4 g, crude) and trimethyl(prop-1-yn-1-yl)silane (5.61 g, 49.94 mmol) was irradiated with microwave radiation at 150°C for 1 h. Once cooled to room temperature, the resulting mixture was concentrated in vacuo to afford the title compound as a yellow solid (4.1 g, crude). MS ES+ m / z 353 [M+H] + .

[0607] The following compounds were prepared in a manner substantially similar to the method of Preparation 19, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0608] Table 5

[0609]

[0610]

[0611] 1 Toluene was used as solvent for this transformation.

[0612] 2 Purify by silica gel chromatography eluting with PE / EA (5:1-3:1).

[0613] 3 Purify by silica gel chromatography eluting with 0% to 100% EA in heptane.

[0614] 4 The reaction was carried out in toluene.

[0615] a 1 H NMR(400MHz,DMSO-d6)δ0.26(s,9H)2.24(s,3H)2.36-2.47(m,2H)2.65-2.75(m,2H)4.4 2-4.59(m,1H)4.97(ttd,J=8.38,8.38,5.14,5.14,0.73Hz,1H)5.31(d,J=4.89Hz,1H).

[0616] Preparation Example 26

[0617] 4-(4-Bromo-5-methyl-triazol-1-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

[0618]

[0619] A mixture of tert-butyl 4-methyl-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate (2.3 g, crude) and SiO2 (0.78 g, 13.05 mmol) in ACN (15 ml) was treated with NBS (1.74 g, 9.79 mmol) at room temperature under N2. The resulting mixture was stirred at 80°C under N2 for 2 h. Once cooled to room temperature, the reaction was quenched with H2O and extracted with EA (2x200 ml). The combined organic layers were washed with brine (2x100 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give the title compound as a yellow solid (2 g, 85%). MS ES+m / z( 79 Br / 81 Br)359 / 361[M+H] + .

[0620] The following compounds were prepared in a manner substantially similar to the method of Preparation 26, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0621] Table 6

[0622]

[0623]

[0624] 1 Purify by silica gel chromatography eluting with PE / EA (3:1).

[0625] 2 Purify by silica gel chromatography eluting with PE / EA (4:1).

[0626] 3 Purify by silica gel chromatography eluting with 0% to 100% EA in heptane.

[0627] a 1 H NMR (400MHz, DMSO-d6) δ2.20(s,3H)2.37-2.47(m,2H)2.69-2.77(m,2H)4.41-4.49(m,1H)4.99-5.09(m,1H)5.09-5.67(m,1H).

[0628] Preparation Example 33

[0629] tert-Butyl 4-(4-ethoxycarbonyl-5-methyl-triazol-1-yl)azepane-1-carboxylate

[0630]

[0631] A solution of tert-butyl 4-(p-tolylsulfonyloxy)azepane-1-carboxylate (15 g, 38.57 mmol) in DMSO (120 ml) was stirred under N2. A solution of NaN3 (2.8 g, 42 mmol) in H2O (16.8 ml) was added. After stirring at room temperature for 30 min, a solution was obtained. The solution was subjected to the following flow chemistry conditions: reactor size 20 ml (Teflon type mas T: 150°C); flow rate: 0.666 ml / min; BPR 1.2 bar; temperature: 100°C; residence time: 30 min. The intermediate azide was isolated as a solution in DMSO / H2O (8:1) (0.28 M, total 130 ml). The solution of the azide intermediate was used in the next step.

[0632] To the solution of the above azide intermediate was added ethyl acetoacetate (5 ml, 39.30 mmol) and K2CO3 (12 g, 86.83 mmol). The reaction was stirred at room temperature for 15 min and then heated at 80°C overnight. The reaction was cooled to room temperature and then diluted with H2O (100 ml). After stirring for 15 min, all solids were dissolved. MTBE (100 ml) was added and the mixture was stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted twice with MTBE (2 x 50 ml). The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was concentrated to give the title compound (3.9 g, 25%, 75% purity). MS ES+ m / z 353 [M+H] + .

[0633] Preparation Example 34

[0634] tert-Butyl (1R,5S)-3-(4-ethoxycarbonyl-5-methyl-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0635]

[0636] To a stirred solution of tert-butyl (3-endo)-3-azido-8-azabicyclo[3.2.1]octane-8-carboxylate (3.63 g, 14.4 mmol) and ethyl 3-oxobutanoate (2.25 g, 17.3 mmol) in DMSO (29 ml) at room temperature under N2 was added K2CO3 (5.97 g, 43.2 mmol). The reaction was stirred at 85°C for 6 h. After cooling to room temperature, the reaction was poured into ice / H2O (200 ml) and stirred. The resulting cream-colored precipitate was collected by filtration, washed with H2O (100 ml) and dried at 40°C overnight to give the title compound (3.10 g, 59%). MS ES+ m / z 365 [MH-tBu] + .

[0637] Preparation Example 35

[0638] 1-(3-Benzyloxycyclobutyl)-5-methyl-triazole-4-carboxylic acid ethyl ester

[0639]

[0640] To a stirred mixture of 3-(azidocyclobutyloxy)methylbenzene (21 g, 103.32 mmol) and ethyl acetoacetate (14.79 g, 113.66 mmol) in DMF (100 ml) at room temperature under N2 was added K2CO3 (42.84 g, 309.97 mmol). The resulting mixture was stirred at 80°C under N2 for 2 h. After cooling to room temperature, the reaction was concentrated in vacuo. The mixture was diluted with H2O (300 ml) and extracted with EA (3 x 200 ml). The combined organic layers were washed with brine (3 x 200 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with 50% EA in PE to give the title compound (29 g, 93%) as a brown oil. ES+ m / z 316 [M+H] + .

[0641] Preparation Example 36

[0642] 1-[(1R,5S)-8-tert-Butyloxycarbonyl-8-azabicyclo[3.2.1]octan-3-yl]-5-methyl-triazole-4-carboxylic acid

[0643]

[0644] A solution of (1R,5S)-3-(4-ethoxycarbonyl-5-methyl-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.5 g, 4.1 mmol) in H2O (8 ml) was treated with KOH (0.28 g, 5 mmol) and stirred at room temperature for 1 h, then at 55°C for 2 h, and then at 40°C overnight. The reaction was cooled to room temperature, quenched with 2M aqueous HCl until the pH was ~2, and extracted with EA (2 x 30 ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound (1.16 g, 84%), which was used in the next synthetic step without purification or analysis.

[0645] The following compounds were prepared in a manner substantially similar to the method of Preparation 36, using appropriate reagents and adjusting the reaction time to ensure completion of the reaction. MeOH was used as a co-solvent.

[0646] Table 7

[0647]

[0648] Preparation Example 38a

[0649] tert-Butyl 6-(4-bromo-5-methyl-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0650]

[0651] tert-Butyl 6-(4-bromo-3-methyl-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0652]

[0653] A suspension of tert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g, 8.6 mmol) and 4-bromo-5-methyl-1H-pyrazole (1.2 g, 7.5 mmol) in DMSO (10 ml) was treated with CsCO (5.7 g, 17 mmol) and the reaction was stirred at 50°C for 12 h and then placed in the refrigerator. After 4 days, the reaction was poured into ice and H2O, which resulted in the formation of a precipitate. Insoluble material was removed by filtration and washed with H2O to give the title compound (2.7 g, 44%) as a mixture. MS ES+ m / z 300 / 302 [M+H-tBu] + .

[0654] Preparation Example 39a

[0655] tert-Butyl 2-(4-bromo-5-methyl-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0656]

[0657] tert-Butyl 2-(4-bromo-3-methyl-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0658]

[0659] At room temperature, a solution of tert-butyl 2-methylsulfonyloxy-7-azaspiro[3.5]nonane-7-carboxylate (1.41 g, 4.41 mmol) and 4-bromo-5-methyl-1H-pyrazole (0.67 g, 4.14 mmol) in DMF (10 ml) was treated with CsCO (2.02 g, 6.2 mmol). The mixture was stirred at 90°C for 3.5 h, and the reaction was stirred at room temperature over the weekend. Another portion of 4-bromo-5-methyl-1H-pyrazole (0.67 g, 4.14 mmol) and CsCO (2.02 g, 6.2 mmol) were added, and the reaction was stirred at 90°C for 2 h. Another portion of 4-bromo-5-methyl-1H-pyrazole (0.67 g, 4.14 mmol) was added, and the mixture was stirred at 90°C for 1 h. After cooling to room temperature, the reaction was diluted with H0 (50 ml) and extracted with EA (2x). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The resulting oil was purified by silica gel chromatography using 33% EA in hexanes as eluent to afford the title compound (1.68 g) as a mixture. MS ES+ m / z 328 / 330 [M+H-tBu] + .

[0660] The following compounds were prepared in a manner substantially similar to the methods of Preparations 39a and 39b, using appropriate reagents, adjusting reaction times to ensure reaction completion, and adjusting the purification system appropriately.

[0661] Table 8

[0662]

[0663] Preparation Example 42

[0664] 1-(1-tert-Butyloxycarbonylazetidin-3-yl)-5-methyl-triazole-4-carboxylic acid

[0665]

[0666] To a solution of 1-(1-tert-butyloxycarbonylazetidine-3-yl)-5-methyl-triazole-4-carboxylic acid ethyl ester (12.15 g, 39.14 mmol) in THF (75 ml) was added LiOH aqueous solution (75 ml, 75 mmol, 1 M), and the reaction was stirred at room temperature overnight. After stirring for 18 h, HCl aqueous solution (1 N) was added until the pH was between 5 and 6. The mixture was extracted with EA and DCM / MeOH (9: 1) (5x). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated to give the title compound (10.3 g, 93%) as a light brown solid. MS ES+m / z 283[M+H] + .

[0667] Preparation Example 43

[0668] 1-(1-tert-Butyloxycarbonylazepan-4-yl)-5-methyl-triazole-4-carboxylic acid

[0669]

[0670] To a stirred solution of tert-butyl 4-(4-ethoxycarbonyl-5-methyl-triazol-1-yl)azepane-1-carboxylate (3.1 g, 8.8 mmol) in THF (15 ml) was added aqueous LiOH (15 ml, 15 mmol, 1 M) and the reaction was stirred at room temperature for 210 minutes. Aqueous HCl (1 N) was added until the pH was approximately 5-6. The reaction was extracted twice with EA and twice with 10% MeOH in DCM. The organic layers were combined, dried over MgSO 4 , filtered and the filtrate was concentrated in vacuo to give the title compound (2.89 g, 96%, 95% by mass). MS ES+ m / z 296 [M+H] + .

[0671] Preparation Example 44

[0672] (3S)-3-(4-Bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[0673]

[0674] At -70 ° C, to a THF solution (5 ml) of (3S)-3-(4-bromopyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.51 mmol) was added a hexane solution of LDA (2.3 ml, 4.6 mmol, 2 M) and stirred for 0.5 h. Next, CH3I (0.19 ml, 3.1 mmol) was added and stirring was continued for 30 min. The reaction was quenched with saturated NH4Cl aqueous solution (50 ml) and concentrated. The mixture was extracted with EA (3 x 20 ml). The combined organic layer was washed with brine (3 x 20 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography and eluted with petroleum ether / EA (1: 0 to 10: 1) to give the title compound (0.4 g, 70% yield) as a yellow oil. MS ES+m / z( 79 Br / 81 Br)344 / 346[M+H] + .

[0675] The following compounds were prepared in a manner substantially similar to the method of Preparation 44, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0676] Table 9

[0677]

[0678] Preparation Example 46

[0679] tert-Butyl 4-(4-bromo-5-methyl-triazol-1-yl)piperidine-1-carboxylate

[0680]

[0681] A solution of 1-(1-tert-butyloxycarbonyl-4-piperidinyl)-5-methyl-triazole-4-carboxylic acid (17 g, 55 mmol) and KOH (3.7 g, 66 mmol) in H O (60 ml) was treated portionwise with Br (10.4 g, 66 mmol) at room temperature. After stirring at room temperature for 3 h, the reaction was extracted with EA (3 x 30 ml). The combined organic layers were washed with brine (2 x 150 ml), dried over anhydrous Na SO , filtered, and concentrated to afford the title compound (13 g, 68%) as a yellow solid. MS ES+ m / z 345 [M+H] + .

[0682] The following compounds were prepared in a manner substantially similar to the method of Preparation 46, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0683] Table 10

[0684]

[0685]

[0686] 1 The reaction solution was diluted with aqueous NaOH (2N) before workup.

[0687] a 1 H NMR(400MHz,DMSO-d6)δ7.40-7.34(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).

[0688] Preparation Example 51

[0689] (1s,3s)-[3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutyl]4-nitrobenzoate

[0690]

[0691] To a solution of DIAD (4.18 g, 20.68 mmol) in THF (40 ml) was added PPh3 (5.88 g, 22.41 mmol) dropwise at 0 ° C under N2. The reaction was stirred at 0 ° C for 30 min. Next, (1r, 3r)-3-(4,5-dimethyl-1H-1,2,3-triazol-1-yl)cyclobutane-1-ol (4.0 g, 17.24 mmol) and p-nitrobenzoic acid (3.46 g, 20.68 mmol) were added in batches at room temperature under N2. The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE / EA (5: 1) to give the title compound (8 g, crude product) as a white solid. MS ES+m / z( 79 Br / 81 Br)381 / 383[M+H] + .

[0692] Preparation Example 52

[0693] (1s,3s)-3-(4-Bromo-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutan-1-ol

[0694]

[0695] To a stirred solution of (1s,3s)-[3-(4-bromo-5-methyl-triazol-1-yl)cyclobutyl]-4-nitrobenzoate (8.0 g, crude) in THF (50 ml) was added portionwise LiOH·H2O (0.79 g, 18.89 mmol) at room temperature under N2. The reaction was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18; mobile phase, 10% to 50% ACN in H2O (0.1% FA) to give the title compound (2.5 g, 51%) as a yellow oil. MSES+ m / z ( 79 Br / 81 Br)232 / 234[M+H] + . 1 H NMR (300MHz, DMSO-d6) δ5.46-5.28(m,1H),4.55-4.40(m,1H),4.14-3.90(m,1H),2.87-2.76(m,2H),2.49-2.41(m,2H),2.25-2.19(m,3H).

[0696] Preparation Example 53

[0697] 3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutanol

[0698]

[0699] A mixture of 1-(3-benzyloxycyclobutyl)-4-bromo-5-methyl-triazole (8.5 g, 26.4 mmol) and FeCl (8.56 g, 52.8 mmol) in DCM (100 ml) was stirred at 50° C. under N for 2 h. After cooling to room temperature, the mixture was diluted with H O (50 ml) and extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (2 x 100 ml), dried over Na SO , filtered, and the filtrate was concentrated in vacuo to give the title compound (8 g, crude product) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ5.09-4.99(m,1H),4.55-4.42(m,1H),2.80-2.71(m,2H),2.48-2.37(m,2H),2.21(s,3H).

[0700] Preparation Example 54

[0701] 4-(4-Bromo-5-methyl-triazol-1-yl)piperidine hydrochloride

[0702]

[0703] A solution of tert-butyl 4-(4-bromo-5-methyl-triazol-1-yl)piperidine-1-carboxylate (58 g, 159.6 mmol) in 2-propanol (60 ml) was treated with a solution of HCl in 2-propanol (250 ml; 1250 mmol; 4.99 M) and stirred overnight. The reaction was diluted with MTBE (250 ml) and the resulting suspension was stirred at room temperature for 1 h. The suspension was filtered to give the title compound (41.5 g, 91%) as a white solid. MS ES+ m / z ( 79 Br / 81 Br)245 / 247[M+H] + .

[0704] Preparation Example 55

[0705] 4-(4-Bromo-3,5-dimethyl-pyrazol-1-yl)piperidine

[0706]

[0707] A solution of tert-butyl 4-(4-bromo-3,5-dimethyl-pyrazol-1-yl)piperidine-1-carboxylate (0.97 g, 2.70 mmol) in DCM (15 ml) was treated with TFA (4 ml) and the reaction was stirred at room temperature. After stirring for 45 min, the reactants were loaded onto an SCX column pretreated with MeOH. The column was washed with MeOH. The title compound was eluted with a 2M NH3 solution in MeOH and concentrated to give the title compound (557 mg, 80%) as a colorless oil. MS ES+ m / z ( 79 Br / 81 Br)258 / 260[M+H] + .

[0708] The following compounds were prepared in a manner substantially similar to the method of Preparation 55, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0709] Table 11

[0710]

[0711] 1 The crude material was loaded onto an SCX column. Non-basic impurities were washed off the column with MeOH and the title compound was then eluted with methanolic ammonia (2N).

[0712] Preparation Example 57

[0713] 3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutanone

[0714]

[0715] A mixture of 3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanol (4.00 g, 17.23 mmol) and Dess-Martin (10.97 g, 25.85 mmol) in DCM (40 ml) was stirred at room temperature under N2 for 2 h. The mixture was diluted with H2O (100 ml), extracted with EA (3 x 100 ml), washed with brine (2 x 100 ml), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography using the following conditions: column, C18; mobile phase, 20% to 40% CAN in H2O (0.1% FA) to give the title compound (2.10 g, 52.96%) as a white solid. ES / MS m / z ( 79 Br / 81 Br)230 / 232[M+H] + .

[0716] Preparation Example 58

[0717] (1s,3s)-[3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutyl]trifluoromethanesulfonate

[0718]

[0719] To a solution of (1s,3s)-3-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutan-1-ol (1.1 g, 4.74 mmol) and DIEA (3.06 g, 23.70 mmol) in DCM (10 ml) was added dropwise (trifluoromethane)sulfonyl trifluoromethanesulfonate (2.01 g, 7.11 mmol) at -70°C under N2. The reaction was stirred at -70°C for 1 h. The mixture was used in the next step without further purification, assuming a 100% conversion. ES / MS m / z ( 79 Br / 81 Br)364 / 366[M+H] + .

[0720] Preparation Example 59

[0721] tert-Butyl 4-((1r,3r)-3-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutyl)piperazine-1-carboxylate

[0722]

[0723] To a solution of (1s,3s)-[3-(4-bromo-5-methyl-triazol-1-yl)cyclobutyl]trifluoromethanesulfonate (1.7 g, 4.67 mmol) and DIEA (1.81 g, 14.01 mmol) in DCM (10 ml) was added portionwise tert-butyl piperazine-1-carboxylate (1.74 g, 9.34 mmol) at -70 ° C under N2. The reaction was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give the title compound (1.1 g, 59%) as a white solid. ES / MS m / z ( 79 Br / 81 Br)400 / 402[M+H] + . 1 H NMR(300MHz,DMSO-d6)δ5.02-4.90(m,1H),3.38-3.35(m,4H),3.08-2.96(m ,1H),2.65-2.52(m,4H),2.32-2.23(m,4H),2.23-2.20(m,3H),1.40(s,9H).

[0724] Preparation Example 60

[0725] tert-Butyl 4-[3-(4-bromo-5-methyl-triazol-1-yl)cyclobutyl]piperazine-1-carboxylate

[0726]

[0727] At room temperature, CH3CO2H (0.29 g, 4.83 mmol) was added in batches to a MeOH solution (5 ml) of 3-(4-bromo-5-methyl-triazole-1-yl)cyclobutanone (1.67 g, 7.25 mmol) and tert-butyl piperazine-1-carboxylate (0.90 g, 4.83 mmol). The resulting mixture was stirred at 50 ° C under N2 for 30 min. Next, NaBH3CN (0.61 g, 9.66 mmol) was added in batches under N2. The reaction was stirred at 50 ° C for 2 h. After cooling to room temperature, the reaction was quenched with H2O (100 ml) and the pH was adjusted to about 7 with a saturated NaHCO3 aqueous solution. The mixture was extracted with EA (3x100 ml). The organic layers were combined, washed with brine (2x100 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 1% to 50% EA in PE to give the title compound (1.4 g, 72%) as an oil. ES / MS m / z ( 79 Br / 81 Br)400 / 402[M+H] + .

[0728] Preparation Example 61

[0729] 4-(4-Bromo-5-methyl-triazol-1-yl)-1-(oxetan-3-yl)piperidine

[0730]

[0731] Under N2, a solution (700ml) of 4-(4-bromo-5-methyl-triazole-1-yl)piperidine hydrochloride (41g, 142.69mmol) in MeOH (700ml) was treated with oxetane-3-one (35g, 485.7mmol) and stirred at room temperature for 5min. The reaction was treated with AcOH (11.53g, 192mmol), stirred for 5min, and then treated in batches with NaBH3CN (35g, 556.95mmol) over 1h. The reaction was stirred at room temperature for 30min and then stirred at 30°C overnight. After cooling to room temperature, the reaction was quenched with H2O (50ml) and the pH was adjusted to 9 with 2M K3PO4 aqueous solution (75ml). The organic solvent was removed in vacuo. The resulting suspension was diluted with H2O (30ml), stirred for 30min, and filtered to give the title compound (30g, 62%) as a pale white solid. MS ES+m / z301 / 303[M+H]+ .

[0732] Preparation Example 62

[0733] 4-(4-Bromo-3,5-dimethyl-pyrazol-1-yl)-1-(oxetan-3-yl)piperidine

[0734]

[0735] NaBH3CN (0.51g) is added to a solution of 4-(4-bromo-3,5-dimethyl-pyrazol-1-yl)piperidine (0.56g, 2.18mmol), oxetanes-3-one (292mg, 4.05mmol) and AcOH (0.15ml, 2.62mmol) in MeOH (10ml). The resulting mixture is stirred at room temperature for 15min and then at 50°C for 18h. After cooling to room temperature, the reactant is concentrated in vacuo. The residue is suspended in DCM and washed with saturated NaHCO3 solution. The organic phase is separated, and the aqueous phase is extracted with DCM (2x). The combined organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography, eluted with a gradient of 0% to 100% EA in cHex solution, followed by 0% to 20% MeOH in DCM solution to give the title compound (510mg, 60%) as a white solid. MS ES+m / z( 79 Br / 81 Br)314 / 316[M+H] + .

[0736] The following compounds were prepared in a manner substantially similar to the method of Preparation 62, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0737] Table 12

[0738]

[0739] 1 Purify by silica gel chromatography eluting with 0% to 10% MeOH in DCM.

[0740] Preparation Example 64

[0741] (1R,5S)-3-(4-Bromo-5-methyl-triazol-1-yl)-8-(oxetan-3-yl)-8-azabicyclo[3.2.1]octane

[0742]

[0743] To a solution of tert-butyl (1R,5S)-3-(4-bromo-5-methyl-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.03 g, 2.77 mmol) in 1,4-dioxane (5 mL, 58.57 mmol) was added HCl in 1,4-dioxane (3 mL, 12 mmol, 4 mol / L). The mixture was stirred at room temperature for 1 hour, then heated at 50°C for 1 hour and stirred at room temperature overnight. The reaction was concentrated in vacuo to afford the intermediate (1R,5S)-3-(4-bromo-5-methyl-triazol-1-yl)-8-azoniabicyclo[3.2.1]octane hydrochloride as a solid. This material was used in the next step without further purification or characterization.

[0744] To a solution of (1R, 5S)-3-(4-bromo-5-methyl-triazole-1-yl)-8-nitrogen cation bicyclo[3.2.1]octane hydrochloride (0.75g, 2.44mmol) in MeOH (10ml) was added 3-oxetanes (0.7ml, 10mmol). The mixture was stirred at room temperature for 5min, and then NaBH3CN (0.7g, 10mmol) was added. The reaction was stirred at room temperature overnight. The reaction was heated at 50°C for 9h. Additional 3-oxetanes (170μl, 2.79mmol) and NaBH3CN (170mg, 2.70mmol) were added, and the reaction was stirred at 50°C overnight. The reaction was quenched with H2O and extracted with EA (3x 25ml). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0% to 20% EA in DCM followed by 0% to 5% MeOH in DCM. The title compound (630 mg, 69%) was obtained as an orange solid. ES+ m / z ( 79 Br / 81 Br)327 / 329[M+H] + .

