Bicyclic compound and application thereof

Abstract

The invention discloses a bicyclic compound serving as an FGFR (fibroblast growth factor receptor) inhibitor, and particularly discloses a compound as shown in a formula (I) or a stereoisomer or pharmaceutically acceptable salt of the compound, a pharmaceutical composition containing the compound or the stereoisomer or the pharmaceutically acceptable salt, and application of the compound or the stereoisomer or the pharmaceutically acceptable salt in preparation of medicines for treating cancers. # imgabs0 #

Description

Bicyclic compounds and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202211725809.1 filed with the State Intellectual Property Office of China on December 30, 2022 and Chinese Patent Application No. 202310485808.2 filed with the State Intellectual Property Office of China on April 28, 2023, and the contents disclosed in the above applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology, and specifically relates to bicyclic compounds of FGFR inhibitors and applications thereof. Background Art

[0004] FGFR (Fibroblast Growth Factor Receptor) is a transmembrane receptor tyrosine kinase family consisting of four main members: FGFR1, 2, 3, and 4. Binding of FGFR to its ligand, FGF (Fibroblast growth factor), causes receptor dimerization, which in turn leads to phosphorylation of tyrosine residues in the kinase domain, activating the receptor. Subsequently, activated FGFR further activates downstream signaling pathways such as RAS / RAF, PI3K / AKT, JAK / STAT, and PLCγ, regulating multiple processes including cell proliferation, apoptosis, migration, repair of damaged tissues, and angiogenesis. Under normal physiological conditions, the FGFR signaling pathway is tightly regulated and weakly activated. However, its overactivation often leads to the development and progression of tumors. The molecular mechanisms of abnormal FGFR activation include 1) gene amplification; 2) gene mutation; and 3) gene fusion caused by gene translocation. For example, FGFR2 gene amplification occurs in gastric cancer (5-10%), FGFR2 gene translocation occurs in intrahepatic bile duct carcinoma (14%), and FGFR2 gene mutation occurs in endometrial cancer (12-14%). FGFR3 gene abnormalities are most commonly seen in bladder cancer, including gene mutations (60-80% of non-muscle invasive bladder cancer and 15-20% of muscle invasive bladder cancer), gene translocations (3-6%), and gene amplification (the incidence has not been reported). Myeloma is the second most common disease, with 15-20% of myeloma patients harboring FGFR3 gene translocations. Some of these FGFR gene abnormalities have been shown to be associated with poor patient prognosis.

[0005] Given the importance of the FGFR signaling pathway in tumor treatment, targeted therapy targeting the FGFR signaling pathway has become a research hotspot in the field of tumor treatment in recent years.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0008] in,

[0009] X1 and X2 are independently selected from N or C;

[0010] Y1 and Y2 are independently selected from N or CR 6 ;

[0011] Z is selected from O, S, NH or a bond;

[0012] R 6 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0013] R 1 Selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl is optionally replaced by R 1a replace;

[0014] R 1a Selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 Aryl or 5-6 membered heteroaryl, the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C6-C 10 Aryl or 5-6 membered heteroaryl is optionally replaced by R 1b replace;

[0015] R 1b is selected from halogen, OH, C1-C6 alkyl or C1-C6 alkoxy;

[0016] R 2 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally replaced by R 2a replace;

[0017] R2a is selected from halogen, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy, wherein the OH, NH2, C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0018] R 3 is selected from H, CN, OH, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0019] Ring A is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0020] Ring C is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl or not present, the C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace;

[0021] Every R a 、R c independently selected from halogen, CN, OH, NH2, -S(=O)-C1-C4 alkyl, -S(=O)2-C1-C4 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl;

[0022] L is selected from a bond, -CH2-, -C(=O)-, -NHC(=O)-, C3-C6 carbocycle, 4-6 membered heterocycle, C6-C 10 Aromatic ring or 5-6 membered heteroaromatic ring;

[0023] W is selected from H, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, 4-6 membered heterocyclic group, CN, -C(=O)CR 4 =C(R 5 )2, -C(=O)C≡CR 5 、-NHC(=O)CR 4 =C(R 5 )2, -NHC(=O)C≡CR 5 、-S(=O)CR 4 =C(R 5 )2、-S(=O)2CR 4 =C(R 5)2, -NHS(=O)CR 4 =C(R 5 )2 or -NHS(=O)2CR 4 =C(R 5 )2;

[0024] R 4 Selected from H, CN, halogen or C1-C6 alkyl;

[0025] Every R 5 independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl is optionally replaced by R 5a replace;

[0026] R 5a Independently selected from halogen, CN, OH, NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C3-C8 cycloalkyl or 4-6 membered heterocyclyl;

[0027] R 8 、R 9 、R 10 Independently selected from H, halogen, OH, NH2, =O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0028] R 11 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or absent;

[0029] or R 8 、R 11 The atoms to which it is attached together form a C3-C6 cycloalkyl group;

[0030] One or more hydrogen atoms of the compound are optionally deuterium atoms.