[0745] Preparation Example 65

[0746] 2-Chloro-4-cyclopropyl-5-fluoropyridine

[0747]

[0748] A solution of 2-chloro-5-fluoro-4-iodopyridine (1.50 g, 5.827 mmol) and Pd(PPh3)4 (674 mg, 0.583 mmol) in THF (5 ml) was degassed by three freeze-pump-thaw cycles. A solution of cyclopropylzinc bromide (30 ml, 15.150 mmol, 0.5 M in THF) was added dropwise at 0°C. The reaction was stirred overnight and allowed to slowly warm to room temperature. The reaction was quenched with H2O and extracted with EA. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EA in heptane to give the title compound as a colorless oil (758 mg, 76%). ES+ m / z 172.1 [M+H] + .

[0749] Preparation Example 66

[0750] 3-Chloro-5-(trifluoromethyl)pyridazine

[0751]

[0752] At 80 ° C, under N2, a solution of 4-(trifluoromethyl)-1H-pyridazin-6-one (10g, 60.94mmol) and POCl3 (46.72g, 304.72mmol) in ACN (80ml) was stirred overnight. The mixture was cooled to room temperature, poured into H2O / ice (300ml) and basified to pH 8 with NaHCO3. The resulting mixture was extracted with EA (3x 100ml). The combined organic layers were washed with brine (1x100ml), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluted with PE / EA (40:1 to 10:1) to give the title compound (5g, 45%) as a yellow oil. MS ES+m / z 183[M+H] + .

[0753] Preparation Example 67

[0754] 5-Fluoro-2-[1-(trifluoromethyl)vinyl]pyridine

[0755]

[0756] Under N2, a solution of 2-bromo-5-fluoropyridine (8 g, 45.46 mmol) and 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (11.10 g, 50.00 mmol) in DME (40 ml) and H2O (10 ml) was treated with K2CO3 (18.85 g, 136.37 mmol) and Pd(PPh3)4 (1.05 g, 0.91 mmol). The mixture was stirred at 100°C for 2 h, diluted with H2O (100 ml), and extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (3 x 100 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (20 to 10:1) to give the title compound (3.4 g, 39%) as an off-white oil. MS ES+ m / z 192 [M+H] + .

[0757] Preparation Example 68

[0758] 3-(1-ethoxyvinyl)-5-(trifluoromethyl)pyridazine

[0759]

[0760] To a mixture of tributyl(1-ethoxyvinyl)stannane (11.87 g, 32.87 mmol) and 3-chloro-5-(trifluoromethyl)pyridazine (5.00 g, 27.39 mmol) in 1,4-dioxane (40 ml) at room temperature under N2 was added Pd(PPh3)4 (0.95 g, 0.82 mmol). The reaction was stirred at 100°C for 2 h. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography eluting with PE / EA (30:1 to 12:1) to give the title compound (4.6 g, 77%) as a yellow oil. MS ES+ m / z 219 [M+H] + .

[0761] The following compounds were prepared in a manner substantially similar to the method of Preparation 68, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0762] Table 13

[0763]

[0764] 1 Purify by silica gel chromatography eluting with PE / EA 10:1 to 5:1.

[0765] 2 The reaction was quenched with saturated aqueous KF solution.

[0766] 3 Purify by silica gel chromatography eluting with EA in heptane

[0767] Preparation Example 72

[0768] N-Methoxy-N-methyl-1-(trifluoromethyl)pyrazole-3-carboxamide

[0769]

[0770] 1-(Trifluoromethyl)-1H-pyrazole-3-carboxylic acid (780 mg, 4.33 mmol) was dissolved in SOCl2 (10 ml) and stirred at reflux for 2 h. The reaction was concentrated in vacuo and then redissolved in DCM (8.5 ml) at 0°C and DIPEA (2.2 ml, 12.84 mmol) was added, followed by N,O-dimethylhydroxylamine hydrochloride (840 mg, 8.56 mmol). The reaction was warmed to room temperature and then stirred for 1 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The combined organic phases were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the title compound as a light yellow oil (809 mg, 85%). MS ES+ m / z 224.1 [M+H] + .

[0771] Preparation Example 73

[0772] N-Methoxy-N-methyl-5-(trifluoromethyl)pyridine-3-carboxamide

[0773]

[0774] A suspension of 5-(trifluoromethyl)pyridine-3-carboxylic acid (4 g, 20.93 mmol) in DCM (60 ml) was treated with 1,1'-carbonyldiimidazole (3.73 g, 23 mmol) and Et3N (5.8 ml, 42 mmol). The reaction was stirred at room temperature for 3 h, diluted with H2O, the organic phase was collected, and the aqueous phase was re-extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3, collected, dried over MgSO4, filtered, and concentrated to give the title compound (3.75 g) as a yellow oil that was used without purification. MS ES+ m / z 235 [M+H] + .

[0775] Preparation Example 74

[0776] N-Methoxy-N,2,5-trimethyl-thiazole-4-carboxamide

[0777]

[0778] To an ice-cold solution of 2,5-dimethylthiazole-4-carboxylic acid (1.25 g, 7.95 mmol) and methoxy(methyl)ammonium chloride (1.95 g, 20.0 mmol) in DMF (10 ml) was added NEt (2.85 g, 28 mmol). The mixture was stirred for 5 min, then HATU (3.6 g, 9.3 mmol) was added. The reaction was stirred at room temperature for 16 h. The reactants were poured into H2O, extracted with DCM (2X) aqueous solution, and the combined organic layers were washed with 10% LiCl aqueous solution, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 30% EA in cHex to give the title compound. The title compound was used in the next step.

[0779] Preparation Example 75

[0780] 1-[5-(Trifluoromethyl)pyridazin-3-yl]ethanone

[0781]

[0782] A solution of 3-(1-ethoxyvinyl)-5-(trifluoromethyl)pyridazine (1.0 g, 4.58 mmol) and concentrated HCl (2.26 g, 22.92 mmol) in THF (10 ml) was stirred at room temperature under N2 for 1 h. The resulting mixture was diluted with H2O (10 ml), basified to pH 8 with NaHCO3, and extracted with MTBE (3 x 20 ml). The combined organic layers were washed with brine (1 x 10 ml), dried over anhydrous Na2SO4, collected, and filtered. The filtrate was concentrated to give the title compound (810 mg, 93%) as a yellow solid. MS ES+ m / z 191 [M+H] + .

[0783] The following compounds were prepared in a manner substantially similar to the method of Preparation 75, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0784] Table 14

[0785]

[0786] Preparation Example 77

[0787] 1-(4-cyclopropyl-5-fluoro-2-pyridyl)ethanone

[0788]

[0789] A solution of 2-chloro-4-cyclopropyl-5-fluoropyridine (617 mg, 3.60 mmol) and Pd(PPh 3 ) 4 (416 mg, 0.36 mmol) in toluene (10 ml) was degassed by vacuum / N 2 circulation (3x). Tributyl(1-ethoxyvinyl)tin (1.56 ml, 4.32 mmol) was added and the mixture was stirred at 100° C. under N 2 for 6 h. The reactant was treated with saturated KF aqueous solution (2.5 ml), filtered through a DE pad, and the filter cake was washed with EA (30 ml). The phases in the filtrate were separated. The organic phase was washed with saturated NaHCO 3 (3x20 ml) aqueous solution and brine (20 ml), dried over MgSO 4 , filtered, and concentrated in vacuo to obtain the intermediate vinyl ether as a brown oil.

[0790] At room temperature, the intermediate vinyl ether was dissolved in THF (10 ml), followed by addition of aqueous HCl (2 M, 5 ml), and the reaction was stirred for 12 h. The reaction was treated with saturated aqueous NaHCO 3 (30 ml), and the mixture was vigorously stirred for 10 min. The aqueous phase was extracted with EA (3 x 25 ml), and the combined organic layers were washed with brine (25 ml), dried over MgSO 4 , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with EA in heptane to give the title compound as a colorless oil (226 mg, 35%). ES+ m / z 180.1 [M+H] + .

[0791] The following compounds were prepared in a manner substantially similar to the method of Preparation 77, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0792] Table 15

[0793]

[0794] Preparation Example 79

[0795] 1-[5-(Trifluoromethyl)-3-pyridyl]ethanone

[0796]

[0797] At 0 ° C, a solution of N-methoxy-N-methyl-5-(trifluoromethyl)pyridine-3-carboxamide (2g, 6.41mmol, 75mass%) in THF (30ml) was dropwise treated with MeMgBr (10ml, 14mmol, 1.4M in toluene / THF [3: 1]) and stirred for 1h. At 0 ° C, the reaction was quenched with saturated NH4Cl aqueous solution, diluted with H2O, and extracted with EA (2x). The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting oil was purified by silica gel chromatography, eluted with a cHex solution with a gradient of 0% to 80% EA to give the title compound (1.0g, 83%) as a white solid. 1 H NMR (400MHz, CDCl3): δ9.35 (d, J = 1.9 Hz, 1H), 9.07 (d, J = 1.5 Hz, 1H), 8.48-8.47 (m, 1H), 2.72 (s, 3H).

[0798] The following compounds were prepared in a manner substantially similar to the method of Preparation 79, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0799] Table 16

[0800]

[0801] a The material was used in the subsequent step without further characterization.

[0802] 1 Purify by silica gel chromatography eluting with 0% to 30% EA in cHex.

[0803] Preparation Example 83

[0804] 1-(5-bromo-2-pyridyl)-3,3-difluoro-cyclobutanecarboxylic acid methyl ester

[0805]

[0806] At -70 ° C, under a nitrogen atmosphere, a toluene (50 ml) solution of 5-bromo-2-fluoropyridine (7.0 g, 39.78 mmol) and 3,3-difluorocyclobutane-1-carboxylic acid methyl ester (6.57 g, 43.75 mmol) was treated dropwise with KHMDS (51.7 ml, 51.71 mmol, 1.0 M in THF). After stirring at -70 ° C for 30 min, the reaction was quenched with saturated NH4Cl aqueous solution at room temperature, acidified to pH 1-2 with HCl aqueous solution (1.2 M), and extracted with EA (3x100 ml). The combined organic layer was washed with brine (2x100 ml), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (11 g, crude product) as a yellow solid. The crude product was used directly without purification. MS ES+m / z( 79 Br / 81 Br)306 / 308[M+H] + .

[0807] Preparation Example 84

[0808] 1-Methyl-2-(2-pyridyl)pyrrolidin-3-ol

[0809]

[0810] To a solution of 2-(2-pyridyl)pyrrolidin-3-ol (450 mg, 2.74 mmol) in DCM (40 ml) was added H CO (13.31 mol / L) in H O (0.65 ml). After stirring for 10 minutes, Na (OAc) BH (0.9 g, 4 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO aqueous solution. The aqueous phase was acidified to pH 2 with HCl and then loaded directly onto an SCX column. The title compound was eluted with 2N NH in MeOH to give the title compound (200 mg, 9%), MS ES+ m / z 179 [M+H] + .

[0811] Preparation Example 85

[0812] 1-[1-(Trifluoromethyl)pyrazol-3-yl]ethanol

[0813]

[0814] MeMgBr (0.21 ml, 1.80 mmol, 3 M) was added to a solution of N-methoxy-N-methyl-1-(trifluoromethyl)pyrazole-3-carboxamide (329 mg, 2.00 mmol) in THF (2.7 ml) at 0°C under N2. After stirring at 0°C for 1 h, the reaction was carefully quenched with AcOH (0.13 ml, 2.25 mmol) and diluted with MeOH (2 ml). Next, NaBH4 (102 mg, 2.70 mmol) was added in one portion, and the reaction was stirred at 0°C for 40 min. The reaction was diluted with saturated aqueous NH4Cl (4 ml), extracted with Et2O (2 x 5 ml) and DCM (2 x 5 ml), and the combined organic phases were dried over MgSO4, filtered, and the solvent concentrated in vacuo to give the title compound as a light yellow oil (174 mg, quantitative). ES+ m / z 180.9 [M+H] + .

[0815] Preparation Example 86

[0816] 1-(1-Methylpyrrolo[2,3-c]pyridin-4-yl)ethanol

[0817]

[0818] A 0.5 M solution of lithium dibutyl(methyl)magnesiumate was prepared in a round bottom flask at 0°C by adding MeMgBr (5 ml, 15 mmol) and n-BuLi (18.75 ml, 30 mmol) to THF (6.25 ml).

[0819] A stock solution of lithium dibutyl(methyl)magnesiumate (10 ml, 5 mmol) was added dropwise to a solution of 4-bromo-1-methyl-1H-pyrrolo[2,3-c]pyridine (979 mg, 4.64 mmol) in THF (25 ml) at -40°C. After 1 h, acetaldehyde (2.6 ml, 46.40 mmol) was added at -40°C. The reaction was stirred for 1 h, allowing the temperature to reach -20°C. The reaction was quenched with saturated NH4Cl and then extracted with EA. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give the title compound as a beige solid (548 mg, 67%). MS ES+ m / z 177.1 [M+H] + .

[0820] Preparation Example 87

[0821] 1-(1-Methylpyrazolo[3,4-c]pyridin-4-yl)ethanol

[0822]

[0823] At 0°C under N2, n-BuLi (6.25ml, 1.6M hexane solution, 10.0mmol) was added to a solution of MeMgBr (1.67ml, 3.0M solution, 5.0mmol) in THF (10ml). The reaction was stirred for 30min. It was then cooled to -40°C. Next, 4-bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine (1.01g, 4.76mmol) was added to the reaction. The resulting suspension was stirred briefly (about 2min) at 0°C to achieve complete dissolution of the solid. The solution was recooled to -40°C and stirred for 1h. Next, acetaldehyde (2.65ml, 8.9mmol) was added dropwise. The solution was stirred at -40°C for 90min. The reaction was then treated with saturated NH4Cl aqueous solution and diluted with EA. The layers were separated, and the aqueous layer was extracted with EA (4x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give the title compound as a beige solid (372 mg, 44%). MS ES+ m / z 178.2 [M+H] + .

[0824] Preparation Example 88

[0825] 1-(1-Isopropyltriazol-4-yl)ethanol

[0826]

[0827] A solution of MeMgBr in Et2O (2.5 M in Et2O, 2.2 ml, 5.47 mmol) was added dropwise to a solution of 1-isopropyl-1H-1,2,3-triazole-4-carbaldehyde (508 mg, 3.65 mmol) in THF (5 ml) at 0°C under N2, and the reaction was stirred at room temperature for 3 h. Afterwards, the solution was cooled to 0°C, quenched with saturated NH4Cl (aqueous solution, 25 ml), and extracted with DCM (3 x 25 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a light yellow oil (558 mg, 99%). MS ES+ m / z 156.2 [M+H] + .

[0828] The following compounds were prepared in a manner substantially similar to the method of Preparation 88, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0829] Table 17

[0830]

[0831] Preparation Example 92

[0832] 1-(2-Isopropyltriazol-4-yl)ethanol

[0833]

[0834] Under N2, 4-bromo-2-isopropyl-2H-1,2,3-triazole (1.00g, 5.26mmol) was dissolved in 10ml THF and cooled to -78°C. n-BuLi solution (3.62ml, 5.79mmol, 1.6M in hexane) was added dropwise. The solution was stirred at -78°C for 45min, then acetaldehyde (1.63ml, 26.31mmol) was added, and the reaction was slowly warmed to room temperature and then stirred for 18h. The reaction was quenched with H2O (30ml), extracted with EA (3x 15ml), and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluted with a solution of MeOH in DCM to give the title compound as a light yellow oil (299mg, 37%). 1 H NMR (400MHz, CDCl3) δ (ppm): 7.51 (s, 1H), 5.04 (q, J = 6.5Hz, 1H), 4.79 (heptane, J = 6.7Hz, 1H), 1.57 (t, J = 6.5Hz, 3H), 1.56 (d, J = 6.7Hz, 6H).

[0835] The following compounds were prepared in a manner substantially similar to the method of Preparation 92, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0836] Table 18

[0837]

[0838] 1 Purify by silica gel chromatography eluting with 10% to 50% EA in cHex.

[0839] Preparation Example 94

[0840] 1-[5-(difluoromethyl)-3-pyridyl]ethanol

[0841]

[0842] At room temperature, in another flask, to a solution of 1-[5-(difluoromethyl)-3-pyridyl]ethanone (856 mg, 5.00 mmol) in FA aqueous solution (2.1 g, 1.7 ml, 45 mmol) and NEt3 (6.0 g, 60 mmol) that had been degassed (by ultrasonic treatment) was added [[(1S, 2S)-2-amino-1,2-diphenyl-ethyl]-(p-tolylsulfonyl)amino]-chloro-ruthenium; 1-isopropyl-4-methyl-benzene (29 mg, 0.05 mmol). The mixture was stirred at room temperature under N2 overnight. H2O and EtOH were added to the mixture and partially evaporated. Saturated NaHCO3 aqueous solution was added to ensure high pH and extracted with EA (4x). The combined organic layers were dried over Na2SO4 and filtered. DE was added and the suspension was evaporated. The residue was purified by silica gel chromatography eluting with 30% to 90% EA in cHex to give the title compound (815 mg, 94%) as a green oil. MS ES+ m / z 174 [M+H] + .

[0843] The following compounds were prepared in a manner substantially similar to the method of Preparation 94, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0844] Table 19

[0845]

[0846]

[0847] 1 Purify by silica gel chromatography eluting with 5% EA in cHex (2 CV), 5% to 50% EA in cHex (15 CV), 50% to 100% EA in cHex (5 CV).

[0848] 2 Purify by silica gel chromatography eluting with 0% to 50% EA in cHex.

[0849] Preparation Example 97

[0850] 1-(2-methoxythiazol-4-yl)ethanol

[0851]

[0852] In a glass pressure flask, a MeOH solution (23 ml) of 1-(2-bromothiazol-4-yl)ethanol (2.14 g, 9.25 mmol) was added to a solution of NaOMe (30% by mass) in MeOH (23 ml). The headspace was purged with N2 and the flask was sealed. The reaction was stirred at 50°C. After 6 hours, the reaction was stirred at room temperature overnight. The next day, it was reheated for 4 hours. After cooling to room temperature, the reactant was poured into a saturated NH4Cl aqueous solution (150 ml) and DCM (30 ml) was added. The organic layer was separated and the aqueous layer was extracted with DCM (3x20 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in DCM, dry loaded onto DE and purified by silica gel column chromatography eluting with 100% cHex (1 CV), 0% to 35% EA in cHex (16 CV), 35% to 50% EA in cHex (14 CV). 1 H NMR (400.21MHz, CDCl3): δ6.50 (d, J=1.0Hz, 1H), 4.82-4.77 (m, 1H), 4.08 (s, 3H), 2.37 (d, J=4.4Hz, 1H, OH), 1.53 (d, J=6.4Hz, 3H).

[0853] Preparation Example 98

[0854] 1-[5-(Trifluoromethyl)pyridazin-3-yl]ethanol

[0855]

[0856] To a stirred solution of 1-[5-(trifluoromethyl)pyridazin-3-yl]ethanone (810 mg, 4.26 mmol) in MeOH (10 ml) was added NaBH (48.35 mg, 1.28 mmol) at 0°C under N2. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with H2O (10 ml) at 0°C. The mixture was extracted with EA (3 x 20 ml). The combined organic layers were washed with brine (2 x 10 ml), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (800 mg, 98%). 1 H NMR (400MHz, DMSO-d6) δ9.61(d,1H),8.10(d,1H),5.88(d,1H),5.14-5.08(m,1H),1.50(d,3H).

[0857] The following compounds were prepared in a manner substantially similar to that of Preparation 98, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0858] Table 20.

[0859]

[0860] a The material was used in the subsequent step without further characterization.

[0861] Preparation Example 104

[0862] [1-(5-Bromo-2-pyridyl)-3,3-difluoro-cyclobutyl]methanol

[0863]

[0864] At room temperature under N2, a solution of 1-(5-bromo-2-pyridyl)-3,3-difluoro-cyclobutanecarboxylic acid methyl ester (11.0 g, crude product) in THF (100 ml) was treated with LiBH4 (0.78 g, 35.94 mmol) in batches. After stirring at room temperature for 3 h, the reaction was quenched with saturated NH4Cl and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (5:1) to give the title compound (1.8 g, 16% over 2 steps) as a yellow solid. MS ES+ m / z 278 / 280 [M+H] + .

[0865] Preparation Example 105

[0866] 2-Benzyloxy-1-(3,5-difluoro-2-pyridyl)ethanol

[0867]

[0868] At 0 ° C under N2, a toluene solution (50 ml) of 2-bromo-3,5-difluoropyridine (5 g, 25.78 mmol) was treated with i-PrMgCl (19.33 ml, 38.66 mmol, 2M in THF). After stirring at room temperature for 3 hours, the reaction was cooled to 0 ° C and treated with 2-(benzyloxy)acetaldehyde (3.10 g, 20.62 mmol). The reaction was stirred at room temperature for 2 hours and then quenched with saturated aqueous NH4Cl (200 ml). The reaction was extracted with EA (3 x 300 ml). The combined organic layers were washed with brine (2 x 200 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (4:1) to give the title compound (1.6 g, 23%) as a light yellow oil. MS ES+ m / z 266 [M+H] + .

[0869] Preparation Example 106

[0870] 1-(5-Fluoropyrimidin-2-yl)ethane-1,2-diol

[0871]

[0872] To a mixture of 2-vinyl-5-fluoropyrimidine (15.0 g, crude) and K₂OsO₄·2H₂O (1.38 g, 3.75 mmol) in ACN:H₂O (6:1, 140 ml) at 0°C under N₂ was added NMO (17.56 g, 149.86 mmol). The resulting mixture was stirred at room temperature under N₂ for 2 h. The reaction was diluted with H₂O (20 ml) and extracted with MTBE (3 x 200 ml). The aqueous layer was extracted with CHCl₃:IPA (3:1) (3 x 250 ml). The combined organic layers were washed with brine (3 x 50 ml), dried over Na₂SO₄, filtered, and concentrated to afford the title compound (6.0 g, 51%) as a black oil. MS ES+ m / z 159 [M+H] + .

[0873] Preparation Example 107

[0874] 1-(5-fluoropyrimidin-2-yl)-2-(2-trimethylsilylethoxymethoxy)ethanol

[0875]

[0876] To a mixture of 1-(5-fluoropyrimidin-2-yl)ethane-1,2-diol (6.0 g, 37.94 mmol) and DIEA (14.71 g, 113.83 mmol) in DCM (60 ml) was added SEM-Cl (4.43 g, 26.56 mmol) dropwise at 0 ° C. under N2. The mixture was stirred at room temperature for 1 h. The reaction was quenched by adding MeOH (20 ml) at room temperature. The mixture was stirred for 30 min and then concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE / EA (6: 1 to 4: 1) to give the title compound (3.0 g, 27%) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ8.93(d,2H),4.93-4.86(m,1H),4.78-4.71(m,2H),4.66-4.60 (m,1H),3.83-3.74(m,2H),3.59-3.41(m,2H),0.84-0.59(m,2H),0.03-0.03(s,9H).MS ES+m / z 289[M+H] + .

[0877] 2-(5-Fluoropyrimidin-2-yl)-2-(2-trimethylsilanylethoxymethoxy)ethanol (600 mg, 5%) was also isolated after chromatography.1 H NMR(300MHz,DMSO-d6)δ8.91(d,2H),5.56(d,1H),4.89-4.75(m,1H),4.61-4.53(m, 2H),3.98-3.71(m,2H),3.47-3.38(m,2H),0.88-0.78(m,2H),0.03-0.03(s,9H).MS ES+m / z 289[M+H] + .

[0878] Preparation Example 108

[0879] 2-[tert-Butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethanol

[0880]

[0881] At 0 ° C, N2, a toluene solution (10 ml) of 2-bromo-5-fluoropyridine (1.2 g, 6.82 mmol) was treated dropwise with i-PrMgCl (5.11 ml, 10.23 mmol, 2 M in THF). The resulting mixture was stirred at 0 ° C for 30 min and treated dropwise with 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (1.78 g, 10.23 mmol) for 10 min. The resulting mixture was stirred at 0 ° C for 2 h, quenched with H2O, and extracted with EA (3 x 20 ml). The combined organic layer was washed with brine (2 x 10 ml), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluted with PE / EA (10: 1 to 5: 1) to give the title compound (420 mg, 23%) as a colorless oil. MS ES+m / z 272[M+H] + .

[0882] Preparation Example 109

[0883] 2-(2-Benzyloxy-1-methoxy-ethyl)-3,5-difluoro-pyridine

[0884]

[0885] A solution of 2-benzyloxy-1-(3,5-difluoro-2-pyridyl)ethanol (1.5 g, 5.66 mmol) and CHI (1.20 g, 8.48 mmol) in THF (20 ml) was treated with t-BuOK (6.79 ml, 6.79 mmol, 1 M in THF) at 0°C under N2. The resulting mixture was stirred at room temperature for 1 h, quenched with saturated aqueous NH4Cl solution (100 ml), and extracted with EA (3 x 200 ml). The combined organic layers were washed with brine (2 x 200 ml), dried over Na2SO4, filtered, and concentrated to give the title compound (1.52 g, 96%) as a light yellow oil. MS ES+ m / z 280 [M+H] + .

[0886] Preparation Example 110

[0887] tert-Butyl-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]-dimethyl-silane

[0888]

[0889] A solution of 2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethanol (3.0 g, 11.05 mmol) and CHI (7.84 g, 55.27 mmol) in THF (30 ml) at 0°C under N2 was treated with NaH (0.53 g, 22.11 mmol, 60% wt) in 30 ml portions. After stirring at room temperature for 2 h, the reaction was quenched with H2O (50 ml) and extracted with EA (2 x 50 ml). The combined organic layers were washed with brine (2 x 80 ml), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (2.9 g, 92%) as a yellow solid. MS ES+ m / z 286 [M+H] + .

[0890] Preparation Example 111

[0891] 2-[[2-(5-Fluoropyrimidin-2-yl)-2-methoxy-ethoxy]methoxy]ethyl-trimethyl-silane

[0892]

[0893] To a stirred mixture of 1-(5-fluoropyrimidin-2-yl)-2-(2-trimethylsilylethoxymethoxy)ethanol (1.01 g, 3.50 mmol) in THF (10 ml) was added portionwise CHI (746 mg, 5.25 mmol) and AgO (2.43 g, 10.51 mmol) at room temperature under N2. The reaction was stirred at 60°C under N2 for 4 h. After cooling to room temperature, the reaction was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / EA (2:1 to 3:1) to give the title compound (948 mg, 90%) as a yellow oil. MS ES+ m / z 303 [M+H] + .

[0894] Preparation Example 112

[0895] 5-Bromo-2-[3,3-difluoro-1-(tetrahydropyran-2-yloxymethyl)cyclobutyl]pyridine

[0896]

[0897] Under N2, a solution of [1-(5-bromo-2-pyridyl)-3,3-difluoro-cyclobutyl]methanol (1.7 g, 6.113 mmol) and DHP (2.57 g, 30.565 mmol) in DCM (10 ml) was treated with TsOH (10.5 mg, 0.06 mmol). After stirring at 50 °C for 2 h, the reaction was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (20:1) to give the title compound (2.1 g, 94.8%) as a yellow oil. MS ES+ m / z 362 / 364 [M+H] + .

[0898] Preparation Example 113

[0899] 2-[3,3-Difluoro-1-(tetrahydropyran-2-yloxymethyl)cyclobutyl]-5-fluoro-pyridine

[0900]

[0901] At -70 ° C under N2, a solution of 5-bromo-2-[3,3-difluoro-1-(tetrahydropyran-2-yloxymethyl)cyclobutyl]pyridine (2.0 g, 5.5 mmol) in THF (20 ml) was treated dropwise with n-BuLi (2.87 ml, 7.18 mmol, 2.5 M in hexane). The reaction was stirred at -70 ° C for 15 min and then treated with NFSI (3.48 g, 11.04 mmol). The reaction was stirred at -70 ° C for another hour and then quenched with H2O at room temperature. The resulting mixture was extracted with EA (3 x 100 ml), and the combined organic layers were washed with brine (2 x 100 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with PE / EA (20:1). The title compound (930 mg, crude product) was obtained as a yellow oil. MS ES+m / z 302[M+H] + .

[0902] Preparation Example 114

[0903] [3,3-Difluoro-1-(5-fluoro-2-pyridyl)cyclobutyl]methanol

[0904]

[0905] At room temperature under N2, a solution of 2-[3,3-difluoro-1-(tetrahydropyran-2-yloxymethyl)cyclobutyl]-5-fluoro-pyridine (900 mg, crude product) in THF (10 ml) was treated with aqueous HCl (2.5 ml, 12 M). After stirring at room temperature for 3 h, the reaction was diluted with H2O (50 ml), basified to pH 7-8 with aqueous NaHCO3 solution, and extracted with EA (3 x 50 ml). The combined organic layers were washed with brine (2 x 50 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC: PE / EA (5: 1) to give the title compound (450 mg, 69%) as a light yellow oil. MS ES+ m / z 218[M+H] + .

[0906] Preparation Example 115

[0907] 2-(3,5-Difluoro-2-pyridyl)-2-methoxy-ethanol

[0908]

[0909] A solution of 2-benzyloxy-1-(3,5-difluoro-2-pyridyl)ethanol (1.5 g, 5.37 mmol) in TFA (15 ml) was stirred at 80°C under N2 for 4 h. The reaction was cooled to room temperature, diluted with H2O (50 ml), basified to pH 9 with K2CO3, and extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (2 x 100 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (5:1 to 4:1) to give the title compound (545 mg, 54%) as a light yellow oil. MS ES+ m / z 190 [M+H] + .

[0910] Preparation Example 116

[0911] 2-(5-Fluoro-2-pyridinyl)-2-methoxy-ethanol

[0912]

[0913] At room temperature, N2, a solution of tert-butyl-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]-dimethyl-silane (2.9 g, 10.16 mmol) in DCM (5 ml) was dropwise treated with 4M HCl in 1,4-dioxane (30 ml). After the reaction was complete, the reactant was concentrated and the residue was dissolved in 50 ml H2O, basified to pH 9 with saturated Na2CO3 aqueous solution, and extracted with EA (2x60 ml). The combined organic layer was washed with brine (2x40 ml), dried over Na2SO4, and concentrated to give the title compound (1.6 g, crude product) as a yellow oil. MS ES+m / z 172[M+H] + .

[0914] Preparation Example 117

[0915] 2-(5-Fluoropyrimidin-2-yl)-2-methoxy-ethanol

[0916]

[0917] To a solution of 2-[[2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethoxy]methoxy]ethyl-trimethyl-silane (925 mg, 3.06 mmol) in MeOH (9 ml) was added concentrated HCl (3 ml) dropwise at room temperature under N2. The reaction was stirred at room temperature for 2 h and then quenched with H2O (100 ml). The mixture was basified to pH 8 with NaHCO3. The aqueous layer was extracted with EA (3 x 100 ml). The combined organic layers were concentrated in vacuo to give the title compound as a white solid (450 mg, 85%). MS ES+ m / z 173 [M+H]+ .

[0918] Preparation Example 118

[0919] 1-[5-(Trifluoromethyl)-3-pyridyl]ethylamine

[0920]

[0921] A solution of 1-[5-(trifluoromethyl)-3-pyridyl]ethanone (0.77 g, 4.06 mmol) in EtOH (30 ml) was treated with NH4OAc (4.7 g, 61 mmol) and stirred at room temperature for 20 min. The reaction was treated with NaBH3CN (0.54 g, 8.12 mmol) and stirred at room temperature for 1 hour, then stirred at 85 ° C for 1.25 h. The reaction was cooled to room temperature and concentrated. The resulting oil was loaded onto an SCX column. The non-basic impurities in the column were washed off with MeOH, and the title compound was eluted with methanolic ammonia (2 M). The resulting oil was purified by reverse phase (Claricep C) chromatography, eluting with a 20% to 50% NH4CO3 aqueous solution in ACN to give the title compound (1.9 g, 77%) as a yellow oil. MS ES+m / z 191[M+H] + .

[0922] Preparation Example 119

[0923] N-Benzyl-3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propan-1-amine

[0924]

[0925] Under N2, a solution of 5-fluoro-2-[1-(trifluoromethyl)vinyl]pyridine (3.4 g, 17.79 mmol) in THF (30 ml) was treated with benzylamine (3.81 g, 35.58 mmol). After stirring at 50°C for 2 h, the reaction was cooled to room temperature, diluted with H2O (100 ml), and extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with PE / EA (20:1 to 10:1) to give the title compound (4.0 g, 75%) as a colorless oil. MS ES+ m / z 299 [M+H] + .

[0926] Preparation Example 120

[0927] 3,3,3-Trifluoro-2-(5-fluoro-2-pyridyl)propan-1-amine

[0928]

[0929] To a solution of N-benzyl-3,3,3-trifluoro-2-(5-fluoro-2-pyridyl)propan-1-amine (3.50 g, 11.73 mmol) in IPA (50 ml) was added Pd / C (2.50 g, 23.47 mmol) and Pd(OH)2 / C (2.82 g, 20.11 mmol) under N2. The resulting mixture was stirred at room temperature under H2 for 2 h. The mixture was filtered and washed with MeOH (3 x 10 ml). The filtrate was concentrated to give the title compound (2.0 g, crude product). MS ES+ m / z 209 [M+H] + .

[0930] Preparation Example 121

[0931] 3-(1-chloroethyl)-5-(trifluoromethyl)pyridine

[0932]

[0933] To a stirred mixture of 1-[5-(trifluoromethyl)pyridin-3-yl]ethanol (36.00 g, 188 mmol) in DCM (400 ml) was added SOCl (44.81 g, 376 mmol) at room temperature under N₂. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with H₂O (500 ml). The mixture was extracted with DCM (3 x 500 ml). The combined organic layers were washed with brine (1 x 500 ml) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (40 g, crude product) as a yellow oil. ES+m / z 210[M+H] + .

[0934] Preparation Example 122

[0935] 4-(1-chloroethyl)-2-isopropyl-triazole

[0936]

[0937] 1-(2-Isopropyltriazol-4-yl)ethanol (344 mg, 2.22 mmol) was dissolved in SOCl2 (3 ml) and toluene (3 ml), then refluxed for 1 h. The reaction was concentrated in vacuo to afford the title compound as a brown oil (365 mg, quantitative). This material was used immediately in the next step.

[0938] The following compounds were prepared in a manner substantially similar to the method of Preparation 122, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0939] Table 21

[0940]

[0941]

[0942] 1 The reaction was refluxed in a mixture of 1:1 SOCl2:toluene.

[0943] 2 The reaction was carried out at room temperature in a mixture of 1:1 SOCl2:DCM.

[0944] 3 The reaction was evaporated and co-evaporated with toluene.

[0945] 4 The reaction was carried out at room temperature in a mixture of 1:5 SOCl2:DCM.

[0946] Preparation Example 127

[0947] 4-[1-chloroethyl]-2-cyclopropyl-thiazole

[0948]

[0949] Under N2, MsCl (0.16ml, 2.1mmol) is added dropwise to a solution of 1-(2-cyclopropylthiazol-4-yl)ethanol (320.5mg, 1.76mmol) and NEt3 (0.49ml, 3.5mmol) in DCM (7ml) cooled to 0°C. The reaction is stirred at 0°C for 1h, and then the cooling bath is removed. After 3.5h, the reaction is recooled to 0°C and quenched by slowly adding H2O (5ml). The layers are separated, and the aqueous layer is extracted with DCM (3ml). The combined organic layers are washed with brine (5ml), dried over Na2SO4, filtered and concentrated to give the title compound (316mg, 95%) as a brown oil. 1 HNMR (400MHz, CDCl3): δ7.03 (s, 1H), 5.18 (qd, J = 6.8, 0.6Hz, 1H), 2.38-2.33 (m, 1H), 1.90 (d, J = 6.8Hz, 3H), 1.18-1.15 (m, 4H).

[0950] The following compounds were prepared in a manner substantially similar to the method of Preparation 127, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0951] Table 22

[0952]

[0953]

[0954] Preparation Example 130

[0955] 1-(3,6-Dimethylpyrazin-2-yl)ethyl methanesulfonate

[0956]

[0957] MsCl (903.09 mg, 7.88 mmol) was added dropwise to a stirred mixture of 1-(3,6-dimethylpyrazin-2-yl)ethanol (1 g, 6.57 mmol) and DIEA (127.38 mg, 0.99 mmol) in DCM (10 ml) at 0°C under N2 and stirred for 2 h. The reaction was removed from the cooling bath, quenched with H2O (10 ml) and extracted with DCM (3 x 10 ml). The combined organic layers were washed with brine (3 x 10 ml), dried over Na2SO4, filtered and concentrated to give the title compound (1.1 g, 73%) as a brown oil. MS ES+ m / z 231 [M+H] + .

[0958] The following compounds were prepared in a manner substantially similar to the method of Preparation 130, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0959] Table 23

[0960]

[0961]

[0962] a The material was used in the subsequent step without further characterization.

[0963] Preparation Example 141

[0964] 2-Bromo-1-(5-fluoro-2-pyridyl)pyridine

[0965]

[0966] NBS (1.14 g, 6.38 mmol) was added in small portions to a solution of 3-chloro-2-(1-ethoxyvinyl)-5-fluoro-pyridine (1.22 g, 6.06 mmol) in a mixture of THF (12 ml) and H O (3 ml) at 0° C. over 5-10 min. The reaction was stirred at 0° C. for 1 hour, then diluted with EA (50 ml), washed with H O (50 ml) and brine (50 ml), dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EA in heptane to give the title compound as a light yellow oil (1.394 g, 91%). 1 H NMR (400MHz, CDCl3) δ (ppm): 8.44 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 7.9, 2.4 Hz, 1H), 4.69 (s, 2H).

[0967] The following compounds were prepared in a manner substantially similar to the method of Preparation 141, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0968] Table 24

[0969]

[0970] 1 Purify by chromatography on silica gel eluting with EA in heptane.

[0971] Preparation Example 143

[0972] 2-Bromo-1-(3,5-difluoro-2-pyridyl)ethanone

[0973]

[0974] At room temperature under N2, a solution of phenyltrimethylammonium bromide (51.36g, 133mmol) in THF (423ml) was treated with a THF solution (181ml) of 1-(3,5-difluoro-2-pyridyl)ethanone (20g, 120.93mmol). After stirring at 60°C for 1.5h, the mixture was cooled to room temperature and stirred for 1h. The resulting suspension was filtered and the solid was washed with THF (2x100ml). The combined filtrate was concentrated to give a brown oil, which was purified by silica gel chromatography eluting with a cHex solution having a gradient of 10% to 50% DCM to give the title compound (15g, 42%) as a yellow oil. MS ES+m / z( 79 Br / 81 Br)237[M+H] + .

[0975] The following compounds were prepared in a manner substantially similar to the method of Preparation 143, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[0976] Table 25

[0977]

[0978] 1 Purify by silica gel chromatography eluting with a gradient of 5% to 30% DCM in cHex.

[0979] Preparation Example 145

[0980] 2-Chloro-1-(5-fluoropyrimidin-2-yl)ethanone

[0981]

[0982] To a stirred solution of 2-bromo-5-fluoropyrimidine (3.0 g, 16.95 g) in toluene (30 ml) at 0°C under N2 was added i-PrMgCl (1 M in THF) (10.17 ml, 20.340 mmol) dropwise. The reaction was stirred at room temperature for 2 h. To the above mixture was added 2-chloro-N-methoxy-N-methylacetamide (2.33 g, 16.95 mmol) dropwise at 0°C under N2 over 20 min. The reaction was stirred at room temperature for 1 h and then quenched with saturated aqueous NH4Cl (200 ml). The mixture was extracted with EA (2 x 300 ml). The combined organic layers were washed with brine (2 x 300 ml), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.3 g, 78%) as a yellow oil. MS ES+ m / z 175 [M+H] + .

[0983] Preparation Example 146

[0984] 6-Bromo-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine

[0985]

[0986] 6-Bromo-4-methoxypyrazolo[1,5-a]pyridine (0.41 g, 1.81 mmol) and NIS (609 mg, 2.71 mmol) were dissolved in ACN (8 ml) and stirred at room temperature for 1 hour. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a linear gradient of 0% to 100% EA in heptane. The fractions containing the title compound were concentrated in vacuo and combined with the filtered solid to give the title compound (0.60 g, 94.1%). ES / MS m / z( 79 Br / 81 Br)352.6 / 354.6[M+H] + .

[0987] Preparation Example 147

[0988] 6-Bromo-4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine

[0989]

[0990] 6-Bromo-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine (2 g, 5.67 mmol) was dissolved in DMF (28 ml) and treated with CuI (3.8 g, 20 mmol). N2 was bubbled through the mixture for 5 min, then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.9 g, 20 mmol) was added and the reaction was stirred at 80 ° C for 2 h. After cooling to room temperature, the reaction was diluted with EA, filtered, and the solid was washed with EA. The filtrate was diluted with H2O and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (582 mg, 29%) as a yellow solid. MS ES+ m / z 295 / 297 [M+H] + .

[0991] Preparation Example 148

[0992] 6-Bromo-3-fluoro-4-methoxy-pyrazolo[1,5-a]pyridine

[0993]

[0994] A solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5 g, 22.021 mmol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (7.04 g, 22.02 mmol) in ACN (50 ml) was stirred overnight at room temperature under N2. The resulting mixture was diluted with H2O (50 ml) and extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (2 x 100 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase C18 flash chromatography using the following conditions: column, C18; mobile phase, elution with a gradient of 30% to 40% ACN in H2O (0.1% FA); 254 nm; to afford the title compound (810 mg, 15%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6) δ8.56(t,1H),8.04(d,1H),6.77(d,1H),3.97(s,3H).

[0995] Preparation Example 149

[0996] 6-Bromo-4-methoxy-3-methyl-pyrazolo[1,5-a]pyridine

[0997]

[0998] Et3Si (8.0 ml, 50.20 mmol) was added dropwise to a solution of (6-bromo-4-methoxypyrazolo[1,5-a]pyridin-3-yl)methanol (6.45 ml, 25.10 mmol) in TFA (50 ml) at 0°C. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated in vacuo and the residue was dissolved in DCM, washed with saturated aqueous Na2CO3 (2x), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with EA in heptane to give the title compound as a white solid (3.81 g, 63%). MS ES+ m / z ( 35 Cl / 37 Cl)241 / 243[M+H] + .

[0999] Preparation Example 150

[1000] 7-Chloro-5-methoxy-imidazo[1,2-a]pyridine

[1001]

[1002] A solution of 4-chloro-6-methoxypyridin-2-amine (7.00 g, 44.14 mmol), chloroacetaldehyde (8.32 g, 52.99 mmol, 50%) and NaHCO (11.12 g, 132.42 mmol) in n-BuOH (140 ml) was divided into fourteen batches and stirred overnight at 65° C. in a sealed tube. The solution was cooled to room temperature, diluted with H O (200 ml) and extracted with EA (3 x 200 ml). The organic layers were combined, dried over Na SO and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50% EA in PE to give the title compound as a light brown solid (6.1 g, 76%). ES / MS m / z 183 [M+H] +.

[1003] Preparation Example 151

[1004] 6-Bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile

[1005]

[1006] A suspension of 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (100 g, 396.72 mmol) in 1L DMA was treated with a solution of NaOH (31.7 g, 793 mmol) in H2O (100 ml) at 40°C in one portion, followed by NDM (161 g, 793 mmol). After stirring at 50°C for 1 h, the reaction was cooled to 0°C and quenched with 37% aqueous HCl (100 ml) to a final pH of 5. The reaction was diluted with H2O (4 L) and the resulting solid was collected by filtration, washed with H2O (1 L) and heptane (500 ml) to afford the title compound (85.5 g, 82%) as a beige solid. MS ES+ m / z 238 [M+H] + .

[1007] Preparation Example 152

[1008] 5,7-Dichloro-3-iodo-imidazo[1,2-a]pyridine

[1009]

[1010] A solution of 5,7-dichloroimidazo[1,2-a]pyridine (5.00 g, 26.74 mmol) in DCM (50 ml) was treated with NIS (12.03 g, 53.47 mmol) in portions at room temperature under N₂. After stirring at room temperature for 2 hours, the reaction was diluted with H₂O (100 ml) and extracted with DCM (3 x 50 ml). The combined organic layers were washed with brine (3 x 50 ml), dried over Na₂SO₄, filtered, and concentrated to afford the title compound (12.0 g, crude) as a dark yellow solid. MS ES+ m / z 313 [M+H] + .

[1011] Preparation Example 153

[1012] 5,7-Dichloroimidazo[1,2-a]pyridine-3-carbonitrile

[1013]

[1014] At room temperature under N2, a DMF solution of 5,7-dichloro-3-iodo-imidazo[1,2-a]pyridine (11.00 g, 35.15 mmol) was treated with CuCN (6.30 g, 70.31 mmol) in batches. After stirring at 100 ° C for 2 h, the reaction was cooled to room temperature, treated dropwise with NH4OH (100 ml) for 5 min, diluted with H2O (300 ml), and stirred at room temperature for 2 h. The reaction was extracted with DCM (3x 400 ml), and the combined organic layers were washed with brine (3x 300 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with PE / EA (5: 1 to 1: 2) to give the title compound (3.5 g, 47%) as a yellow solid. MS ES+m / z( 35 Cl / 37 Cl)212 / 214[M+H] + .

[1015] Preparation Example 154

[1016] 7-Chloro-5-[2-(3,5-difluoro-2-pyridinyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridine

[1017]

[1018] At 0 ° C, under N2, a stirred mixture of 2-(3,5-difluoro-2-pyridyl)-2-methoxy-ethanol (6.57g, 34.76mmol) and 5,7-dichloroimidazo[1,2-a]pyridine (6.5g, 34.76mmol) in THF (120ml) was treated dropwise with t-BuOK (48.66ml, 48.66mmol, 1M in THF). After stirring at room temperature for 2h, the reaction was quenched with saturated aqueous NH4Cl solution, extracted with EA (2x500ml), washed with brine (2x200ml), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase C18 flash chromatography eluting with a gradient of 40% to 50% ACN in H2O to give the title compound as a light yellow solid (1.75g, 15%). MS ES+m / z 340[M+H] + .

[1019] Preparation Example 155

[1020] 6-Bromo-4-[1-[5-(trifluoromethyl)-3-pyridinyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[1021] To a DMF solution (350 ml) of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (45.43 g, 190.84 mmol) was added K2CO3 (79.13 g, 572.52 mmol) and 3-(1-chloroethyl)-5-(trifluoromethyl)pyridine (40 g, crude) in portions at 80°C over a period of 2 min. The reaction was stirred at room temperature under N2 for 2 h. The resulting mixture was diluted with H2O (1 L) and extracted with EA (3x1.5 L). The combined organic layers were washed with brine (5x 1 L), dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 2:1) to give the racemate of the title compound (32 g, 40.78%) as a yellow solid. MSES+m / z( 79 Br / 81 Br)411 / 413[M+H] + .

[1022] The racemate of the title compound (32 g) was subjected to the following chromatographic conditions: SFC, column: NB_CHIRAL ART cellulose-SB; 5 x 25 cm, 5 μm, eluted with 15% IPA (0.2% DEA) in CO2 to give the title compound, isomer 2 (13.5 g, 42.19%), t R 6.58 min, 99% ee. MS ES+ m / z ( 79 Br / 81 Br)411 / 413[M+H] + .