[0031] In some embodiments, in Formula (I),

[0032] X1 and X2 are independently selected from N or C;

[0033] Y1 and Y2 are independently selected from N or CR 6 ;

[0034] Z is selected from O, S, NH or a bond;

[0035] R 6 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0036] R 1Selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl is optionally replaced by R 1a replace;

[0037] R 1a is selected from halogen, OH, C1-C6 alkyl or C1-C6 alkoxy;

[0038] R 2 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally replaced by R 2a replace;

[0039] R 2a is selected from halogen, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy, wherein the OH, NH2, C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0040] R 3 is selected from H, CN, OH, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0041] Ring A is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0042] Ring C is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl or not present, the C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace;

[0043] Every R a 、R cindependently selected from halogen, CN, OH, NH2, -S(=O)-C1-C4 alkyl, -S(=O)2-C1-C4 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl;

[0044] L is selected from a bond, -CH2-, -C(=O)-, -NHC(=O)-, C3-C6 carbocycle, 4-6 membered heterocycle, C6-C 10 Aromatic ring or 5-6 membered heteroaromatic ring;

[0045] W is selected from C1-C6 alkyl, -S(=O)2C1-C6 alkyl, CN, -C(=O)CR 4 =C(R 5 )2, -C(=O)C≡CR 5 、-NHC(=O)CR 4 =C(R 5 )2, -NHC(=O)C≡CR 5 、-S(=O)CR 4 =C(R 5 )2、-S(=O)2CR 4 =C(R 5 )2, -NHS(=O)CR 4 =C(R 5 )2 or -NHS(=O)2CR 4 =C(R 5 )2;

[0046] R 4 Selected from H, CN, halogen or C1-C6 alkyl;

[0047] Every R 5 independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl is optionally replaced by R 5a replace;

[0048] R 5a Independently selected from halogen, CN, OH, NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C3-C8 cycloalkyl or 4-6 membered heterocyclyl;

[0049] R 8 、R 9 、R 10 Independently selected from H, halogen, OH, NH2, =O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0050] R11 For H.

[0051] In some embodiments, in Formula (I),

[0052] X1 and X2 are independently selected from N or C;

[0053] Y1 and Y2 are independently selected from N or CR 6 ;

[0054] Z is selected from O, S, NH or a bond;

[0055] R 6 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl or C3-C6 cycloalkyl;

[0056] R 1 Selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl is optionally replaced by R 1a replace;

[0057] R 1a is selected from halogen, OH, C1-C6 alkyl or C1-C6 alkoxy;

[0058] R 2 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally replaced by R 2a replace;

[0059] R 2a is selected from halogen, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy, wherein the OH, NH2, C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0060] R 3 is selected from H, CN, OH, halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0061] Ring A is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace;

[0062] Ring C is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl or not present, the C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace;

[0063] Every R a 、R c independently selected from halogen, CN, OH, NH2, -S(=O)-C1-C4 alkyl, -S(=O)2-C1-C4 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl;

[0064] L is selected from a bond, -CH2-, -C(=O)-, -NHC(=O)-, C3-C6 carbocycle, 4-6 membered heterocycle, C6-C 10 Aromatic ring or 5-6 membered heteroaromatic ring;

[0065] W is selected from CN, -C(=O)CR 4 =C(R 5 )2, -C(=O)C≡CR 5 、-NHC(=O)CR 4 =C(R 5 )2, -NHC(=O)C≡CR 5 、-S(=O)CR 4 =C(R 5 )2、-S(=O)2CR 4 =C(R 5 )2, -NHS(=O)CR 4 =C(R 5 )2 or -NHS(=O)2CR 4 =C(R 5 )2;

[0066] R 4 Selected from H, CN, halogen or C1-C6 alkyl;

[0067] Every R 5independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl is optionally replaced by R 5a replace;

[0068] R 5a Independently selected from halogen, CN, OH, NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C3-C8 cycloalkyl or 4-6 membered heterocyclyl;

[0069] R 8 、R 9 、R 10 All are H;

[0070] R 11 is H. In some embodiments, at least one of X1 or X2 is N.

[0071] In some embodiments, X1 is N and X2 is C. In some embodiments, X1 is C and X2 is N.

[0072] In some embodiments, at least one of Y1 or Y2 is N.

[0073] In some embodiments, Y1 is N, Y2 is CR 6 In some embodiments, Y1 is CR 6 , Y2 is N.

[0074] In some embodiments, Z is O.

[0075] In some embodiments, R 6 Selected from H, C1-C6 alkyl or C3-C6 cycloalkyl.