[1023] Preparation Example 156

[1024] 6-Bromo-4-[(1R)-1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile tosylate

[1025]

[1026] At room temperature, a THF solution (300 ml) of PPh3 (34.1 g, 130 mmol) was treated dropwise with DIAD (23.2 g, 115 mmol) over 4 min. After stirring at room temperature for 30 min, a THF solution (100 ml) of 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (20 g, 76.5 mmol) and (1S)-1-(2-pyridyl)ethanol (11.3 g, 91.8 mmol) was added dropwise over 6 min. After stirring at room temperature for 45 min, the reactants were concentrated under vacuum. The residue was slurried in hexane / MTBE (4:1; 250 ml) and stirred at room temperature overnight. The resulting solid was collected by filtration, washed with hexane (2 x 100 ml), and purified by silica gel chromatography, eluting with a gradient of 0% to 15% acetone in hexane. The resulting solid was dissolved in MTBE (100 ml) and treated with 4-methylbenzenesulfonic acid hydrate (8.85 g, 46.5 mmol). The resulting suspension was stirred at room temperature overnight. The solid was collected by filtration and washed with MTBE (3 x 50 ml) to give the title compound (43.4 g, 87%) as a white solid. MS ES+( 79 Br / 81 Br)m / z 343 / 345[M+H] + .

[1027] Preparation Example 157

[1028] 6-Bromo-3-chloro-4-[2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine

[1029]

[1030] To a THF solution (10 ml) of PPh3 (3.50 g, 13.34 mmol) was added dropwise DIAD (2.52 g, 12.45 mmol) at 0°C under N2. The reaction was stirred at 0°C for 0.5 h. Next, a THF solution (10 ml) of 6-bromo-3-chloropyrazolo[1,5-a]pyridine-4-ol (1.1 g, 4.45 mmol) and 2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethanol (918.26 mg, 5.334 mmol, 1.2 equivalents) was added at room temperature. The reaction was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18; mobile phase, 50% to 55% ACN in H2O to give the title compound (700 mg, 39%) as a yellow solid. MS ES+m / z 402 / 403[M+H] + .

[1031] Preparation Example 158

[1032] 6-Bromo-4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1033]

[1034] A mixture of 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (4 g, 16.80 mmol) and CsCO (8.21 g, 25.2 mmol) in ACN (20 ml) was stirred at room temperature under N2 for 0.5 h. A solution of 2-bromo-1-(5-fluoro-2-pyridyl)ethanone (4.6 g, 20 mmol) in ACN (20 ml) was added and the reaction was stirred at room temperature for 1 h. The reaction was diluted with H2O (100 ml) to give a suspension. The solid was collected by filtration and washed with H2O to give the title compound (5.86 g, 93%) as a white solid. MS ES+ m / z 375 / 377 [M+H] + .

[1035] The following compounds were prepared in a manner substantially similar to the method of Preparation 158, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1036] Table 26

[1037]

[1038] 1 DIPEA was used as the base for this transformation.

[1039] 2 Workup: The reaction was concentrated in vacuo. The residue was dissolved in methanol and triturated with H2O. The precipitated product was collected by filtration.

[1040] 3 The reaction was heated at 80 °C.

[1041] 4 Workup: The reaction was concentrated in vacuo. The residue was triturated with H2O. The precipitated product was collected by filtration.

[1042] 5 Work-up: the reaction was diluted with H2O, extracted with EA, dried over Na2SO4, filtered and concentrated in vacuo.

[1043] 6 Purify by silica gel chromatography eluting with EA in DCM (1:30 to 1:15).

[1044] Preparation Example 162

[1045] 1-(6-Bromopyrazolo[1,5-a]pyridin-4-yl)oxy-2-(5-fluoro-2-pyridinyl)propan-2-ol

[1046]

[1047] A solution of 2-(6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy-1-(5-fluoro-2-pyridyl)ene ketone (3 g, 8.57 mmol) in THF (10 ml) was added to a stirred solution of MeMgBr (3 M in Et2O, 14.3 ml, 42.84 mmol) in THF (30 ml) at room temperature under N2, and the reaction was stirred for 2 h. The solution was quenched with H2O (50 ml) and extracted with EA (3 x 50 ml). The combined organic layers were washed with brine (3 x 50 ml), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (3 g, crude product) as a brown oil. MS ES+ m / z ( 79 Br / 81 Br)366 / 368[M+H] + .

[1048] The following compounds were prepared in a manner substantially similar to the method of Preparation 162, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1049] Table 27

[1050]

[1051] 1 The reaction was quenched at 0°C with saturated aqueous NH4Cl (30 ml).

[1052] 2 Purify by silica gel chromatography eluting with DCM / PE (1:2-2:1).

[1053] 3 Purified by Prep-TLC PE / EA (8:1).

[1054] Preparation Example 165

[1055] 6-Bromo-4-[2-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1056]

[1057] A suspension of 6-bromo-4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (2.18 g, 5.82 mmol) in MeOH (50 ml) was cooled in an ice bath and then treated with NaBH4 (0.85 g, 22.47 mmol) in one portion. The reaction was stirred at 0°C for 5 min and then at room temperature for 1 h. The reaction was concentrated and the residue was dissolved in DCM and washed with H2O and brine. The organic layer was collected, dried over MgSO4, filtered and concentrated to give the title compound (1.98 g, 83%) as a beige solid. MS ES+ m / z 377 / 379 [M+H] + .

[1058] The following compounds were prepared in a manner substantially similar to the method of Preparation 165, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1059] Table 28

[1060]

[1061] 1 Workup: The reaction was concentrated in vacuo. The residue was triturated in H2O and the precipitate was collected by filtration.

[1062] Preparation Example 168

[1063] 6-Bromo-3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine

[1064]

[1065] To a THF solution (10 ml) of 2-(6-bromo-3-chloro-pyrazolo[1,5-a]pyridin-4-yl)oxy-1-(5-fluoro-2-pyridinyl)ethanol (1.62 g, 4.19 mmol) was added NaH (335 mg, 8.38 mmol, 60%) in portions at 0°C under N2. CHI (2.97 g, 20.95 mmol) was added dropwise to the mixture at 0°C. The reaction was stirred at room temperature for 2 h and then quenched with H2O (50 ml). The mixture was extracted with EA (3 x 100 ml), the organic layers were combined, washed with brine (3 x 50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 5:1) to give the title compound (1.01 g, 60%) as a light yellow solid. MS ES+m / z 402[M+H] + .

[1066] Preparation Example 169

[1067] 6-Bromo-4-[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1068]

[1069] To a stirred solution of 6-bromo-4-[2-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (3 g, 7.95 mmol) and CH3I (2.26 g, 15.91 mmol) in THF (30 ml) was added NaH (60%) (636 mg, 15.91 mmol) in portions at 0 ° C under N2. The mixture was stirred at room temperature for 2 hours and then quenched with H2O (20 ml). The mixture was extracted with EA (3x 40 ml). The combined organic layers were washed with brine (2x 20 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE / EA (4: 1 to 1: 1) to give the title compound (2.9 g, 93%) as a yellow solid. MS ES+m / z( 79 Br / 81 Br)391.0 / 393.0[M+H] + .

[1070] Preparation Example 170

[1071] 7-Chloro-5-[[3,3,3-trifluoro-2-(5-fluoro-2-pyridinyl)propyl]amino]imidazo[1,2-a]pyridine-3-carbonitrile

[1072]

[1073] Under N2, a stirred solution of 3,3,3-trifluoro-2-(5-fluoro-2-pyridinyl)propan-1-amine (2.0 g, 9.6 mmol) and 5,7-dichloroimidazo[1,2-a]pyridine-3-carbonitrile (2.64 g, 12.5 mmol) in DMF (5 ml) was treated with DIEA (3.72 g, 28.8 mmol). After stirring at 100°C for 24 h, the reaction was purified by reverse phase flash C18 chromatography using the following conditions: column, C18; eluting with a gradient of 50% to 70% ACN in H2O to provide the title compound (1.2 g, 34%). MS ES+ m / z 384 [M+H] + .

[1074] Preparation Example 171

[1075] 6-Bromo-4-[1-[5-(trifluoromethyl)-3-pyridinyl]ethylamino]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1076]

[1077] A pressure flask was charged with Pd2(dba)3 (0.05 g, 0.05 mmol), dppf (0.06 g, 0.1 mmol), K3PO4 (1.3 g, 6 mmol), and DME (5 ml). The suspension was degassed by bubbling N2 through the mixture for several minutes, followed by the addition of 11-[5-(trifluoromethyl)-3-pyridyl]ethanamine (0.40 g, 1.89 mmol) and 4,6-dibromopyrazolo[1,5-a]pyridine-3-carbonitrile (0.52 g, 1.7 mmol), and the N2 was bubbled through the mixture for several more minutes. The tube was capped, and the reaction was heated at 207°C for 15 min. After stirring at room temperature overnight, additional DME (5 ml), Pd2(dba)3 (0.05 g, 0.05 mmol), and dppf (0.06 g, 0.1 mmol) were added to the reaction. After the mixture was degassed, the reaction was capped and heated at 100°C for 8 h. The reaction was cooled to room temperature, diluted with H2O, and extracted with EA (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 50% EA in cHex to give the title compound (393 mg), which was used in the next synthetic reaction without further purification. MS ES+ m / z 410 / 412 [M+H] + .

[1078] The following compounds were prepared in a manner substantially similar to the method of Preparation 171, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1079] Table 29

[1080]

[1081] 1 Purify by silica gel chromatography eluting with 0% to 100% EA in cHex.

[1082] 2 Purify by silica gel chromatography eluting with 0% to 50% EA in cHex.

[1083] Preparation Example 174

[1084] 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[1-[5-(trifluoromethyl)-3-pyridinyl]ethylamino]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1085]

[1086] To a high pressure flask was added 6-bromo-4-[[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethyl]amino]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.39 g, 0.55 mmol), bis(pinacolato)diboron (0.21 g, 0.82 mmol), KOAc (0.21 g, 2.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.01 g, 0.01 mmol), and 1,4-dioxane (4 ml). N₂ was bubbled through the mixture for several minutes, then the flask was closed and the reaction was heated at 90°C for 5.5 h. After cooling to room temperature, the reaction was diluted with H₂O and extracted with EA (3x). The combined organic layers were dried over MgSO4, filtered, concentrated, and the residue was purified by silica gel chromatography eluting with 0% to 80% EA in cHex to give the title compound (0.39 g, 82%) as a thick brown oil. MS ES+ m / z 376 [M+H] + , is boric acid.

[1087] The following compounds were prepared in a manner substantially similar to the method of Preparation 174, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1088] Table 30

[1089]

[1090] Preparation Example 177

[1091] 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[1092]

[1093] A solution of 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine (50.0 g, 220.2 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (61.0 g, 240.3 mmol) in 1,4-dioxane (500 ml) was degassed with N2 for 15 min at room temperature. KOAc (64.0 g, 652.1 mmol) was added at 25°C under N2, followed by Pd(dppf)Cl2 (6.0 g, 8.2 mmol) added portionwise. The mixture was degassed with N2 for 15 min. The reaction was stirred at 80°C under N2 for 12 h. The reaction was cooled to 25°C and filtered through DE. The filter cake was washed with 1,4-dioxane (3 x 100 ml). The filtrate was concentrated in vacuo at 45°C to give an oily black residue. The residue was purified by filtration through a silica gel plug (300 g, 12 cm column diameter). The plug was eluted with 20:1 to 3:1 c-Hex:EA to give the title compound (62.7 g, 206 mmol) as a light yellow solid. MS ES+ m / z 275 [M+H] + .

[1094] Preparation Example 178

[1095] 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

[1096]

[1097] A stirred solution of 6-bromo-4-methoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (20.0 g, 79.34 mmol) in 1,4-dioxane (200 ml) was treated with bis(pinacolato)diboron (30.22 g, 119.01 mmol), KOAc (23.36 g, 238.03 mmol), and Pd(dppf)Cl (2.90 g, 3.97 mmol) at room temperature under N2. The reaction was stirred at 80°C for 1 hour and the crude reaction was used in the next synthetic step without purification. MS ES+ m / z 300 [M+H] + .

[1098] The following compounds were prepared in a manner substantially similar to that of Preparation 178, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1099] Table 31

[1100]

[1101]

[1102] 1 Purify by silica gel chromatography eluting with 0% to 50% EA in cHex.

[1103] 2 Purify by silica gel chromatography eluting with 0% to 80% EA in cHex.

[1104] 3 The compound was degraded on MS. The MS data showed a mixture of boronate ester and boronic acid.

[1105] 4 The compound was degraded on MS. The MS data were consistent with boronic acid.

[1106] 5 Xphos Palladacycle Gen 4 was used as the catalyst for this transformation.

[1107] 6 Pd(dppf)Cl2.CH2Cl2 was used as a catalyst for this transformation.

[1108] 7 The reaction was heated at 100 °C.

[1109] a The material was used in the subsequent step without further characterization.

[1110] 8 Purify by chromatography on silica gel eluting with EA in heptane.

[1111] Preparation Example 189

[1112] (3S,4R)-4-[4-[3-chloro-4-[2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine

[1113] -6-yl]-5-methyl-triazol-1-yl]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester

[1114]

[1115] To a solution of 6-bromo-3-chloro-4-[2-(5-fluoropyrimidin-2-yl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine (626 mg, 1.56 mmol) and bis(pinacolato)diboron (475 mg, 1.87 mmol) in dioxane (7 ml) was added Pd(dppf)Cl2·CH2Cl2 (64 mg, 0.08 mmol) and KOAc (459 mg, 4.68 mmol) portionwise at room temperature under N2. The reaction was stirred at 100°C under N2 for 2 h and then allowed to cool to room temperature. Next, (3S, 4R) -4- (4-bromo-5-methyl-triazol-1-yl) -3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (534 mg, 1.47 mmol), K2CO3 (554 mg, 4.01 mmol), PdCl2 (DtBPF) (44 mg, 0.07 mmol) and H2O (2 ml) were added at room temperature and N2. The mixture was stirred at 100 ° C overnight. After cooling to room temperature, H2O (100 ml) was added to quench the reaction. The mixture was extracted with EA (3 x 100 ml), the organic layers were combined, dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluted with PE / EA (10: 1 to 100% EA). The title compound (585 mg, 72%) was obtained as a brown solid. MS ES+m / z 605 [M+H] + .

[1116] The following compounds were prepared in a manner substantially similar to that of Preparation 189, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1117] Table 32

[1118]

[1119] 1 Purify by silica gel chromatography eluting with PE / EA (2:3 to 1:4).

[1120] 2 Purify by silica gel chromatography eluting with PE / EA (1:3 to 1:4).

[1121] 3 Purify by silica gel chromatography eluting with PE / EA (1:2 to 1:3).

[1122] 4 Purify by silica gel chromatography eluting with PE / EA (1:2 to 1:3).

[1123] Preparation Example 194

[1124] 4-[4-(3-Cyano-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester

[1125]

[1126] At room temperature under N2, the resulting mixture of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (20.0 g, 79.34 mmol) was treated with tert-butyl 4-(4-bromo-5-methyl-triazol-1-yl)piperidine-1-carboxylate (27.70 g, 80.23 mmol), K2CO3 (27.72 g, 200.57 mmol), PdCl2(DtBPF) (2.18 g, 3.34 mmol), and H2O (50 ml). The reaction was stirred at 80°C for 1 hour and allowed to cool to room temperature. The reaction was diluted with H2O (300 ml) and extracted with EA (3 x 300 ml). The combined organic layers were washed with brine (3 x 300 ml), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (15.31 g, 44% yield over two steps) as a yellow solid. MS ES+ m / z 438 [M+H] + .

[1127] Preparation Example 195

[1128] tert-Butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[1129]

[1130] To 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (5.160 g, 18.83 mmol) and KCO (5.0 g, 36.18 mmol) was added a solution of tert-butyl 4-(4-bromo-5-methyl-triazol-1-yl)piperidine-1-carboxylate (7.0 g, 20.28 mmol) in toluene (50 ml), followed by H2O (12.5 ml). The mixture was degassed with N2 for 10 min, then PdCl2(DtBPF) (1.0 g, 1.54 mmol) was added. Degassing with N2 was continued for 5 min. The reaction was stirred and heated at 90°C for 18 h. After cooling to room temperature, the reaction was concentrated in vacuo to remove most of the toluene. The residue was diluted with H2O to give a brown solid. The solid was decanted from the H2O. EA (50 ml) was added to the solid and then evaporated. This process was repeated three times. EA (25 ml) was added and the mixture was heated to 50°C and then cooled to room temperature. The yellow solid was collected by filtration to give the title compound (4.6 g, 53%). MS ES+ m / z 413.2 [M+H] + The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with 10% to 100% EA in c-Hex to give the title compound (2.0 g, 24%) as an oily yellow solid. MS ES+ m / z 413.2 [M+H] + .

[1131] Preparation Example 196

[1132] tert-Butyl 4-[4-[3-cyano-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate

[1133]

[1134] A mixture of 4-[(1R)-1-(2-pyridyl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (5.0 g, 12.81 mmol) and tert-butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate (5.0 g, 14.53 mmol) in toluene (50 ml) was degassed with N bubbling for 5 min. Next, a solution of K CO (4.0 g, 28.94 mmol) in H O (12.5 ml) was added, and the mixture was degassed for another 5 min. PdCl (DtBPF) (500 mg, 0.77 mmol) was added, and the mixture was degassed with N while the reaction was heated to 60° C. The N bubbling was stopped at this point. The reaction was then heated to 100°C under N2.

[1135] After 2 h, the reaction was cooled to room temperature and DE (6 g) was added with stirring. After 30 min, the mixture was filtered through a DE plug and the solid was washed with H2O (50 ml) and toluene (150 ml). The layers of the filtrate were separated and the organic layer was dried over MgSO4, filtered and concentrated to give the title compound (7.0 g, 98%) as an oily brown substance. MS ES+ m / z 528 [M+H] + .

[1136] The following compounds were prepared in a manner substantially similar to that of Preparation 196, using appropriate reagents, adjusting the reaction time to ensure completion, and adjusting the purification system appropriately. K3PO4 can be used in place of K3CO2.

[1137] Table 33

[1138]

[1139]

[1140]

[1141]

[1142] 1 Silica gel column chromatography, eluting with PE / EA (2:1 to 1:1).

[1143] 2 Pd(PPh3)4 was used as a catalyst for this transformation.

[1144] 3 Purify by silica gel chromatography eluting with 10% to 100% EA in cHex.

[1145] 4Purify by silica gel chromatography eluting with 0% to 100% EA in hex followed by 0% to 20% MeOH in EA.

[1146] 5 Purify by silica gel chromatography eluting with 0% to 100% EA in cHex.

[1147] 6 Purify by silica gel chromatography eluting with EA / EtOH (30:1).

[1148] 7 Dioxane was used as solvent.

[1149] 8 The reaction was heated at 80 °C.

[1150] 9 Work-up: The reaction was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated.

[1151] 10 Purify by silica gel column chromatography eluting with PE / EA (10:1 to 3:1).

[1152] 11 Purify by column chromatography on silica gel eluting with 50% EA in PE.

[1153] 12 Work-up: The reaction was concentrated. The residue was slurried in H2O and the resulting insoluble material was collected by filtration.

[1154] 13 Purify by reverse phase C18 chromatography eluting with 40% to 60% ACN in H2O.

[1155] 14 Work-up: The reaction was diluted with H2O and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated.

[1156] 15 Purify by silica gel chromatography eluting with 20% EA in PE.

[1157] 16 Workup: Concentrate the reaction.

[1158] 17 Purify by column chromatography on silica gel eluting with 50% to 75% EA in PE.

[1159] 18 Purify by column chromatography on silica gel eluting with 10% MeOH in DCM.

[1160] 19 Pd(dppf)Cl2 was used as a catalyst for this transformation. The reaction was heated at 90°C.

[1161] 20 Purify by silica gel chromatography eluting with MeOH in DCM.

[1162] 21 Purify by column chromatography on silica gel eluting with DCM / MeOH (15:1 to 10:1).

[1163] 22 Purify by silica gel column chromatography eluting with DCM / MeOH (10:1).

[1164] Preparation Example 214a

[1165] tert-Butyl 2-[4-[3-cyano-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate

[1166]

[1167] and

[1168] Preparation Example 214b

[1169] tert-Butyl 2-[4-[3-cyano-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-3-methyl-pyrazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate

[1170]

[1171] A mixture of tert-butyl 2-(4-bromo-5-methyl-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate, tert-butyl 2-(4-bromo-3-methyl-pyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1.68 g, 3.11 mmol) and 4-[(1R)-1-(2-pyridinyl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.33 g, 3.41 mmol) in toluene (40 ml) and H2O (4 ml) was treated with K2CO3 (1.14 g, 8.25 mmol). N2 was bubbled through the reaction for 2 min, then PdCl2(DtBPF) (135 mg, 0.21 mmol) was added and the tube was sealed. After stirring at 90°C for 20 h, the reaction was cooled and diluted with EA (50 ml) and H2O (20 ml). The layers were separated and the aqueous layer was extracted with EA. The combined organic layers were concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 10% acetone in DCM to give a mixture of the title compounds (621 mg, 74%) as a thick yellow oil. MS ES+ m / z 568 [M+H] + .

[1172] The following compounds were prepared in a manner substantially similar to the methods of Preparations 214a and 214b, using appropriate reagents, adjusting reaction times to ensure reaction completion, and adjusting the purification system appropriately.

[1173] Table 34

[1174]

[1175]

[1176] Preparation Example 216

[1177] 4-methoxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[3-yl]-

[1178] [1,5-a]pyridine-3-carbonitrile

[1179]

[1180] N2 was bubbled through a mixture of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (39 g, 117 mmol 90 mass %), K2CO3 (40 g, 289 mmol) and 4-(4-bromo-5-methyl-triazol-1-yl)-1-(oxetan-3-yl)piperidine (42.6 g, 135 mmol) in toluene (390 ml) and H2O (116 ml). After 10 min, PdCl2(DtBPF) (0.68 g, 1.04 mmol) was added and N2 was bubbled through the reaction for an additional 5 min. The reaction was stirred at 90°C for 8 h and then at room temperature for approximately 60 h. The reaction was diluted with H2O (100 ml) and the mixture was concentrated to remove toluene. The resulting suspension was stirred at room temperature for 15 min, filtered, and the solid was washed with H2O (2 x 30 ml) to give the title compound (42.6 g, 83%). MS ES+ m / z 394 [M+H] + .

[1181] The following compounds were prepared in a manner substantially similar to the method of Preparation 216, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1182] Table 35

[1183]

[1184] 1 Purify by silica gel chromatography eluting with 0% to 100% EA in cHex followed by 0% to 10% MeOH in DCM.

[1185] Preparation Example 219

[1186] 4-[4-(3-Chloro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester

[1187]

[1188] A solution of tert-butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (4 g, 9.12 mmol) in DCM (50 ml) was treated with NCS (700 mg, 5.24 mmol). After stirring at room temperature for 24 h, another portion of NSC (700 mg, 5.24 mmol) was added and stirring was continued for 24 h. The reaction was treated with H2O (100 ml) and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% and 100% EA in cHex to give the title compound as a white solid (3.4 g, 82%). MS ES+ m / z 447 / 449 [M+H] + .

[1189] Preparation Example 220

[1190] 3-Chloro-4-methoxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine

[1191]

[1192] Under N2, 4-methoxy-6-[5-methyl-1-[1-(oxetane-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine (34 g, 83.06 mmol) was dissolved in DCM (500 ml) and treated with NCS (12 g, 89.86 mmol). After stirring at room temperature for 18 h, more NCS (6.5 g, 49 mmol) was added and stirred overnight. The mixture was diluted with H2O (200 ml), the layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 10% MeOH in DCM to give the title compound (16 g, 45%) as an amber oil. MS ES+ m / z 403 / 405 [M+H] + .

[1193] The following compounds were prepared in a manner substantially similar to the method of Preparation 220, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1194] Table 36

[1195]

[1196]

[1197] 1Purify by silica gel chromatography eluting with 0% to 100% EA in cHex.

[1198] 2 The reaction was heated at 50 °C.

[1199] 3 Purified by Prep TLC: PE / EA (1:1).

[1200] 4 Purified by Prep TLC: DCM / MeOH (20:1).

[1201] 5 The residue was used in the next step without purification.

[1202] 6 Workup: Concentrate the reaction.

[1203] 7 Workup: quench the reaction with 40% aqueous NaHSO 3 , separate the layers, and dry the organic layer over MgSO 4 , filter, and concentrate.

[1204] 8 Purify by reverse flash, eluting with 40% to 50% MeOH in H2O.

[1205] 9 Column: XB-phenyl, 50 x 250 mm, 10 μm; eluted with 60 to 70% ACN in H2O (10 mM NH3-H2O).

[1206] 10 Use NBS instead of NCS.

[1207] 11 Purify by reverse flash, eluting with 45% to 55% ACN in H2O.

[1208] Preparation Example 229

[1209] 4-Hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]

[1210] Pyridine-3-carbonitrile

[1211]

[1212] To a mixture of 4-methoxy-6-[5-methyl-1-[1-(oxetane-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (20 g, 45.75 mmol) in DMA (250 ml) was added NDM (21.9 ml, 91.51 mmol) and aqueous NaOH (7.25 ml, 137.3 mmol, 18.94 mol / L) under N₂. The reaction was degassed with N₂ for 15 min and then heated at 50°C for 2 h. After cooling to room temperature, H₂O (2 L) was added. After stirring for 15 min, the pH was adjusted to 6.9 by adding aqueous HCl (10% w / w) followed by K₂HPO₄. The reaction was stirred for 15 min. The insoluble material was collected by filtration and washed with H₂O (2 x 25 ml) to give the title compound as a light grey solid (11.0 g, 62% yield). MS ES+m / z 380[M+H] + .

[1213] Preparation Example 230

[1214] 4-[4-(3-Chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester

[1215]

[1216] Under N2 atmosphere, to 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 (3.4 g, 7.5 mmol) in DMA (20 ml) was added NDM (5.5 ml, 23 mmol) and a solution of NaOH (18.94 mol / L) in H2O (1.4 ml). The reaction was heated at 60°C overnight. After cooling to room temperature, the mixture was diluted with H2O (100 ml) and the pH was adjusted to pH = 5 with aqueous HCl. A cream-colored solid was obtained. After stirring for 15 minutes, the insoluble material was collected by filtration and the solid was rinsed with H2O to give the title compound (1.4 g, 43%). MS ES+ m / z 433 [M+H] + .

[1217] Preparation Example 231

[1218] 4-[4-(3-Cyano-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester

[1219]

[1220] NaOH (50% aqueous solution) (36.57 g, 457.14 mmol) was added dropwise to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (40.00 g, 91.43 mmol) and NDM (55.51 g, 274.28 mmol) in DMA (400 ml) at 0°C. The mixture was stirred at 50°C for 8 h. The mixture was diluted with H2O (400 ml), acidified to pH 6 with FA, filtered, and the filter cake washed with H2O and dried in vacuo. The solid was triturated in hexane (200 ml) and Et2O (200 ml), filtered, and then stirred in MeOH (400 ml) at 60°C for 2 h. The mixture was filtered and the filter cake was concentrated in vacuo to afford the title compound as a light yellow solid (32 g, 82.6%). ES / MS m / z 424.3 [M+H] + .

[1221] The following compounds were prepared in a manner substantially similar to the method of Preparation 231, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1222] Table 37

[1223]

[1224] 1 Workup: The reaction was cooled to room temperature and then aqueous citric acid (3%) was added until pH was approximately 5. The resulting insoluble material was isolated by filtration, triturated in cHex, filtered and rinsed with cHEx followed by MTBE.

[1225] 2 Workup: The reaction was neutralized with NH4Cl solution to pH 7-8 and concentrated in vacuo. The residue was treated with DCM and H2O, the layers were separated, and the organic layer was dried over MgSO4, filtered and concentrated. The residue was triturated in heptane, filtered and washed with heptane.

[1226] 3 Workup: The reaction was cooled to room temperature, then aqueous citric acid (3%) was added. The resulting precipitate was isolated by filtration, washed with H2O, and then washed with cHex. The solid was dissolved in DCM, then cHex was added. The solution was sonicated until a precipitate formed. The precipitate was collected by filtration.

[1227] 4 Purify by silica gel chromatography eluting with 0% to 50% acetone in DCM.

[1228] Preparation Example 240

[1229] 4-Hydroxy-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride

[1230]

[1231] A solution of tert-butyl 4-[4-(3-cyano-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (50 g, 118.07 mmol) in MeOH (100 ml) was treated with 4M HCl in MeOH (300 ml) at room temperature under N2. The reaction was concentrated to afford the title compound (40 g, crude HCl salt) as a white solid. MS ES+ m / z 417 [M+H] + .

[1232] The following compounds were prepared in a manner substantially similar to the method of Preparation 240, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1233] Table 38

[1234]

[1235] a HCl in 2-propanol was used for this transformation.

[1236] Preparation Example 242

[1237] 4-Hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1238]

[1239] A solution of 4-hydroxy-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (40 g, crude HCl salt) in MeOH (300 ml) was basified to pH 12 with NaOH (5 g) at room temperature under N2, then acidified to pH 5-6 with AcOH (10 g), and then treated with 3-oxetanone (53.49 g, 742.21 mmol). After stirring at 50°C for 2 h, the reaction was treated with NaBH3CN (23.32 g, 371.10 mmol) at room temperature and then stirred at 50°C for 2 h. After cooling to room temperature, the reaction was concentrated, and the residue was suspended in H2O (500 ml) and basified to pH 8 with solid NaHCO3. The suspension was filtered, the solid was washed with MTBE (3 x 100 ml), and the solid was lyophilized to give the title compound (30 g, 64%) as a white solid. MSES+ m / z 380 [M+H] + .

[1240] The following compounds were prepared in a manner substantially similar to the method of Preparation 242, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1241] Table 39

[1242]

[1243] Preparation Example 244

[1244] 4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1245]

[1246] To a suspension of 4-hydroxy-6-[5-methyl-1-[1-(oxetanes-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (1 g, 2.64 mmol) in ACN (10 ml) was added Cs2CO3 (1.12 g, 3.43 mmol). The suspension was stirred at room temperature for 30 minutes. Next, a solution of 2-bromo-1-(5-fluoro-2-pyridinyl)ethanone (0.747 g, 3.43 mmol) in ACN (3 ml) was added dropwise at room temperature for 30 minutes. The reaction was vigorously stirred at room temperature for about 8 hours. H2O was added and the suspension was stirred for 10 minutes, then allowed to stand overnight. The suspension was further diluted with H2O and then filtered. The solid was rinsed with EA, then rinsed with c-Hex, and then dried in vacuo to give the title compound (1.2 g, 83%). MS ES+m / z 517[M+H] + .

[1247] Preparation Example 245

[1248] tert-Butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[1249]

[1250] A solution of tert-butyl 4-[4-(3-chloro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1.5 g, 3.47 mmol) and 2-bromo-1-(5-fluoro-2-pyridinyl)pyridine (1.51 g, 6.93 mmol) in ACN (30 ml) was treated with DIPEA (1.34 g, 10.40 mmol) at room temperature under N2. After stirring at 50°C for 1 hour, the reaction was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EA (1:1 to 1:2) to give the title compound (1.1 g, 56%) as a brown solid. MS ES+ m / z 570 [M+H] + .

[1251] The following compounds were prepared in a manner substantially similar to that of Preparation 245, using appropriate reagents, adjusting the reaction time to ensure completion, and adjusting the purification system appropriately. Cs2CO3 can be used in place of DIPEA.

[1252] Table 40

[1253]

[1254]

[1255]

[1256]

[1257] 1 Purify by reverse phase flash C18 chromatography using the following conditions: Column, C18; elution with 75% to 80% ACN in H2O.

[1258] 2 Purify by reverse phase C18 chromatography eluting with 50% to 60% ACN in H2O (0.1% FA).

[1259] 3 Work-up: The reaction was concentrated, diluted with H2O and the insoluble material was collected by filtration.

[1260] 4 Cs2CO3 was used as a base in this synthesis.

[1261] 5 Purify by silica gel chromatography eluting with MeOH in DCM.

[1262] 6 Purify by silica gel chromatography eluting with 5% (EA / EtOH 3:1) in cHex (2CV), 5% to 50% (EA / EtOH 3:1) in cHex (20CV), then 100% EA / EtOH (3:1).

[1263] 7 Work-up: The reaction was concentrated, diluted with H2O and the insoluble material was collected by filtration.

[1264] 8 Work-up: EA and H2O were added, the layers were separated, and the organic layer was washed with 1N NaOH and brine. The organic layer was dried over MgSO4, filtered and concentrated.

[1265] 9 Workup: Concentrate the reaction in vacuo. Dissolve the residue in H2O and acetone. Concentrate the solution until a solid precipitates. Stir the suspension overnight, then collect the solid by filtration.

[1266] 10 Purify by silica gel chromatography eluting with DCM (5 CV), 2% MeOH in DCM (15 CV), 5% MeOH in DCM (10 CV) and MeOH (5 CV).

[1267] 11Workup: H2O was added to the reaction, which was then concentrated. The residue was triturated in H2O and the insoluble material was collected by filtration.

[1268] 12 Workup: The reaction was diluted with H2O and triturated for 30 min. The insoluble material was collected by filtration and washed with H2O, MTBE, and cHex.

[1269] 13 Purify by silica gel chromatography eluting with 0% to 50% acetone in DCM (25CV), 50% to 100% acetone in DCM (5CV), then 100% acetone.

[1270] 14 Workup: H2O was added to the reaction and then concentrated. The resulting suspension was diluted with H2O and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated.

[1271] 15 Workup: H2O was added to the reaction, which was then concentrated. The resulting suspension was diluted with H2O, triturated, and the insoluble material was collected by filtration.

[1272] 16 Purify by silica gel chromatography eluting with 5% MeOH in DCM.

[1273] 17 The isolated material was sonicated in 2M aqueous Na2CO3 for 10 min, then filtered and washed with water.

[1274] 18 Work-up: H2O was added and the resulting precipitate was collected by filtration.

[1275] Preparation Example 269

[1276] tert-Butyl 4-[4-[3-cyano-4-[1-(1-isopropyltriazol-4-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[1277]

[1278] Cs2CO3 (1.41 g, 4.31 mmol) was added to a degassed solution of tert-butyl 4-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (665 mg, 1.57 mmol) and 4-(1-chloroethyl)-1-isopropyl-1H-1,2,3-triazole (495 mg, 2.35 mmol) in DMF (5 ml), and the mixture was stirred at 65 ° C for 2 h. The reaction was diluted with EA (25 ml) and washed with H2O (25 ml) and brine (25 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solution of MeOH in DCM to give the title compound as a light yellow oil (601 mg, 68%). MS ES+m / z 561.5[M+H] + .

[1279] The following compounds were prepared in a manner substantially similar to the method of Preparation 269, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1280] Table 41

[1281]

[1282]

[1283] 1 Purify by silica gel chromatography eluting with MeOH in DCM.

[1284] 2 Purify by silica gel chromatography eluting with 20% to 100% EA in cHex.

[1285] 3 Purify by silica gel chromatography eluting with 20% to 40% (3:1 EA:EtOH) in cHex.

[1286] 4 Purify by silica gel chromatography eluting with 5% EA in cHex (2CV), 5% to 50% EA in cHex (20CV), 50% to 100% EA in cHex (10CV), then 100% EA.

[1287] 5Purify by silica gel chromatography eluting with 10% 3:1 EA / EtOH in cHex (3CV), a gradient of 10% to 20% 3:1 EA / EtOH in cHex (12CV), 20% 3:1 EA / EtOH in cHex (2CV), a gradient of 20% to 50% 3:1 EA / EtOH in cHex (18CV).

[1288] 6 After cooling to room temperature, the reaction was treated with H 2 O. The insoluble material was collected by filtration to give the title compound.

[1289] a The material was used in the subsequent step without further characterization.

[1290] Preparation Example 281

[1291] 4-[4-[4-[2-(3,5-difluoro-2-pyridinyl)-2-methoxy-ethoxy]-3-fluoro-pyrazolo[1,5-a]pyridine-6-

[1292] tert-Butyl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[1293]

[1294] At 0 ° C, N2, a solution of PPh3 (1.04 g, 3.96 mmol) in THF (10 ml) was treated dropwise with DIAD (0.77 g, 3.83 mmol). The reaction was stirred at 0 ° C for 0.5 h and then added to a mixture of 2-(3,5-difluoro-2-pyridyl)-2-methoxy-ethanol (0.30 g, 1.59 mmol) and 4-[4-(3-fluoro-4-hydroxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 1.32 mmol) in THF (10 ml). The resulting mixture was stirred at room temperature for 2 h and then concentrated. The residue was purified by reverse phase flash C18 chromatography using the following conditions: column, C18; elution with a gradient of 45% to 55% ACN in H2O (0.1% FA) to give the title compound (480 mg, 62%) as a yellow solid. MS ES+ m / z 588 [M+H] + .

[1295] The following compounds were prepared in a manner substantially similar to the method of Preparation 281, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1296] Table 42

[1297]

[1298]

[1299] 1 Purify by flash reverse phase C18 chromatography eluting with 30% to 50% ACN in H2O (0.1% NH4HCO3).

[1300] 2 Purify by flash reverse phase C18 chromatography eluting with 60% to 70% ACN in H2O.

[1301] Preparation Example 284

[1302] 4-[4-[3-chloro-5-[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-

[1303] tert-Butyl]piperidine-1-carboxylate

[1304]

[1305] A solution of tert-butyl 4-[4-[5-[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1.4 g, 2.54 mmol) in DMF (15 ml) was treated with DCDMH (400 mg, 2.03 mmol) at 0°C. After stirring at 0°C for 0.5 h, the residue was purified by reverse phase flash C18 chromatography using the following conditions: column, C18; eluting with a gradient of 60% to 70% ACN in H2O to give the title compound (700 mg, 47%) as a yellow solid. MS ES+ m / z 586 [M+H] + .

[1306] The following compounds were prepared in a manner substantially similar to the method of Preparation 284, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1307] Table 43

[1308]

[1309]

[1310] 1 Purify by reverse phase C18 chromatography eluting with 45% to 50% AcCN in H2O.

[1311] 2Purified by Prep-TLC (PE / EA 1:3).

[1312] Preparation Example 287

[1313] 4-[4-[3-cyano-4-[2-(3,5-difluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-6-

[1314] tert-Butyl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate, Isomer 1

[1315]

[1316] In a sealed tube, chloro(N-[(1R,2R)-2-[(S)-[2-[[1,2,3,4,5,6-η)-4-methylphenyl]methoxy]ethyl]amino]-1,2-diphenylethylmethanesulfonamido)ruthenium(II) (25 mg, 0.04 mmol, 98 mass %) was added to a stirred mixture of tert-butyl 4-[4-[3-cyano-4-[2-(3,5-difluoro-2-pyridinyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (3.5 g, 4.2 mmol) in FA NEt complex (5:2 ratio) (18 ml, 42.21 mmol) and DCM (14 ml, 218 mmol). The reaction was heated at 45° C. under N for 75 minutes. After cooling to room temperature, the reaction was diluted with DCM and washed with H2O, saturated aqueous NaHCO3, H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 20% acetone in DCM to afford the title compound as an orange solid (3.23 g, 99%). MS ES+ m / z 581 [M+H] + .

[1317] The following compounds were prepared in a manner substantially similar to the method of Preparation 287, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1318] Table 44

[1319]

[1320]

[1321] 1 Purify by silica gel chromatography eluting with MeOH in DCM.

[1322] 2 The crude product was used in the next step after aqueous workup.

[1323] Preparation Example 291

[1324] 4-[2-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1325]

[1326] To a suspension of 4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetaned-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (4.01 g, 6.58 mmol) in MeOH (65 ml) was added NaBH4 (1.0 g, 26.43 mmol) in one portion at 0°C. The mixture was stirred at 0°C for 5 min and then at room temperature for 1 h. The reaction was diluted with H2O (100 ml). The resulting precipitate was collected by filtration and washed with H2O / MeOH (4:1) (20 ml). The resulting solid was dried under vacuum at 40°C to give the title compound (3.40 g, 91%). MS ES+ m / z 519 [M+H] + .

[1327] Preparation Example 292

[1328] tert-Butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[1329]

[1330] A solution of tert-butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1 g, 1.75 mmol) in MeOH (20 ml) was treated with NaBH (66.37 mg, 1.75 mmol) at room temperature under N. After stirring at room temperature for 1 h, the reaction was quenched with H.sub.2O (50 ml) and extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (2 x 50 ml), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to afford the title compound (1.0 g, 100%) as a brown solid. MS ES+ m / z 572 [M+H] + .

[1331] The following compounds were prepared in a manner substantially similar to that of Preparation 292, using appropriate reagents, adjusting reaction times to ensure reaction completion, and adjusting the purification system appropriately. DCM was used as a co-solvent.

[1332] Table 45

[1333]

[1334]

[1335]

[1336] 1 Purify by silica gel chromatography eluting with 0% to 10% MeOH in DCM.

[1337] 2 Purify by silica gel chromatography eluting with DCM (5 CV), 2% MeOH in DCM (10 CV), 5% MeOH in DCM (10 CV).

[1338] 3 Purify by silica gel chromatography eluting with 0% to 40% (10% MeOH in DCM).

[1339] 4 Purify by silica gel chromatography eluting with 0% to 40% (10% MeOH in DCM).

[1340] Preparation Example 307

[1341] 4-[4-[4-[2-(3,5-difluoro-2-pyridinyl)-2-hydroxy-propoxy]-3-fluoro-pyrazolo[1,5-a]pyridine-6-

[1342] tert-Butyl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[1343]

[1344] Under N2, a solution of tert-butyl 4-[4-[4-[2-(3,5-difluoro-2-pyridinyl)-2-oxo-ethoxy]-3-fluoro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (0.61 g, 1.07 mmol) in DCM (10 ml) was slowly added to a solution of MeMgBr in THF (3 ml, 4.2 mmol, 1.4 mol / L) pre-cooled to 0 ° C. Additional DCM (2 ml) was added and the reaction was stirred overnight. The reaction was quenched with aqueous NH4Cl, extracted with DCM, and washed with H2O and brine. The organic phase was concentrated to give a residue. The residue was purified by silica gel chromatography eluting with 0% to 20% acetone in DCM to give the title compound (175 mg, 0.25 mmol, 24%, 85% by mass) as a yellow oil. MS ES+m / z 588[M+H] + .

[1345] The following compounds were prepared in a manner substantially similar to the method of Preparation 307, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately. DCM was used as a co-solvent.

[1346] Table 46

[1347]

[1348] 1 Purify by silica gel chromatography eluting with 30% (10% MeOH in DCM) in DCM.

[1349] Preparation Example 309

[1350] 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridinyl)-2-methylsulfonyloxy-ethoxy]pyrazolo[1,5-a]

[1351] [6-pyridinyl]-5-methyl-triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester

[1352]

[1353] At 0 ° C, a solution of tert-butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (0.60 g, 0.74 mmol) in DCM (6 ml) was treated with NEt3 (0.152 g, 1.51 mmol) and MsCl (0.13 g, 1.2 mmol) successively. After 15 min, the cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 h, the mixture was washed with H2O (1.5 ml), dried over MgSO4, and concentrated in vacuo to give the title compound as a green solid. The product was used in the next step without further purification. MS ES+m / z( 35 Cl / 37 Cl) 668 / 670[M+H] + .

[1354] Preparation Example 310

[1355] tert-Butyl 4-[4-[3-cyano-4-[2-(3,5-difluoro-2-pyridinyl)-2-isopropoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate, Isomer 1

[1356]

[1357] To a mixture of tert-butyl 4-[4-[3-cyano-4-[(2S)-2-(3,5-difluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1.0 g, 1.3 mmol, 75 mass %), Ag O (600 mg, 2.59 mmol), and 2-iodopropane (2.6 ml, 26 mmol) in DMF (10 ml) was added NaH in mineral oil (62 mg, 1.55 mmol, 60 mass %) at room temperature under N . The reaction was stirred at room temperature for 10 min, and then additional NaH in mineral oil (62 mg, 1.55 mmol, 60 mass %) was added. NaH in mineral oil (62 mg, 1.55 mmol, 60 mass %) was added approximately every 10-20 min. After 90 minutes and 7 additions of NaH, H2O was added to the mixture. The mixture was extracted with EA, and the organic phase was washed with brine (3x), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 20% to 50% EA in cHex. The isolated material was purified by silica gel chromatography eluting with 20% EA in MTBE. The impurities co-eluted with the title compound (720 mg, 56%, 63% purity). MS ES+ m / z 523 [M+H]+ .

[1358] Preparation Example 311

[1359] 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridinyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-6-

[1360] tert-Butyl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[1361]

[1362] A solution of tert-butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (0.63 g, 0.78 mmol) in N,N-dimethylacetamide (6 ml) was treated with NaH (65 mg, 1.63 mmol, 60% wt) at room temperature followed by CHI (0.08 ml, 1.28 mmol). After stirring at room temperature for 90 min, the reaction was quenched with MeOH (0.5 ml) and purified by reverse phase C18 chromatography eluting with a gradient of 30% to 90% ACN in H2O (NH4HCO3 buffer pH 9) to afford the title compound (192 mg, 38%) as an orange solid. MS ES+m / z 604 / 606[M+H] + .

[1363] The following compounds were prepared in a manner substantially similar to the method of Preparation 311, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1364] Table 47

[1365]

[1366] 1 Purify by reverse phase C18 chromatography eluting with aqueous NH4HCO3 pH 9 (5CV) followed by 30% to 60% ACN in aqueous NH4HCO3 pH 9.

[1367] 2 Ag2O (3.95 eq) was added to the reaction.

[1368] 3 Purify by silica gel chromatography eluting with 0% to 50% [DCM:MeOH (9:1)] in DCM.

[1369] 4Purify by SCX chromatography. Wash off non-basic impurities with DCM, 5% MeOH in DCM. Elute the title compound with methanolic ammonia (2M).

[1370] 5 THF was used as solvent.

[1371] 6 Workup: the reaction was extracted with DCM, washed with H2O (3x), brine, dried over MgSO4, filtered and concentrated.

[1372] 7 Work-up: the reaction was diluted with H2O, extracted with DCM, washed with brine, dried over MgSO4, filtered and concentrated.

[1373] Preparation Example 318

[1374] tert-Butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridinyl)-2-(dimethylamino)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

[1375]

[1376] A mixture of tert-butyl 4-[4-[3-chloro-4-[2-(3,5-difluoro-2-pyridinyl)-2-methylsulfonyloxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (0.50 g, 0.74 mmol) and dimethylamine in THF (2M solution, 2 ml) was stirred at room temperature for 48 h. The crude mixture was purified by silica gel chromatography eluting with a gradient of 0% to 100% acetone in DCM to give the title compound as a yellow solid (0.15 g, 27.8%, purity >85%). MS ES+ m / z ( 35 Cl / 37 Cl)617 / 619[M+H] + .

[1377] Preparation Example 319

[1378] 4-[1-(1-isopropyltriazol-4-yl)ethoxy]-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[3-yl]-1 ...