[0076] In some embodiments, R 6 Selected from halogen, C1-C6 alkyl or C3-C6 cycloalkyl.

[0077] In some embodiments, R 6 Selected from C1-C6 alkyl or C3-C6 cycloalkyl.

[0078] In some embodiments, R 6 is selected from Cl, methyl or cyclopropyl.

[0079] In some embodiments, R 1is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C6 cycloalkyl is optionally replaced by R 1a replace.

[0080] In some embodiments, R 1 is selected from CN, OH, halogen, C1-C6 alkyl, C2-C6 alkynyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally replaced by R 1a replace.

[0081] In some embodiments, R 1 is selected from CN, halogen or C2-C6 alkynyl, the C2-C6 alkynyl being optionally replaced by R 1a replace.

[0082] In some embodiments, R 1 is selected from CN, Cl or propynyl.

[0083] In some embodiments, R 1 Selected from CN or halogen.

[0084] In some embodiments, R 1a is selected from halogen, OH, C1-C6 alkyl or C1-C6 alkoxy.

[0085] In some embodiments, R 2 is selected from CN, OH, NH2, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 2a replace.

[0086] In some embodiments, R 2 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R 2a replace.

[0087] In some embodiments, R 2 is selected from methyl, said methyl being optionally replaced by R 2a replace.

[0088] In some embodiments, R 2 Selected from methyl or CH2OH.

[0089] In some embodiments, R 2ais selected from halogen, OH, C1-C6 alkyl or C1-C6 alkoxy, wherein the OH, C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl.

[0090] In some embodiments, R 3 For H.

[0091] In some embodiments, R 2 and R 3 One of them is H.

[0092] In some embodiments, R 2 is methyl, R 3 is H. In some embodiments, R 2 is CH2OH, R 3 For H.

[0093] In some embodiments, Ring A is selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace.

[0094] In some embodiments, Ring A is selected from 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally replaced by R a replace.

[0095] In some embodiments, Ring A is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally replaced by R a replace.

[0096] In some embodiments, the 5-10 membered heteroaryl or 5-6 membered heteroaryl each independently contains 1, 2, or 3 heteroatoms independently selected from N, O, or S.

[0097] In some embodiments, the 5-10 membered heteroaryl or 5-6 membered heteroaryl each independently contains 1 N atom. In some embodiments, Ring A is pyridinyl, which is optionally replaced by R a replace.

[0098] In some embodiments, Ring A is 2-pyridyl, which is optionally replaced by R a replace.

[0099] In some embodiments, R a It is a halogen.

[0100] In some embodiments, R a For F.

[0101] In some embodiments, Ring A is

[0102] In some embodiments, Ring C is selected from a 4-10 membered heterocyclyl group or is absent, wherein the 4-10 membered heterocyclyl group is optionally replaced by R c replace.

[0103] In some embodiments, Ring C is selected from a 4-10 membered heterocyclyl group, wherein the 4-10 membered heterocyclyl group is optionally replaced by R c replace.

[0104] In some embodiments, Ring C is selected from a 4-7 membered heterocyclyl group, wherein the 4-7 membered heterocyclyl group is optionally replaced by R c replace.

[0105] In some embodiments, Ring C is selected from a 4-6 membered heterocyclyl group, wherein the 4-6 membered heterocyclyl group is optionally replaced by R c replace.

[0106] In some embodiments, the 4-10 membered heterocyclyl, the 4-7 membered heterocyclyl, or the 4-6 membered heterocyclyl each contains 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, the 4-10 membered heterocyclyl, the 4-7 membered heterocyclyl, or the 4-6 membered heterocyclyl each contains 1, 2, or 3 N or O atoms. In some embodiments, the 4-10 membered heterocyclyl, the 4-7 membered heterocyclyl, or the 4-6 membered heterocyclyl each contains 1 N or O atom.

[0107] In some embodiments, Ring C is selected from azetidinyl, piperidinyl, tetrahydropyrrolyl, said azetidinyl, piperidinyl or tetrahydropyrrolyl being optionally replaced by R c In some embodiments, ring C is selected from described Optionally R c replace.

[0108] In some embodiments, R c Selected from halogen or C1-C6 alkyl.

[0109] In some embodiments, R c is selected from F or methyl.

[0110] In some embodiments, each R a 、R c Independently selected from halogen, CN, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl.

[0111] In some embodiments, each Ra 、R c In some embodiments, W is selected from C1-C6 alkyl, -S(=O)2C1-C6 alkyl, CN, -C(=O)CR 4 =C(R 5 )2, -C(=O)C≡CR 5 、-NHC(=O)CR 4 =C(R 5 )2, -NHC(=O)C≡CR 5 、-S(=O)CR 4 =C(R 5 )2、-S(=O)2CR 4 =C(R 5 )2, -NHS(=O)CR 4 =C(R 5 )2 or -NHS(=O)2CR 4 =C(R 5 )2.