[1379] [1,5-a]Pyridine-3-carbonitrile hydrochloride

[1380]

[1381] A solution of HCl in dioxane (4M, 2.0 ml, 5.98 mmol) was added to a solution of tert-butyl 4-(4-(3-cyano-4-(1-(1-isopropyl-1H-1,2,3-triazol-4-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (600 mg, 1.07 mmol) in DCM (10 ml), and the mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo to give the title compound as a hygroscopic beige solid (689 mg, quantitative). MS ES+ m / z 461.4 [M+H] + .

[1382] The following compounds were prepared in a manner substantially similar to the method of Preparation Example 319, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately. For compounds in which amine salts were isolated, the formation of monovalent, divalent, or trivalent salts depended on the pKa of the amine and the acid used to form the salt. The exact monovalent, divalent, or trivalent salt form was not determined for each example.

[1383] Table 48

[1384]

[1385]

[1386]

[1387]

[1388] 1 The reaction was carried out in MeOH. After work-up, the residue was triturated in EA, filtered and collected by filtration to give the title compound.

[1389] 2 The reaction was concentrated in vacuo. The residue was diluted with EA and slurried for 1 h. The precipitate was collected by filtration.

[1390] Preparation Example 340

[1391] 2-[3-chloro-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-

[1392] 2-Fluoro-2-pyridyl)ethanol, 2,2,2-trifluoroacetic acid

[1393]

[1394] A solution of tert-butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1.0 g, 1.75 mmol) in DCM (10 ml) was treated with TFA (10 ml) and stirred at room temperature for 1 h. The reaction was concentrated and the crude product was used in the next synthetic step without purification. MS ES+ m / z 472 [M+H] + .

[1395] The following compounds were prepared in a manner substantially similar to the method of Preparation Example 340, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately. For compounds isolated as amine salts, the formation of monovalent, divalent, or trivalent salts depended on the pKa of the amine and the acid used to form the salt. The exact monovalent, divalent, or trivalent salt form was not determined for each example.

[1396] Table 49

[1397]

[1398]

[1399]

[1400] a The material was used in the subsequent step without further characterization.

[1401] Preparation Example 355

[1402] 4-[2-(2,4-difluorophenyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1403]

[1404] Tert-butyl 4-[4-[3-cyano-4-[2-(2,4-difluorophenyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1.0 g, 1.73 mmol) was suspended in 4M HCl in 1,4-dioxane (20 ml) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated and the residue was basified to pH 9 with saturated aqueous Na2CO3 (10 ml). The resulting solid was collected by filtration and washed with H2O (3 x 50 ml) to give the title compound (0.80 g, crude) as a brown solid. MS ES+ m / z 480 [M+H] + .

[1405] The following compounds were prepared in a manner substantially similar to that of Preparation 355, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1406] Table 50

[1407]

[1408]

[1409]

[1410] 1 Work-up: The reaction was concentrated. The residue was dissolved in MeOH and applied directly to an SCX column, previously conditioned with MeOH. Non-basic impurities were washed off with MeOH, and the title compound was then eluted with methanolic ammonia (2M). 2 Workup: The reaction was concentrated. The residue was suspended in DCM and washed with 2M aqueous NaOH solution, then with brine. The organic layer was dried over MgSO4, filtered and concentrated.

[1411] 3 Workup: The reaction was concentrated. The residue was suspended in DCM and washed with aqueous NaOH (1 M). The phases were separated and the organic layer was dried over MgSO 4 , filtered and concentrated.

[1412] 4 The product contains impurities from the previous step.

[1413] 5 Workup: The reaction was concentrated. The residue was dissolved in DCM and washed with saturated aqueous NaHCO 3 , dried over MgSO 4 , filtered and concentrated.

[1414] 6 Workup: The reaction was concentrated. The residue was dissolved in MeOH and treated with NaHCO 3 to pH 8. The mixture was concentrated in vacuo.

[1415] Preparation Example 369a

[1416] 6-[1-(7-Azaspiro[3.5]nonan-2-yl)-5-methyl-pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1417]

[1418] and

[1419] Preparation Example 369b

[1420] 6-[1-(7-Azaspiro[3.5]nonan-2-yl)-3-methyl-pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1421]

[1422] A solution of tert-butyl 2-[4-[3-cyano-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate and tert-butyl 2-[4-[3-cyano-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-3-methyl-pyrazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate (621 mg, 0.77 mmol, 70%) in DCM (6 ml) was treated with TFA (1.2 ml). After stirring at room temperature for 3 days, the reaction was concentrated and loaded onto an SCX column pre-conditioned with MeOH. After washing with MeOH, the title compound was eluted with 2M NH3 in MeOH to give a mixture of the title compounds (398 mg, 96%) as a light yellow solid. MS ES+ m / z 468 [M+H] + .

[1423] Preparation Example 370

[1424] [2-[3-cyano-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[3-yl]-

[1425] [1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridinyl)ethyl]methanesulfonate

[1426]

[1427] A solution of 4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-[1-(oxetanes-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (1.39 g, 2.69 mmol) and NEt3 (0.80 ml, 5.7 mmol) in DCM (14 ml) was cooled to 0 ° C and purged with N2. The reaction was treated dropwise with MsCl (0.26 ml, 3.4 mmol). The reaction was allowed to slowly warm to room temperature. After 75 min, the reaction was cooled to 0 ° C, quenched with H2O (15 ml) and the organic layer was removed. The aqueous layer was extracted with DCM (2x5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound as a light brown foamy solid (1.80 g, 100% yield, 90% purity) which was used without purification. MS ES+ m / z 597 [M+H] + .

[1428] The following compounds were prepared in a manner substantially similar to the method of Preparation 370, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1429] Table 51

[1430]

[1431] Preparation Example 373

[1432] 7-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]-5-[[3,3,3-trifluoro-2-(5-

[1433] [2-fluoro-pyridyl)propyl]amino]imidazo[1,2-a]pyridine-3-carbonitrile

[1434]

[1435] A mixture of 7-chloro-5-[[3,3,3-trifluoro-2-(5-fluoro-2-pyridinyl)propyl]amino]imidazo[1,2-a]pyridine-3-carbonitrile (1.2 g, 3.28 mmol), bis(pinacolato)diboron (1.19 g, 4.69 mmol), and KOAc (0.92 g, 9.38 mmol) in dioxane (20 ml) was treated with Xphos Palladacycle Gen 4 (56.06 mg, 0.07 mmol) at 80°C under N2. The resulting mixture was stirred at 80°C for 2 h. The reaction was used in the next step without workup or purification.

[1436] Under N2, the above reaction was cooled and treated with KF (0.53g, 9.38mmol), 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)-1-(oxetane-3-yl)piperidine (1.20g, 3.97mmol), H2O (4ml) and PdCl2(DtBPF) (0.10g, 0.15mmol). After stirring at 100°C for 2h, the reaction was cooled to room temperature, quenched with H2O (100ml) and extracted with EA (2x100ml). The combined organic layers were washed with brine (150ml), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with DCM / MeOH (100 to 20:1) to give the title compound (315mg, 18%) as a white solid. MS ES+m / z 570[M+H] + .

[1437] Preparation Example 374

[1438] (1S)-2-[3-Bromo-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[3-ol]-

[1439] [1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridinyl)ethanol, Isomer 1

[1440]

[1441] A solution of (1S)-2-[3-bromo-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridinyl)ethanol hydrochloride (7.57 g, 11.0 mmol) in MeOH (76 ml) was treated with oxetane-3-one (1.97 g, 27.3 mmol), AcOH (1.60 ml, 27.9 mmol), and NaCNBH (2.80 g, 44.6 mmol) at room temperature. After 48 h, the reaction was quenched with 1N aqueous KCO (150 ml) and extracted with DCM (300 ml). The organic phase was dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0% to 100% acetone in DCM to afford the title compound as a white solid (0.352 g, 6%).

[1442] Example 1

[1443] 4-[[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethyl]amino]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1444]

[1445] To a vial was added 4-[[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethyl]amino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (0.51 mmol, 224 mg), 4-(4-bromo-5-methyl-triazol-1-yl)-1-(oxetan-3-yl)piperidine (278 mg, 0.92 mmol), K2CO3 (142 mg, 1.03 mmol), toluene (2 ml), and H2O (200 μl). The vial was flushed with N2, and then PdCl2(DtBPF) (51 mg, 0.08 mmol) was added. The reaction was heated at 100°C for 3 h. The mixture was filtered through DE, and the filtrate was loaded onto an SCX column pre-treated with MeOH. The column was washed with MeOH. The product was eluted with 2M NH3 in MeOH and concentrated. The residue was purified by silica gel chromatography using 0% to 100% (25% EtOH in EA) in cHex to give the title compound (0.40 g, 16%). MS ES+ m / z 532 [M+H] + .

[1446] Example 2

[1447] 4-[1-(7-fluoro-4-isoquinolyl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1448]

[1449] 4-[1-(7-Fluoro-4-isoquinolyl)ethoxy]-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (305 mg, 0.54 mmol) and DIPEA (0.28 ml, 1.61 mmol) were dissolved in MeOH (5 ml) and activated 4A molecular sieves were added. 3-Oxetanone (0.17 ml, 2.70 mmol), NaBH3CN (172 mg, 2.74 mmol), and AcOH (0.37 ml, 6.43 mmol) were added to the solution, and the reaction was stirred at 70°C for 2 h. Upon completion, the reaction was cooled to room temperature and diluted with EA. The mixture was washed with H2O (25 ml) and brine (25 ml), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to afford the title compound as an off-white solid (35 mg, 15%). MS ES+ m / z 553.3 [M+H] + .

[1450] The following compounds were prepared in a manner substantially similar to the method of Example 2, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1451] Table 52

[1452]

[1453]

[1454] 1 14A molecular sieves and DIPEA were not included in the reaction.

[1455] 2 Purify by silica gel chromatography eluting with 0% to 10% MeOH in DCM.

[1456] 3 Purify by silica gel chromatography eluting with 5% EA in cHex (2CV), 5% to 50% EA in cHex (20CV), 50% to 100% EA in cHex (5CV), 100% EA (10CV).

[1457] 4 Purification by C18 reverse phase C18 chromatography: Column: XBridge C18, 19 x 150 mm, 5 μm, eluting with 45% to 65% ACN in H2O (10 mM NH4HCO3 buffer, pH 9).

[1458] 5Column: Luna Hilic, 30 x 150 mm, 5 μm, eluted with 10% to 20%: MeOH (10 mM NH 4 HCO 3 pH 8).

[1459] 6 Purify by silica gel chromatography eluting with 10% to 50% acetone in DCM.

[1460] 7 Column: Luna Omega Polar, 21 x 150 mm, 5 μm; elution was with 25% to 55% ACN (0.1% FA) in H2O (0.1% FA).

[1461] 8 Purify by silica gel chromatography eluting with 0% to 10% MeOH in DCM.

[1462] 9 Purify by silica gel chromatography eluting with 50% (10% MeOH in DCM) in DCM.

[1463] 10 Chiral method: LUX-2-propyl-AMY-CELL-1Amy2-iAmy1.

[1464] Example 12

[1465] 4-[2-(5-fluoro-2-pyridinyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1466]

[1467] A suspension of 4-hydroxy-6-[5-methyl-1-[1-(oxetanes-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.162 g, 0.43 mmol) in ACN (1.8 ml) was treated with KCO (53 mg, 0.53 mmol) and 2-bromo-1-(5-fluoropyridin-2-yl)ethanone (100 mg, 0.44 mmol). The suspension was stirred at 80 ° C for 16 h. After cooling to room temperature, EA and H O were added, and the mixture was filtered. The layers of the filtrate were separated and washed with 2N NaOH, H O and brine, dried over MgSO , filtered and concentrated. The residue was purified by silica gel chromatography, eluting with 0% to 10% EtOH in EA to give the title compound (91 mg, 47%). MS ES+m / z 517[M+H] + .

[1468] Example 13

[1469] 4-[2-(5-Fluoro-2-pyridinyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1

[1470]

[1471] and

[1472] Example 14

[1473] 4-[2-(5-Fluoro-2-pyridinyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2

[1474]

[1475] At room temperature, NaBH4 (3.0 mg, 0.08 mmol) was added once to a solution of 4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetanes-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (28.3 mg, 0.05 mmol) in EtOH (0.78 ml) and DCM (0.55 ml) for 3 h. The reaction was quenched with saturated NH4Cl. The layers were separated, and the organic layer was washed with brine, dried over MgSO4, and filtered through DE. The filtrate was concentrated to give 16 mg. The combined aqueous layer was extracted with DCM, and the organic layer was concentrated to give 5 mg. The two batches were combined to give 21 mg. This material was subjected to the following chiral chromatography conditions: Column: Chiralpak AD, 30 x 250 mm, 5 μm; eluting with 35% IPA (0.5% DMEA) in CO2 to afford the title compound, Isomer 1 (9.0 mg, 32%), t R 1.28 min, 98% ee. MSES+ m / z 519 [M+H] + , and the title compound, isomer 2 (9.2 mg, 32%), t R is 1.60min, 85%ee. MS ES+m / z 519[M+H] + The retention times were obtained using analytical method A. (See Table A for specific analytical conditions).

[1476] Example 15

[1477] 4-[[2-(5-fluoro-2-pyridyl)oxetane-2-yl]methoxy]-6-[5-methyl-1-[1-(oxetane

[1478] -3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, isomer 2

[1479]

[1480] At room temperature, t-BuOK (260 mg, 2.29 mmol) was added to a suspension of trimethylsulfoxide iodide (545 mg, 2.40 mmol) in 2-methyl-2-butanol (0.1 M). Under N2, a sealed vial was stirred at 50 ° C for 90 min. The suspension was cooled to room temperature and 4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]-6-[5-methyl-1-[1-(oxetanes-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (400 mg, 0.77 mmol) was added in one go. At room temperature, under N2, in a sealed tube, the resulting mixture was vigorously stirred overnight. Next, the suspension was heated at 50 ° C for 3 days and then stirred at room temperature for 3 days.

[1481] At room temperature, in a separate test tube, t-BuOK (260mg, 2.29mmol) was added to a suspension of trimethylsulfoxide iodide (545mg, 2.40mmol) in 2-methyl-2-butanol (0.1M). Under N 2 , a sealed vial was stirred at 50 ℃ for 90min. The above-mentioned reactants were added to the suspension once, and the resulting mixture was stirred overnight in a sealed tube at 50 ℃ and N 2 . The reactants were poured into a saturated NH 4 Cl aqueous solution, extracted with DCM, and extracted with DCM aqueous layer. The combined organic layer was washed with 1N NaOH (2x), then with H 2 O, then with salt water, and dried over MgSO 4 . The resulting residue was purified by reverse phase chromatography using a Claricep C-series column eluted with 30% ACN in H2O (NH4HCO3, pH 9) (2 CV), followed by a linear gradient from 30% to 60% ACN in H2O (NH4HCO3, pH 9) (8 CV) and 60% ACN in H2O (NH4HCO3, pH 9). Fractions containing the title compound were partially evaporated, DCM was added, and the two layers were passed through a hydrophobic filter. The filtrate was dried over MgSO4, filtered, and evaporated.

[1482] The material separated after reverse phase chromatography was subjected to the following chiral chromatography conditions: column: Chiralpak IA, 20x250 mm, 5 μm; eluted with 40% IPA (0.5% DMEA) in CO2 to give the title compound (29 mg, 7%), t R 2.82 (method P), ee>98% ee; MS ES+ m / z 545 [M+H] + Retention times were obtained using analytical method P.

[1483] Example 16

[1484] 6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]-4-[1-[5-(trifluoromethyl)pyridazin-3-yl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2

[1485]

[1486] DIAD (384 mg, 1.90 mmol) was added dropwise to a solution of PPh (539 mg, 2.06 mmol) in THF (10 ml) at 0°C under N2. The resulting mixture was stirred at 0°C for 0.5 h and then added to a solution of 4-hydroxy-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (600 mg, 1.58 mmol) and 1-[5-(trifluoromethyl)pyridazin-3-yl]ethanol (456 mg, 2.37 mmol) in THF (10 ml) and stirred overnight. The reaction was adjusted to pH 5 with concentrated HCl, diluted with H2O (80 ml), and extracted with EA (3 x 50 ml). The aqueous phase was basified to pH 8 with saturated aqueous NaHCO₃, extracted with CHCl₃:IPA (3:1) (3 x 100 ml), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by reverse phase chromatography using the following conditions: Column: XB-C18, 50 x 250 mm, 10 μm; elution with a gradient of 35% to 55% ACN in H₂O (10 mM FA) to afford the racemate of the title compound (345 mg, 39%) as a green solid. MS ES+ m / z 554 [M+H] + .

[1487] The racemate (345 mg) was subjected to chiral chromatography using the following conditions: column: CHIRALPAK IC, 2x25 cm, 5 μm; eluted with 50% MeOH in MTBE (10 mM NH 3 -MeOH), 248 / 208 nm; the title compound (117 mg, 34%) was obtained. Ris 9.82min, 100%ee. MS ES+m / z 554[M+H] + .

[1488] The following compounds were prepared in a manner substantially similar to the method of Example 16, using appropriate reagents, adjusting reaction times to ensure reaction completion, and appropriately adjusting the purification system and, where applicable, separating enantiomers.

[1489] If the retention times were obtained from an analytical column, this method will be listed in the last column. Specific analytical conditions for each method are given in Table A.

[1490] Table 53

[1491]

[1492] 1 Purify by silica gel chromatography eluting with DCM:MeOH (20 to 1).

[1493] 2 Purification by reverse phase chromatography: Column: Welch-XB C18, 50X 250 mm, 10 μm; elution with 28% to 35% ACN in H2O (0.1% NH4HCO3).

[1494] 3 The residue was dissolved in MeOH and treated with TFA then applied directly to an SCX column previously conditioned with MeOH. Non-basic impurities were washed off with MeOH before eluting the title compound with methanolic ammonia (2M). 4 Column: Chiralpak IA, 20 x 250 mm, 5 μm; eluted with 35% EtOH (0.5% DMEA) in CO 2 .

[1495] Example 19

[1496] 4-[1-(3,6-dimethylpyrazin-2-yl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1

[1497]

[1498] At 80 ° C, under N2, a mixture of 1-(3,6-dimethylpyrazin-2-yl)ethyl methanesulfonate (395 mg, 1.71 mmol), K2CO3 (546 mg, 3.95 mmol) and 4-hydroxy-6-{5-methyl-1-[1-(oxetane-3-yl)piperidin-4-yl]-1,2,3-triazol-4-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.32 mmol) was stirred for 2 h in ACN (10 ml). The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash C18 chromatography eluting with 20% to 40% ACN in H2O to give the title compound (450 mg, 66%) as a brown solid.

[1499] The brown solid was subjected to chiral chromatography using the following conditions: column: CHIRALPAK AD-H, 3 x 25 cm, 5 μm; eluted with 40% MeOH in CO 2 ; the title compound (163 mg, 36%) was obtained, t R The reaction mixture was stirred at 5.77 min and the ee was 100%.

[1500] The following compounds were prepared in a manner substantially similar to that of Example 19, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately. Cs2CO3 and DMF may be used.

[1501] If the retention times were obtained from an analytical column, this method will be listed in the last column. Specific analytical conditions for each method are given in Table A.

[1502] Table 54

[1503]

[1504]

[1505] 1 Purify by silica gel chromatography eluting with 0% to 50% EA (25% EtOH) in cHex.

[1506] 2 Column: Chiralpak IA, 20 x 250 mm, 5 μm; eluted with 35% IPA (0.5% DMEA) in CO 2 .

[1507] 3 Purify by flash reverse phase C18 chromatography eluting with 40% to 70% ACN in H2O (NH5CO3 pH 9 buffer).

[1508] 4Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 35% IPA (0.5% DMEA) in CO 2 .

[1509] 5 Chiralcel OJ, 20 x 250 mm, 5 μm; eluted with 20% MeOH (0.5% DMEA) in CO 2 .

[1510] 6 Purify by flash reverse phase C18 chromatography eluting with 30% to 60% ACN in H2O (NH5CO3 pH 9 buffer).

[1511] 7 Column: Chiralcel OJ, 20 x 150 mm, 5 μm; elution with MeOH (0.5% DMEA) in CO 2 .

[1512] 8 Purify by silica gel chromatography eluting with 20% to 60% EA in cHex.

[1513] 9 Column: Chiralcel OJ, 20 x 250 mm, 5 μm; elution with 30% MeOH (0.5% DMEA) in CO 2 , flow rate: 80 (ml / min).

[1514] 10 Purify by silica gel chromatography eluting with 20% 3:1 EA / EtOH in cHex (2CV), a gradient from 20% to 65% 3:1 EA / EtOH in cHex (25CV), 65% 3:1 EA / EtOH in cHex (10CV), a gradient from 65% to 100% 3:1 EA / EtOH in cHex (15CV), and 100% 3:1 EA / EtOH in cHex (10CV).

[1515] 11 Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 35% EtOH (0.5% DMEA) in CO2.

[1516] Example 26

[1517] 4-[2-(5-Fluoro-2-pyridinyl)-2-pyrrolidin-1-yl-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1

[1518]

[1519] and

[1520] Example 27

[1521] 4-[2-(5-Fluoro-2-pyridinyl)-2-pyrrolidin-1-yl-ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidin-4-yl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2

[1522]

[1523] Under N2, [2-[3-cyano-6-[5-methyl-1-[1-(oxetanes-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridinyl)ethyl]methanesulfonate (155 mg, 0.26 mmol) was placed in a screw cap vial and dissolved in ACN (0.65 ml). Pyrrolidine (183 mg, 0.002 mmol) was added. The reaction mixture was heated at 50 ° C for 46 h. The reactants were concentrated and the residue was treated with DCM (4 ml) and brine (2 ml). The organic layer was separated, washed with brine (2x2 ml), dried over Na2SO4, and filtered. The filtrate was concentrated to give a brown oil (160 mg).

[1524] The brown oil was subjected to the following chiral chromatography conditions: Column: Amylose-1, 30 x 250 mm, 5 μm; eluted with 40% IPA (0.5% DMEA) in CO2 to give the title compound, Isomer 1 (59 mg, 37%), t R 1.83, ee>98%ee; 572[M+H] + and the title compound, isomer 2 (47 mg, 29%), t R is 2.58, ee>98%ee. MS ES+m / z 572[M+H] + The retention times were obtained using analytical method G (see Table A for specific analytical conditions).

[1525] The following compounds were prepared in a manner substantially similar to the methods of Examples 26 and 27, using appropriate reagents, adjusting reaction times to ensure reaction completion, and adjusting the purification system appropriately.

[1526] If the retention times were obtained from an analytical column, this method will be listed in the last column. Specific analytical conditions for each method are given in Table A.

[1527] Table 55

[1528]

[1529] 1 The reaction was carried out in a solution of dimethylamine (2M) in THF at room temperature.

[1530] 2 Column: Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 35% IPA (0.5% DMEA) in CO 2 .

[1531] 3 Cs2CO3 was used as a base.

[1532] 4 Column: XBridge C18, 19 x 150 mm, 5 μm; eluted with 45% to 75% ACN in H2O (NH4HCO3 10 mM pH 9).

[1533] 5 Column: Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 45% EtOH (0.5% DMEA) in CO 2 .

[1534] 6 Refluxed for 5 h, then stirred at room temperature for 10 days.

[1535] 7 Purify by reverse phase chromatography, eluting with 0% to 50% (10% MeOH in DCM) in DCM (20 CV), then eluting with 50% (10% MeOH in DCM) in DCM (20 CV). 8 Column: Chiral Art Amylose C, 30 x 250 mm, 5 μm; eluted with 40% IPA (0.5% DMEA) in CO2.

[1536] Example 31

[1537] 4-[4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl]tetrahydrofuran-3-ol, isomer 1

[1538]

[1539] and

[1540] Example 32

[1541] 4-[4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl]tetrahydrofuran-3-ol, isomer 2

[1542]

[1543] 3,6-dioxabicyclo [3.1.0] hexane (157mg, 1.73mmol) is added to a solution of 3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridine (350mg, 0.72mmol) in EtOH (3ml), and it is stirred at 80 DEG C overnight. Additional 3,6-dioxabicyclo [3.1.0] hexane (157mg, 1.73mmol) is added, and the reaction is stirred overnight. The reaction is diluted with DCM (50ml), washed with H o (2x20ml) and brine (20ml). The crude material is purified by silica gel chromatography, eluted with a solution of MeOH in DCM to give a brown oil. The oil was subjected to SFC, eluting with 55% (50% 2-propanol in ACN) in CO2 (0.1% DEA). After chiral separation, the two diastereomeric pairs were purified separately by flash chromatography, eluting with a gradient of MeOH in DCM. The material isolated in each purification was triturated in pentane and washed with pentane followed by Et2O to give the title compound, Isomer 1 (36 mg, 8%), t R 6.46min, 96% EE, MS ES+m / z 572[M+H] + , and the title compound, isomer 2 (45 mg, 11%), t R 6.86 min, 96% EE, MS ES+ m / z 572 [M+H] + .

[1544] Example 33

[1545] 2-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]

[1546] [4-pyridinyl]oxy-1-(5-fluoro-2-pyridinyl)ethanol, Isomer 2

[1547]

[1548] To a stirred mixture of 2-[3-chloro-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridinyl)ethanol 2,2,2-trifluoroacetic acid (800 mg, 1.37 mmol) in MeOH (20 ml) at room temperature was added 3-oxetanone (611 mg, 8.48 mmol). The resulting mixture was stirred at 50°C under N2 for 1 hour. NaBH3CN (426 mg, 6.78 mmol) was added portionwise to the mixture at room temperature. The resulting mixture was stirred at 50°C under N2 for an additional 2 hours. After cooling to room temperature, the reaction was diluted with H2O (50 ml) and the mixture was basified to pH 9 with saturated aqueous Na2CO3. The mixture was extracted with EA (3 x 150 ml). The combined organic layers were washed with brine (2 x 50 ml), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18; eluting with 30% to 35% ACN in H2O (0.1% NH3·H2O) to afford the racemate of the title compound (420 mg, 58%) as a yellow solid. MS ES+ m / z 528 [M+H] + .

[1549] Subject the yellow solid to chiral chromatography using the following conditions:

[1550] CHIRAL ART Amylose-SA, 2 x 25 cm, 5 μm; 50% MeOH in MtBE (10 mM NH 3 -MeOH) elution; flow rate: 20 mL / min; 214 / 244 nm; to obtain the title compound (140 mg, 19%) t R =10.92,ee=100%. MSES+m / z 528[M+H] + .

[1551] Example 34

[1552] 4-[1-(1-Isopropyltriazol-4-yl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1

[1553]

[1554] 4-[1-(1-Isopropyltriazol-4-yl)ethoxy]-6-[5-methyl-1-(4-piperidinyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile hydrochloride (689 mg, 1.29 mmol) and DIPEA (0.67 ml, 3.87 mmol) were dissolved in MeOH (10 ml), and activated 4A molecular sieves were added. 3-Oxetanone (0.46 ml, 6.46 mmol), NaBH3CN (406 mg, 6.46 mmol), and AcOH (0.89 ml, 15.50 mol) were added sequentially, and the reaction was stirred at 70°C for 90 min. After cooling to room temperature, the reaction was diluted with EA. The mixture was washed with H2O (1 x 25 ml) and brine (1 x 25 ml), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with MeOH in DCM to give an off-white solid (490 mg, 73%). The off-white solid was subjected to SFC eluting with 50% EtOH (0.1% DEA) in CO2 to give the title compound (140 mg, 21%). RT was 6.93 min. MS ES+ m / z 517.3 [M+H] + .

[1555] The following compounds were prepared in a manner substantially similar to the method of Example 34, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1556] If the retention times were obtained from an analytical column, this method will be listed in the last column. Specific analytical conditions for each method are given in Table A.

[1557] Table 56

[1558]

[1559]

[1560]

[1561]

[1562]

[1563]

[1564] 1 Purify by silica gel chromatography eluting with MeOH in DCM.

[1565] 2 SFC, eluting with 60% MeOH (0.1% DEA) in CO2.

[1566] 3 SFC, eluting with 50% EtOH (0.1% DEA) in CO2.

[1567] 4 Column: Chiralpak IG, 3 x 25 cm columns, 5 mm; eluted with 60% ACN in H2O (0.5% DEA).

[1568] 5 Purified by Prep-TLC (DCM / MeOH 20:1).

[1569] 6 Column: Chiralpak IA, 2 x 25 cm columns, 5 mm; eluted with 20% MeOH in 1:1 hexanes / MTBE (0.5% 2M NH3 in MeOH).

[1570] 7 Purification by reverse phase chromatography: Column: AQ-C18, 250 x 50 mm, 10 μm; elution with 20% to 35% ACN in FA.

[1571] 8 Column: Chiralpak IG, 2 x 25 cm columns, 5 mm; eluted with 25% MeOH in MTBE (10 mM NH3-MeOH).

[1572] 9 Purify by silica gel chromatography eluting with 0% to 100% acetone in DCM.

[1573] 10 Column: Amylose-C, 20 x 250 mm columns, 5 mm; eluted with 45% EtOH (0.5% DMEA) in CO2.

[1574] 11 Purify by reverse phase C18 chromatography eluting with 30% to 60% ACN in H2O (NH4CO3 pH 9 buffer).

[1575] 12 Column: Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 45% EtOH (0.5% DMEA) in CO 2 .

[1576] 13Purify by silica gel chromatography eluting with 100% DCM (2CV), gradient 0% to 2% MeOH in DCM (13CV), 2% MeOH in DCM (10CV), gradient 2% to 5% MeOH in DCM (10CV), gradient 5% to 10% MeOH in DCM (2CV), 10% MeOH in DCM (15CV).

[1577] 14 Column: Chiralart Amylose C, 30 x 250 mm, 5 μm; eluted with 40% EtOH (0.5% DMEA) in CO2.

[1578] 15 Column: Chiralpak AD, 30 x 250 mm, 5 μm; eluted with 40% IPA (0.5% DMEA) in CO 2 .

[1579] 16 Purify by silica gel chromatography eluting with DCM / MeOH (10:1).

[1580] 17 Column: CHIRALPAK IE-3, 4.6 x 50 cm, 3 μm; eluted with 50% EtOH in MTBE (0.1% DEA).

[1581] 18 Column: Chiralpak IA, 2 x 25 cm columns, 5 mm; eluted with 50% EtOH in MTBE (10 mM NH3-MeOH).

[1582] 19 SFC, eluting with 50% IPA (0.1% DEA) in CO2.

[1583] 20 Column: Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 35% EtOH in CO2.

[1584] 21 4A molecular sieves, DIPEA and AcOH were not included in the reaction.

[1585] 22 Purified by Prep-TLC (PE / EA 1:1).

[1586] 23 Column: CHIRALPAK IE, 3 x 25 cm, 5 μm; eluted with 50% MeOH in MTBE (0.5% 2M NH 3 -MeOH).

[1587] 24 Purify by reverse phase C18 chromatography eluting with 50% to 60% ACN in H2O.

[1588] 25 Column: CHIRALPAK ID, 2 x 25 cm, 5 μm; eluted with 30% MeOH in MTBE (10 mM NH 3 -MeOH).

[1589] 26 Workup: The reaction was concentrated. The residue was dissolved in DCM and aqueous Na2CO3 and filtered through a phase separator. The organic phase was dried over MgSO4, filtered and concentrated.

[1590] 27 Purify by reverse phase flash chromatography eluting with 30% ACN in NH4HCO3, pH 9 (2CV), 30% to 60% ACN in NH4HCO3, pH 9 (8CV), 60% ACN in NH4HCO3, pH 9 (2CV), then 100% ACN.

[1591] 28 Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 45% IPA (0.5% DMEA) in CO 2 .

[1592] 29 The reaction was carried out at 50°C.

[1593] 30 Work-up: the reaction was quenched with H2O at rt, adjusted to pH 8 with aqueous NaHCO3 solution, extracted with EA (3 x 30 ml), washed with brine (2 x 20 ml), dried over Na2SO4, filtered and concentrated.

[1594] 31 Purified by Prep-TLC (5% MeOH in DCM).

[1595] 32 Column: CHIRALPAK ID, 3 x 25 cm, 5 μm; eluted with 30% EtOH in 2:1 DCM / MeOH (0.1% 2M NH 3 -MeOH).

[1596] 33 4A molecular sieves and DIPEA were not included in the reaction.

[1597] 34 Work-up: the reaction was diluted with saturated K2CO3 (30 ml) at rt, extracted with EA (3 x 50 ml), washed with brine (3 x 50 ml), dried over Na2SO4, filtered and concentrated.

[1598] 35 Column: CHIRALPAK IE, 2 x 25 cm, 5 μm; eluted with 50% MeOH in MTBE (0.5% 2M NH 3 -MeOH).

[1599] 36 Workup: the reaction was quenched with saturated NaHCO3 (20 ml) at room temperature, extracted with 25% i-PrOH in CHCl3 (3 x 30 ml), washed with brine (2 x 20 ml), dried over Na2SO4, filtered and concentrated.

[1600] 37 Column: CHIRALPAK IE, 2 x 25 cm, 5 μm; eluted with 50% MeOH in MTBE (10 mM NH 3 -MeOH).

[1601] 38 Workup: The reaction was concentrated and diluted with H2O (10 ml), extracted with 20% i-PrOH in CHCl3 (3 x 30 ml), dried over Na2SO4, filtered and concentrated.

[1602] 39 Purified 100% by Prep-TLC EA.

[1603] 40 Purify by silica gel chromatography eluting with 40% (10% MeOH in DCM) in DCM.

[1604] 41 SFC chromatography, eluting with 40% EtOH (1% DEA) in 60% CO2.

[1605] 42 Workup: quench the reaction with H2O at room temperature, adjust pH to 8 with aqueous NaHCO3, extract with CHCl3:IPA, dry over Na2SO4, filter and concentrate.

[1606] 43 Purify by silica gel chromatography eluting with MeOH in EA (1:30 to 1:20).

[1607] 44 Column: CHIRALPAK IE, 2 x 25 cm, 5 μm; eluted with 30% to 50% MeOH in MTBE (0.5% 2M NH 3 -MeOH).

[1608] 45Column: Chiralpak IA, 2 x 25 cm columns, 5 mm; eluted with 15% ACN:EtOH (2:1) in MTBE (10 mM NH3 in MeOH).

[1609] 46 Purification by reverse phase C18 chromatography: Column: Ultimate XB-C18, 50 x 250 mm, 10 μm; elution with 20% to 50% ACN in H2O (0.5% NH3H2O).

[1610] 47 Column: CHIRALPAK ID, 2 x 25 cm, 5 μm; eluted with 50% [MeOH in DCM (1:1) (2M NH 3 -MeOH)] in MeOH.

[1611] 48 Column: CHIRALPAK ID, 2 x 25 cm, 5 μm; eluted with 50% [MeOH in DCM (1:1) (0.1% 2M NH 3 -MEOH)] in MeOH.

[1612] 49 Workup: quench the reaction with H2O at room temperature, adjust the pH between 8 and 9 with aqueous Na2CO3 solution, extract with i-PrOH in CHCl3, wash with brine, dry over Na2SO4, filter and concentrate.

[1613] 50 Purified by Prep-TLC MeOH in DCM (1 to 15).

[1614] 51 Column: CHIRAL ART cellulose-SC, 2 x 25 cm, 5 μm; elution was with 50% MeOH in MTBE (10 mM NH 3 -MeOH).

[1615] 52 Purified by Prep-TLC (DCM / MeOH 10:1).

[1616] 53 Column: Chiralpak IA, 2 x 25 cm columns, 5 mm; eluted with 50% MeOH in MTBE (10 mM NH3-MeOH).

[1617] 5 Purify by reverse phase C18 chromatography eluting with 10% to 40% ACN in H2O (10 mmol / L NH3H2O).

[1618] Example 66

[1619] 6-[3,5-Dimethyl-1-[1-(oxetan-3-yl)-4-piperidinyl]pyrazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridinyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2

[1620]

[1621] A mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[1-[5-(trifluoromethyl)-3-pyridinyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (95 mg, 0.21 mmol), 4-(4-bromo-3,5-dimethyl-pyrazol-1-yl)-1-(oxetan-3-yl)piperidine (73 mg, 0.23 mmol), and KCO (78 mg, 0.56 mmol) in toluene (0.85 ml) and H O (0.21 ml) was degassed by sonication under N. PdCl(DtBPF) (9 mg, 0.14 mmol) was added, the vessel was sealed, and the mixture was stirred at 80° C. overnight. The reaction was diluted with EA and H O, the layers were separated, and the organic layer was dried over MgSO , filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 0% to 60% EtOH in EA (1:3) to afford the title compound (91 mg, 76%) as a green solid. MS ES+ m / z 566 [M+H] + .

[1622] The following compounds were prepared in a manner substantially similar to the method of Example 66, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1623] Table 57

[1624]

[1625] 1 Workup: Concentrate the reaction. Dilute the residue with H₂O and add 35% aqueous HCl to adjust the pH to 1. Gradually add i-PrOH until a solution forms. Add activated carbon and stir the reaction for 1 hour. Add DE and stir for 30 minutes. Filter the suspension and wash the solid with i-PrOH:H₂O (1:2). Adjust the pH of the filtrate to 10 with aqueous NaOH (10 M). Collect the resulting insoluble material by filtration to provide the title compound.

[1626] Example 68

[1627] 6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridinyl]ethylamino]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1

[1628]

[1629] To a pressure tube was added 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[1-[5-(trifluoromethyl)-3-pyridinyl]ethylamino]pyrazolo[1,5-a]pyridine-3-carbonitrile (0.39 g, 0.45 mmol), 4-(4-bromo-5-methyl-triazol-1-yl)-1-(oxetan-3-yl)piperidine (0.17 g, 0.55 mmol), K2CO3 (0.16 g, 1.12 mmol), toluene (8 ml) and H2O (1 ml). The mixture was degassed by bubbling N2 through it for several minutes, then PdCl2(DtBPF) (0.02 g, 0.03 mmol) was added and degassed for an additional 2 min. The tube was capped and the reaction was heated to 95°C with stirring for 6 h. The reaction was cooled to room temperature, diluted with H2O, and extracted with EA (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography and eluted with 0% to 100% EA in cHex, then 0% to 5% MeOH in DCM to give a brown foam (184 mg, 65%). MS ES+ m / z 552 [M+H] + .

[1630] Chiral chromatography of the brown foam was performed using the following conditions: Column: Chiralpak IH, 3 x 100 mm, 3 μm; eluting with 10% to 50% EtOH (0.2% IPAm) in CO2 to give the title compound (69 mg, 24%), t R is 1.70, ee>98%. MS ES+m / z 552[M+H] + Retention times were obtained using analytical method K (see Table A for specific analytical conditions).

[1631] The following compounds were prepared in a manner substantially similar to that of Example 68, using appropriate reagents, adjusting the reaction time to ensure completion of the reaction, and adjusting the purification system appropriately. K3PO4 and IPA may also be used.

[1632] If the retention times were obtained from an analytical column, this method will be listed in the last column. Specific analytical conditions for each method are given in Table A.

[1633] Table 58

[1634]

[1635]

[1636] 1 Purify by silica gel chromatography eluting with 0% to 100% (25% EtOH:EA) in cHex.

[1637] 2 Column: Chiralpak AD, 20 x 250 mm, 5 μm; eluted with 45% MeOH (0.2% DMEA) in CO 2 .

[1638] 3 Column: Chiralpak IH, 3 x 100 mm, 3 μm; eluted with 10% to 50% EtOH (0.2% IPAm) in CO2.

[1639] 4 Column: Chiralpak IA, 3 x 100 mm, 3 μm; eluted with 25% to 50% EtOH (0.2% IPAm) in CO 2 .

[1640] 5 Purify by reverse phase flash C18 chromatography using the following conditions: column, C18; elution with 20% to 60% ACN in H2O (NH5CO3 pH 9).

[1641] 6 Column: Chiralcel OD, 20 x 250 mm, 5 μm; eluted with 45% MeOH (0.5% DMEA) in CO2.

[1642] Example 73

[1643] 6-[5-methyl-1-[1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)-4-piperidinyl]pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1644]

[1645] A solution of 6-[5-methyl-1-(4-piperidinyl)pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (55 mg, 0.13 mmol) and 2,2,6,6-tetramethyltetrahydropyran-4-one (36 mg, 0.23 mmol) in MeOH (3 ml) was treated with NEt (90 ml, 0.65 mmol) and ZnCl (10 ml, 0.02 mmol, 1.9 M in MeTHF), and the reaction was stirred at 50 ° C. After stirring overnight, the reaction was cooled to room temperature and treated with NaBH CN (33 mg, 0.53 mmol). After stirring at 50 ° C for 3 days, the reaction was quenched with H O and EA. The phases were separated and the aqueous phase was extracted with EA. The organic layers were combined, dried over MgSO , filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with 5% MeOH in DCM to afford the title compound (50 mg, 66%) as an amber oil. MS ES+ m / z 568 [M+H] + .

[1646] Example 74

[1647] 6-[5-methyl-1-[2-(oxetane-3-yl)-2-azaspiro[3.3]heptane-6-yl]pyrazole-4-

[1648] 1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1649]

[1650] 6-[1-(2-Azaspiro[3.3]heptan-6-yl)-5-methyl-pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile 2,2,2-trifluoroacetic acid (106 mg, 0.16 mmol) was dissolved in DCE (3 ml) and treated with NEt (100 ml, 0.72 mmol), 3-oxetanone (25 ml, 0.43 mmol) and Na(OAc)BH (89 mg, 0.42 mmol) and the reaction was stirred at room temperature for 16 h. Another aliquot of 3-oxetanone (25 ml, 0.43 mmol) was added and the reaction was stirred at 50° C. for 4 h. The reaction was diluted with EA (25 ml) and the organic layer was washed with saturated aqueous NaHCO (50 ml) and brine (50 ml). The organic layer was collected, dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0% to 15% MeOH in DCM to afford the title compound (26 mg, 31%) as an off-white solid. MS ES+ m / z 496 [M+H] + .

[1651] Example 75

[1652] 2-[3-Chloro-6-[5-methyl-1-[1-(oxetan-3-yl)azetidin-3-yl]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(3,5-difluoro-2-pyridinyl)ethanol, Isomer 2

[1653]

[1654] 2-[3-Chloro-6-[5-methyl-1-[1-(oxetan-3-yl)azetidin-3-yl]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(3,5-difluoro-2-pyridinyl)ethanol (126 mg) was subjected to the following chiral chromatography conditions: Column: Amylose-C, 30 x 250 mm column, 5 mm; eluted with 40% IPA in CO2 to give the title compound (32 mg, 25%), t R is 2.51, 90%ee, MS ES+m / z 518.2[M+H] + Retention times were obtained using analytical method H (see Table A for specific analytical conditions).

[1655] The following compounds were prepared in a manner substantially similar to the method of Example 75, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1656] Table 59

[1657]

[1658]

[1659]

[1660] 1 Purify by silica gel chromatography eluting with MeOH in DCM.

[1661] 2 SFC chromatography, eluting with 60% 2-propanol (0.1% DEA) in 40% CO2.

[1662] 3 SFC chromatography, eluting with 60% MeOH (0.1% DEA) in 40% CO2.

[1663] 4 Column: Chiralpak IE-3; 4.6 x 50 cm column, 3 mm; eluted with 50% EtOH in MTBE (0.1% DEA).

[1664] 5 Column: Chiral ART Cellulose-SB, 2 x 25 cm columns, 5 mm; eluted with 10% EtOH in MTBE (10 mM NH3-MeOH).

[1665] 6 Column: Chiral Art Amyl C, 30 x 250 mm, 5 μm; eluted with 45% EtOH (0.5% DMEA) in CO 2 .

[1666] 7 Column: Amylose-C, 30 x 250 mm column, 5 mm; eluted with 45% EtOH (0.5% DMEA) in CO2.

[1667] 8 Column: Chiralpak AD, 30 x 250 mm column, 5 mm; eluted with 55% IPA (0.5% DMEA) in CO2.

[1668] 9 Column: Chiral Art Amyl C, 20 x 250 mm columns, 5 mm; eluted with 60% IPA (0.5% DMEA) in CO2.

[1669] 10 Column: Chiral Art Amylose C, 30 x 250 mm, 5 μm; eluted with 40% IPA (0.5% DMEA) in CO2.

[1670] Example 88

[1671] 1-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]

[1672] [4-pyridinyl]oxy-2-(3,5-difluoro-2-pyridinyl)propan-2-ol, isomer 1

[1673]

[1674] Under N2, to an ice-cooled solution of 2-[3-chloro-6-[5-methyl-1-[1-(oxetanes-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(3,5-difluoro-2-pyridyl)ethanone (190 mg, 0.19 mmol, 55 mass %) in DCM (4 ml) was added a solution of MeMgBr (0.26 ml, 0.78 mmol, 3 M) over 5 minutes. The resulting mixture was stirred for 3 h, then diluted with DCM and slowly quenched with MeOH (2 ml). NaBH4 (5 mg, 0.132161 mmol) was added, and the mixture was stirred for 20 min. The reaction was purified by silica gel chromatography, eluting with a DCM solution of 0% to 50% (10% MeOH in DCM). The material was crashed into the column and the title compound and impurities were dissolved and eluted with 50% MeOH in DCM. The residue was further purified by reverse phase chromatography on an XBridge C18 column, 19x150mm, 5mm; eluting with 45% to 75% ACN in H2O (10mM NH4HCO3, pH 9).

[1675] The material separated after reverse phase chromatography was subjected to the following chiral chromatography conditions: Chiral Art Amylose C, 30x250mm, 5μm; eluted with 40% IPA (0.5% DMEA) in CO2 to give the title compound, isomer 1 (7.5mg, 7%), t R is 2.36, ee>98%ee; MS ES+m / z 560 / 562[M+H] + .

[1676] Example 89

[1677] 1-[3-chloro-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]

[1678] [4-pyridinyl]oxy-2-(5-fluoro-2-pyridinyl)butan-2-ol, isomer 2

[1679]

[1680] At 0 ° C, under N2, EtMgBr (0.25 ml, 0.75 mmol, 3 M in Et2O) was treated with ZnCl2 (0.09 ml, 0.2 mmol, 1.9 M in MeTHF). After stirring at 0 ° C for 1 hour, the reaction was treated dropwise with a solution of 2-[3-chloro-6-[5-methyl-1-[1-(oxetanes-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridinyl)ethanone (304 mg, 0.58 mmol) in DCM (1 ml) and stirred at 0 ° C for 2 hours. The reaction was diluted with DCM and slowly quenched with aqueous NH4Cl solution. The reaction was filtered through a phase separator and washed with DCM. The eluent was concentrated and the residue was dissolved in MeOH (5 ml), treated with NaBH4 (15 mg, 0.40 mmol) and stirred at room temperature for 1 h. The reaction was quenched with H2O, the MeOH was removed in vacuo, extracted with DCM, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 5% MeOH in DCM to give a colorless oil (125.6 mg, 35%). The colorless oil was subjected to the following chiral chromatography conditions: column: cellulose-1, 30x 250mm column, 5 mm; eluted with 35% IPA (0.5% DMEA) in CO2 to give the title compound (18 mg, 6%), t R 2.64, 98% ee. MS ES+m / z( 35 Cl / 37 Cl)556 / 558[M+H] + Retention times were obtained using analytical method M.

[1681] The following compounds were prepared in a manner substantially similar to the method of Example 89, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1682] If the retention times were obtained from an analytical column, this method will be listed in the last column. Specific analytical conditions for each method are given in Table A.

[1683] Table 60

[1684]

[1685] 1Purify by silica gel chromatography eluting with 0% to 40% (9:1 DCM in MeOH) in DCM.

[1686] 2 Column: Chiralpak IH, 20 x 250 mm column (5 mm), eluted with 35% MeOH (0.5% DMEA) in CO2.

[1687] Example 92

[1688] 4-[1-(6-cyclopropylpyrazin-2-yl)ethoxy]-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2

[1689]

[1690] 4-[1-(6-bromopyrazin-2-yl)ethoxy]-6-[5-methyl-1-[1-(oxetane-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (182.2 mg, 0.32 mmol) and cyclopropylboronic acid (48 mg, 0.56 mmol) were dissolved in 1,4-dioxane (3 ml) and CsF (197 mg, 1.30 mmol) was added. The mixture was degassed, and then PdCl2(DtBPF) (21 mg, 0.03 mmol) was added and the mixture was stirred at 90 ° C overnight. After cooling to room temperature, EA was added to the reaction. The mixture was washed with saturated NaHCO3 aqueous solution and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 20% to 100% EA in cHex to give a light yellow solid (120 mg, 67%). The yellow solid was subjected to chiral chromatography using the following conditions: Column: Chiralpak IH, 20 x 250 mm, 5 μm; eluting with 25% MeOH (0.5% DMEA) in CO2 to give the title compound (47 mg, 28%). R is 2.32min, 97%ee. MS ES+m / z 526[M+H] + Retention times were obtained using analytical method N.

[1691] Example 93

[1692] 6-[5-methyl-1-[7-(oxetane-3-yl)-7-azaspiro[3.5]nonan-2-yl]pyrazole-4-

[1693] 1-(2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1694]

[1695] and

[1696] Example 94

[1697] 6-[3-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3.5]nonan-2-yl]pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1698]

[1699] A solution of 6-[1-(7-azaspiro[3.5]nonan-2-yl)-5-methyl-pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, 6-[1-(7-azaspiro[3.5]nonan-2-yl)-3-methyl-pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (101 mg, 0.19 mmol) and oxetan-3-one (20 mg, 0.28 mmol) in MeOH (5 ml) was treated with AcOH (21 ml, 0.37 mmol) and NaBHCN (35 mg, 0.56 mmol) and stirred at room temperature for 2 hours and then at 50° C. for 18 hours. The reaction was allowed to cool and then concentrated. The residue was suspended in saturated aqueous NaHCO₃ and extracted with DCM (2X). The combined organic layers were dried over MgSO₄, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 10% acetone in DCM to afford a light yellow solid containing two compounds. The compounds were separated using the following conditions: column, Chiralpak 1H, 20 x 250 mm, 5 mm; column eluted with 20% MeOH in CO₂ to afford 6-[3-methyl-1-[7-(oxetane-3-yl)-7-azaspiro[3.5]nonan-2-yl]pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (27 mg; 27%). MS ES+ m / z 524 [M+H] + ,t R = 1.80 min (Analytical Chiral Chromatography N, Table A), 1H NMR (400 MHz, DMSO-d6): 8.60-8.58 (m, 3H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.69-7.62 (m, 2H), 7.34 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 6.92 (s, 1H), 5.87 (q, J = 6.4 Hz, 1H), 4.89 (quintet, J = 8.2 Hz, 1H), 4.51 (t, J = 6.5 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H), 2.29-2.18 (m, 11H), 1.71 (d, J = 6.4 Hz, 5H), 1.60 (t, J = 5.4 Hz, 2H), and 6-[5-methyl-1-[7-(oxetan-3-yl)-7-azaspiro[3.5]nonan-2-yl]pyrazol-4-yl]-4-[(1R)-1-(2-pyridinyl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (14 mg, 14%) MS ES+ m / z 524 [M+H] + ,t R = 1.69 min (Analytical Chiral Chromatography N, Table A), 1 H NMR (400 MHz, DMSO-d6): 8.60-8.52 (m, 3H), 8.13 (s, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.03 (s, 1H), 5.89 (q, J = 6.4 Hz, 1H), 4.78 (quintet, J = 8.4 Hz, 1H), 4.51 (t, J = 6.5 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H), 2.33-2.18 (m, 11H), 1.72-1.61 (m, 7H). It was a viscous colorless oil.

[1700] The following compounds were prepared in a manner substantially similar to the method of Example 94, using appropriate reagents, adjusting the reaction time to ensure reaction completion, and adjusting the purification system appropriately.

[1701] Table 61

[1702]

[1703] 1 Column: Chiralpak AD, 20 x 250 mm columns, 5 mm; eluted with 35% EtOH (0.5% DMEA) in CO2.

[1704] a 11H NMR (400 MHz, DMSO-d6): δ 8.60 - 8.58 (m, 2H), 8.50 (d, J = 1.0 Hz, 1H), 8.14 (s, 1H), 7.85 (td, J = 7.7, 1.9 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.35 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.07 (s, 1H), 5.91 (q, J = 6.4 Hz, 1H), 4.54 (td, J = 6.5, 2.4 Hz, 2H), 4.42 - 4.35 (m, 3H), 3.66 (quintet, J = 6.4 Hz, 1H), 2.45 - 2.41 (m, 4H), 2.19 (s, 7H), 1.88 - 1.79 (m, 1H), 1.71 (d, J = 6.4 Hz, 4H).

[1705] b 1 1H NMR (400 MHz, DMSO-d6): δ 8.60 - 8.58 (m, 2H), 8.50 (d, J = 1.0 Hz, 1H), 8.14 (s, 1H), 7.85 (td, J = 7.7, 1.9 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.35 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 7.07 (s, 1H), 5.91 (q, J = 6.4 Hz, 1H), 4.54 (td, J = 6.5, 2.4 Hz, 2H), 4.42 - 4.35 (m, 3H), 3.66 (quintet, J = 6.4 Hz, 1H), 2.45 - 2.41 (m, 4H), 2.19 (s, 7H), 1.88 - 1.79 (m, 1H), 1.71 (d, J = 6.4 Hz, 4H).

[1706] c 1H NMR(400MHz, DMSO):8.68–8.56(m,2H),8.50(d,J=1.0Hz,1H),8.14(s,1H),7.85(td,J=7.7,1.8Hz,1H),7.6 6(dt,J=7.9,1.1Hz,1H),7.37–7-34(dd,J=7.5,1.2Hz,1H),7.36–7.32(dd,J=7.5,1.2Hz,1H),7.07(d,J=1. 1Hz,1H),5.91(q,J=6.4Hz,1H),4.55(td,J=6.5,2.5Hz,2H),4.44–4.32(m,2H),3.66(p,J=6.4Hz,1H),2.50 –2.38(m,4H),2.19(s,3H),2.15–1.95(m,4H),1.88–1.77(m,1H),1.71(d,J=6.4Hz,3H),1.69–1.58(m,2H).

[1707] Example 98

[1708] 1-(5-fluoro-2-pyridyl)-2-[6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazole-4-

[1709] 1-Methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy-ethanol, Isomer 1

[1710]

[1711] A solution of (1S)-2-[3-bromo-6-[5-methyl-1-[1-(oxetan-3-yl)-4-piperidinyl]triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-1-(5-fluoro-2-pyridinyl)ethanol (0.066 g, 0.10 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.115 g, 0.54 mmol), and XPhos Pd G4 (0.02 g, 0.02 mmol) in toluene (1.3 ml) was treated with aqueous K2CO3 (1 M, 0.55 ml, 0.55 mmol) at room temperature and heated to 90°C. After 5 h, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (0.35 g, 1.62 mmol), XPhos Pd G4 (0.02 g, 0.02 mmol) and H2O (0.65 ml) were added. After 7 h, the reaction was cooled to room temperature and EA (10 ml) was added. The phases were separated and the organic phase was dried, filtered and concentrated. The residue was purified by reverse phase chromatography eluting with 20% to 60% ACN in NH4CO3 (pH = 9) in water to give the title compound as a white solid (0.017 mg, 28%). MS ES+ m / z 574 [M+H] + .

[1712] Example 99

[1713] 6-[1-[(3S,4R)-3-fluoro-1-(oxetan-3-yl)-4-piperidinyl]-5-methyl-triazole-4-

[1714] 1-[(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile]-4-[2-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

[1715]

[1716] To a mixture of 6-[1-[(3S,4R)-3-fluoro-4-piperidinyl]-5-methyl-triazol-4-yl]-4-[2-(5-fluoro-2-pyridinyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile; hydrochloride (2 g, crude product) in MeOH (20 ml) was added 3-oxetanone (1.49 g, 20.63) at room temperature under N2. The resulting mixture was stirred at 50 ° C for 60 min. Next, NaBH3CN (432 mg, 6.88 mmol) was added at room temperature. The mixture was stirred at 50 ° C for 2 hours. After cooling to room temperature, the reaction was quenched with H2O (30 ml) and the mixture was basified to pH 9 with saturated Na2CO3 aqueous solution. The mixture was extracted with EA (2x80 ml). The combined organic layers were washed with brine (2 x 20 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by C18 reverse phase flash chromatography eluting with 30% to 50% ACN in H2O (0.1% NH3.H2O) to afford the title compound (1.4 g, 73.97%) as a white solid. MS ES+ m / z 551 [M+H] + .

[1717] Biological experiments

[1718] The following experiments demonstrate that the compounds provided herein are FGFR2 inhibitors.The following experiments demonstrate that certain compounds provided herein selectively target FGFR2 relative to FGFR1.

[1719] FGFR2 and FGFR1 enzyme assays

[1720] FGFR1 and FGFR2 proteins were purchased from ThermoFisher Scientific (Cat. Nos. PR4660A and PR5332A, respectively). Enzyme activity was monitored using the KinEASE™-TK Assay Kit (CisBio, Cat. No. 62TKOPEC) according to the manufacturer's instructions. All experiments were performed in KinEASE™ kinase buffer with the corresponding KmATP for each kinase. Reactions were performed in white, small-volume polystyrene 384-well plates.

[1721] Each protein was incubated with 50 nM TK-biotin substrate (CisBio), 6.25 nM streptavidin-XL665 (CisBio), and 0.25x anti-phospho-TK-biotin-cryptate (CisBio). In a 10 μL reaction, the final enzyme concentration was 0.08 nM for FGFR1 and 0.04 nM for FGFR2. Compounds were titrated starting at 2.5 μM in 100% dimethyl sulfoxide (DMSO) using a 1:3 serial dilution. Each protein and compound were preincubated at room temperature for 15 minutes before initiating the reaction with adenosine triphosphate (ATP). Reactions were performed at 30°C for 30 minutes. The plate was quenched by adding the anti-TK cryptate antibody / streptavidin-XL665 mixture. After 1 h in stop solution, the plates were read on a plate reader (PerkinElmer (Ex. Filter. 320 nm and Em1 665 nm / Em2 615 nm)).

[1722] The ratios were converted to percentages of control (POC) using a ratiometric emission factor. 100 POC was determined without test compound (DMSO only) and 0 POC was determined in the presence of 2.5 μM of the appropriate control inhibitor. A 4-parameter logistic curve was fitted to the POC values ​​as a function of compound concentration, IC 50 The value is the point where the best-fit curve passes through 50POC.

[1723] FGFR2 and FGFR1 cell-based assays

[1724] HEK293 cells transfected with doxycycline (dox)-inducible human wild-type FGFR1 and human wild-type FGFR2 were plated at 10,000 cells / well in poly-D-lysine-coated 384-well plates (Becton Dickinson, Catalog No. 356663) in Dulbecco's Modified Eagle Medium (Sigma, Catalog No. D5796) containing 10% FBS (Sigma, Catalog No. F2442), 1% penicillin-streptomycin (Gibco, Catalog No. 15140), and 1 μg / ml doxycycline and allowed to attach for 24 hours at 37°C and 5% CO2. NCI-H716 cells (ATCC, Catalog No. CCL-251) were plated at 5,000 cells / well in poly-D-lysine-coated 384-well plates (Becton Dickinson, Catalog No. 356663) in RPMI 1640 medium (Gibco, Catalog No. A10491) containing 10% FBS and 1% penicillin-streptomycin and allowed to attach for 24 hours at 37°C, 5% CO2.

[1725] Cells were treated with compounds using a 1:3 serial dilution to a maximum final concentration of 3 μM. Compounds were incubated on cells at 37°C, 5% CO2 for 1 hour. Cells were fixed with formaldehyde for 20 minutes at room temperature and permeabilized with 0.3% Triton-X 100 for 15 minutes at room temperature. Cells were then blocked with 0.05% Tween containing 1% bovine serum albumin for 1 hour at room temperature and incubated with anti-phospho-FGFR primary antibodies (Cell Signaling, Cat. No. 52928 for HEK293 FGFR1; Millipore, Cat. No. 06-1433 for the remaining cell lines) in blocking buffer at 4°C overnight. The next day, cells were incubated with goat anti-rabbit IgG Alexa 488-labeled secondary antibody (Invitrogen, Cat. No. A11008) at room temperature for 1 hour, and a solution containing 0.4 μg / ml DAPI (Sigma, Cat. No. D9564) and 50 μg / mL RNase A (Sigma, Cat. No. R-6513) was added to stain the cell nuclei. The fluorescent plate was scanned using an Acumen Explorer laser scanning fluorescence microplate cytometer (SPTLabtech) to quantify the number of cells and FGFR phosphorylation, thereby calculating the percentage of phosphorylated-FGFR-positive cells.

[1726] 100POC was determined without test compound (DMSO only), and 0POC was determined in the presence of 3 μM of the appropriate control inhibitor. A 4-parameter logistic curve was fitted to the POC values ​​as a function of compound concentration, IC 50 The value is the point where the best-fit curve passes through 50POC.

[1727] Biological test results

[1728] In the above enzyme assay, the compounds of Examples 1-33, 35-60, and 62-99 all showed an IC200 lower than 200 nM for FGFR2. 50 value.

[1729] In the above enzyme assay, the compounds of Examples 1, 2, 4, 7, 9-11, 13-16, 18-24, 26-28, 31-35, 38, 40, 42-59, 61-67, 69, 71-73, 75-77, 79-85, 87-93, 95-97 and 99 all showed an IC2 lower than 100 nM for FGFR2. 50 values, and the selectivity for FGFR2 is at least 3-fold higher than that for FGFR1.

[1730] In the above enzyme assay, the compounds of Examples 1, 2, 7, 9-11, 15-16, 18, 20-22, 27-28, 31, 33-34, 40, 42, 44, 47-53, 55-57, 61-67, 69, 71, 73, 79, 81-82, 87-89, 91, 92, 96 and 99 all showed an IC2 of less than 50 nM for FGFR2. 50 values, and the selectivity for FGFR2 is at least 8-fold higher than that for FGFR1.

[1731] In the above cell-based assay, the compounds of Examples 1-99 all showed an IC2 lower than 60 nM for FGFR2. 50 value.

[1732] In the above cell-based assay, the compounds of Examples 1-14, 16-29, 31-40, 42, 44, 45, 47-71, 73-75, 77, 79, 81-82, 84 and 86-99 all showed an IC<30 nM for FGFR2. 50 values, and is at least 5-fold more selective for FGFR2 than for FGFR1.

[1733] In the above cell-based assays, the compounds of Examples 3-5, 7-9, 14, 16, 18-23, 28, 33, 42, 44, 51-53, 56, 60-63, 66-67, 69, 74-75, 77, 81, 88-89, 91, 95-97, and 99 all exhibited an IC<10 nM for FGFR2. 50 values, and the selectivity for FGFR2 is at least 10-fold higher than that for FGFR1.

Claims

1. A compound of the formula: in Z2 is A is pyrazole, triazole, thiadiazole or oxadiazole, which is 1 and R 1A replace; R 1 is hydrogen or C1-C3 alkyl; R 1A is hydrogen, halo, CN or C1-C3 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH and OCH3; X1 and X2 are independently selected from N and C, wherein when one of X1 or X2 is N, the other is C; X3 is N or CH; X4 is N or CR 9 ; Y is NH, O, S or a bond; Y1 is a key, CHR 7 、CH2-CHR 7 , CHR 7 -CH2, CF2, CH2-CF2 or CF2-CH2; Y2 is a bond, CHR 3 、CH2-CHR 3 , CHR 3 -CH2, CF2, CH2-CF2 or CF2-CH2; Y3 is CR 4 R 5 or CF2; Y4 is CR 3 R 4 or CF2; Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2CR 13 R 14 ; Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2CR 13 R 14 ; Z is a key, CHR 9A , CR 4 R 4A , CR 4 R 4A -CH2, CH2-CR 4 R 4A , cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine; When Z is the key, CR 4 R 4A , CR 4 R 4A -CH2, CH2-CR 4 R 4A , cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine, Z1 is a bond, or when Z is CHR 9A When Z1 is CH2 or CH2-CH2; Z3 is a bond, C(O), SO2 or -NR 4 C(O); Z4 is a bond, C(O), SO2 or -NR 4 C(O); R 2 is C1-C5 alkyl or R 8 , wherein the C1-C5 alkyl is optionally substituted by one or more substituents independently selected from halo, OH, CN, oxo, -OC1-C4 alkyl, -OC3-C5 cycloalkyl, -Z3-R 11 and R 10 , wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; R 3 is hydrogen, F, OH, OCH3, C1-C3 alkyl, cyclopropyl, or one R 3 With R 5 or R 7 Fused to form CH2, CH2-CH2 or CH2OCH2; 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 with one R 3 Fused to form CH2, CH2-CH2 or CH2OCH2; R 6 is hydrogen, halo, C1-C5 alkyl, CN, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, wherein 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, methyl, halomethyl, OH or OCH3, and wherein C1-C5 alkyl is optionally substituted with one or more substituents independently selected from halo, OH and OCH3; R 7 is hydrogen, F, OH, OCH3, C1-C3 alkyl or with one R 3 Fused to form CH2, CH2-CH2 or CH2OCH2; R 8 is a 3-6 membered cycloalkyl, a 4-6 membered heterocycloalkyl, a 5-6 membered aryl or a 5-6 membered heteroaryl, which is optionally 8A Fused or R 8A replace; R 8A is a 3-6 membered cycloalkyl group, a 4-6 membered heterocycloalkyl group, a 5-6 membered aryl group or a 5-6 membered heteroaryl group; R 9 is hydrogen, C1-C3 alkyl, or R 9A Fused to form CH2 or CH2-CH2; R 10 is a 3-6 membered cycloalkyl, a 4-6 membered heterocycloalkyl, a 5-6 membered aryl or a 5-6 membered heteroaryl, which is optionally 8A Fused or R 8A replace; R 11 is C1-C4 alkyl, NH2, NHC1-C3 alkyl, NHC3-C5 cycloalkyl or N(C1-C3 alkyl)2, wherein 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 C1-C4 alkyl, C1-C3 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; R 13 is hydrogen, halo or C1-C3 alkyl; R 14 is hydrogen, halo or C1-C3 alkyl; and R 8 , R 10 and R 8A Optionally substituted with one or more substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z4-R 12 , wherein C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X1 is C, and X2 is N; or X1 is N, and X2 is C.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1 is N, and X2 is C.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X1 is C, and X2 is N.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X3 is CH.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A is pyrazole or triazole, which is replaced by R 1 and R 1A replace.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein A is a triazole, which is replaced by R 1 and R 1A replace.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 1A is hydrogen or C1-C3 alkyl, which is optionally substituted with one or more substituents independently selected from halo, OH and OCH3.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 1A It is hydrogen or CH3.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1A It's hydrogen.

11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R 1 It is CH3.

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

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein Y is O.

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 6 It is CN, F, Cl, CH3, CF3 or cyclopropyl.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein R 6 is CN, F or Cl.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein R 6 It is CN.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 6 It is Cl.

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

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein Z is a bond, azetidine or piperidine.

20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

21. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Z is CHR 9A , Z1 is CH2 and R 9 With R 9A Fused to form CH2.

22. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Z1 is a bond.

23. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein X4 is N.

24. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein X4 is CR 9 , where R 9 It is hydrogen or CH3.

25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein Y1 is a bond, CHR 7 、CH2-CHR 7 or CHR 7 -CH2, where R 7 Selected from hydrogen, F, OH and CH3.

26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein Y2 is a bond, CHR 3 、CH2-CHR 3 or CHR 3 -CH2, where R 3 Selected from hydrogen, F, OH and CH3.

27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Y3 is CR 4 R 5 or CF2, where R 4 is hydrogen or CH3 and R 5 It is hydrogen, F, OH or CH3.

28. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Y3 is CR 4 R 5 , where R 4 is hydrogen and R 5 With an R 3 Condensed to form CH2, CH2-CH2 or CH2OCH2.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein Y4 is CR 3 R 4 , where R 4 is hydrogen or CH3 and R 3 With R 5 Condensed to form CH2, CH2-CH2 or CH2OCH2.

30. A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein Y4 is CR 3 R 4 or CF2, where R 4 is hydrogen or CH3 and R 3 It is hydrogen, F, OH or CH3.

31. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Y3 is CR 4 R 5 , where R 4 is hydrogen or CH3 and R 5 It is hydrogen or CH3.

32. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein Y5 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 are independently selected from H and CH3; and Y6 is CR 13 R 14 , CR 13 R 14 -CH2 or CH2-CR 13 R 14 , where R 13 and R 14 Independently selected from H and CH3.

33. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein Y5 is CH2 or CH2-CH2 and Y6 is CH2 or CH2-CH2.

34. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein Y5 and Y6 are CH2.

35. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C3 alkyl, which is optionally substituted by one, two, three or four substituents independently selected from 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.

36. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: It is optionally substituted with one, two, three or four substituents independently selected from 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 by one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * represents the point of connection to Y.

37. A compound according to claim 36 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: It is optionally substituted with one, two, three or four substituents independently selected from 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 by one or more substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN, wherein * represents the point of connection to Y.

38. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 10 is a 4-6 membered heterocycloalkyl or a 5-6 membered heteroaryl, which is optionally substituted by R 8A Replace or with R 8A Condensed.

39. A compound according to claim 38 or a pharmaceutically acceptable salt thereof, wherein R 10 is a 5-6 membered heteroaryl group, which is optionally substituted by R 8A Replace or with R 8A Condensed.

40. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 10 independently selected from cyclopropane, cyclobutane, cyclopropane, pyrrolidine, thiazole, pyrazole, triazole, phenyl, pyridine, pyrazine and pyridazine, which are optionally replaced by R 8A Replace or with R 8A Condensed.

41. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 10 and R 8A Optionally substituted with one, two or three substituents independently selected from halo, OH, CN, -OC1-C4 alkyl, -OC3-C5 cycloalkyl and -Z4-R 12 , wherein the C1-C4 alkyl and C3-C5 cycloalkyl are optionally substituted with one, two or three substituents independently selected from halo, OH, OCH3, methylamine, N,N-dimethylamine and CN.

42. A compound according to claim 41 or a pharmaceutically acceptable salt thereof, wherein R 10 and R 8A Optionally substituted with one or two substituents independently selected from F, Cl, CN, C1-C3 alkyl, CH2F, CHF2, CF3, -OCH3, -C(O)NH2 and -S(O)2CH3.

43. A compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein R 10 and R 8A Optionally substituted with one or two substituents independently selected from F, Cl, C1-C3 alkyl, CH2F, CHF2, CF3 and -OCH3.

44. A compound according to claim 1 selected from: or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

50. The method according to any one of claims 46-49, wherein the cancer is a FGFR2-related cancer.

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

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

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

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

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

56. A compound for use in treating cancer according to any one of claims 51 to 55, or a pharmaceutically acceptable salt thereof, wherein the cancer is a FGFR2-related cancer.

57. Use of a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.

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