[0112] In some embodiments, W is selected from CN, -C(=O)CR 4 =C(R 5 )2, -C(=O)C≡CR 5 、-NHC(=O)CR 4 =C(R 5 )2, -NHC(=O)C≡CR 5 、-S(=O)CR 4 =C(R 5 )2、-S(=O)2CR 4 =C(R 5 )2, -NHS(=O)CR 4 =C(R 5 )2 or -NHS(=O)2CR 4 =C(R 5 )2.

[0113] In some embodiments, W is selected from H, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, 4-6 membered heterocyclyl, CN, -C(=O)CR 4 =C(R 5 )2 or -C(=O)C≡CR 5 .

[0114] In some embodiments, W is selected from C1-C6 alkyl, -S(=O)2C1-C6 alkyl, CN, -C(=O)CR 4 =C(R 5 )2 or -C(=O)C≡CR 5 .

[0115] In some embodiments, W is selected from CN or -C(=O)CR 4 =C(R 5 )2.

[0116] In some embodiments, W is selected from H, CH3, CH(CH3)2, -S(=O)2CH3, CN, -C(=O)CH=CH2 or -C(=O)C≡CCH3.

[0117] In some embodiments, W is selected from CH3, CH(CH3)2, -S(=O)2CH3, CN, -C(=O)CH=CH2, or -C(=O)C≡CCH3.

[0118] In some embodiments, W is selected from CN or -C(=O)CH=CH2.

[0119] In some embodiments, W is attached to a N atom on ring C.

[0120] In some embodiments, Ring C is And W is connected to the N atom on the ring C.

[0121] In some embodiments, ring C and W together form a structural fragment

[0122] In some embodiments, L is selected from a bond or -C(=O)-.

[0123] In some embodiments, L is a bond.

[0124] In some embodiments, each R 5 independently selected from H, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 5a replace.

[0125] In some embodiments, each R 5 Independently selected from H or C1-C6 alkyl.

[0126] In some embodiments, each R 5 Independently selected from H or CH3.

[0127] In some embodiments, each R 4 is H. In some embodiments, R 5a Independently selected from halogen, CN, OH, NH2, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)2.

[0128] In some embodiments, R 8 、R 9 、R 10 Independently selected from H, =O, C1-C6 alkyl or C3-C6 cycloalkyl.

[0129] In some embodiments, R 8 、R 10 R is independently selected from H, =O, C1-C6 alkyl or C3-C6 cycloalkyl, 9 For H.

[0130] In some embodiments, R 8 、R 9 、R 10 Independently selected from H or ═O.

[0131] In some embodiments, R 8 Selected from =O, R 11 Does not exist, R 9 、R 10 Both are H.

[0132] In some embodiments, R 8 、R 9 、R 10 Both are H.

[0133] In some embodiments, R 11 Selected from H or absent.

[0134] In some embodiments, R 11 H, R 9 、R 10 Both are H.

[0135] In some embodiments, R 8 、R 11 The atoms to which it is attached together form a cyclopropyl group.

[0136] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (II) or its stereoisomer or its pharmaceutically acceptable salt:

[0137] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, and W are as defined above.

[0138] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (III) or its stereoisomer or its pharmaceutically acceptable salt:

[0139] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, and W are as defined above.

[0140] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (IV-b) or its stereoisomer or its pharmaceutically acceptable salt:

[0141] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, W, R 8 、R 9 、R 10 、R 11 As defined above.

[0142] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (IV-a) or its stereoisomer or its pharmaceutically acceptable salt:

[0143] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, W, R 8 、R 9 、R 10 As defined above.

[0144] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (IV) or its stereoisomer or its pharmaceutically acceptable salt:

[0145] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, and W are as defined above.

[0146] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (V) or its stereoisomer or its pharmaceutically acceptable salt:

[0147] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, and W are as defined above.

[0148] In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:

[0149] Furthermore, the present disclosure also provides a pharmaceutical composition comprising a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0150] Furthermore, the present disclosure relates to the use of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a disease mediated by FGFR.

[0151] Furthermore, the present disclosure relates to the use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating diseases mediated by FGFR.

[0152] Furthermore, the present disclosure relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preventing or treating a disease mediated by FGFR.

[0153] The present disclosure also relates to a method for preventing or treating a disease mediated by FGFR, which comprises administering to an individual a therapeutically effective dose of a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a pharmaceutical preparation comprising a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0154] Preferably, the disease mediated by FGFR is selected from diseases mediated by FGFR2 or FGFR3.

[0155] Preferably, the disease mediated by FGFR is selected from diseases mediated by FGFR3.

[0156] Furthermore, the disease mediated by FGFR is selected from cancer.

[0157] In some embodiments, the cancer is, for example, a solid tumor. In some embodiments, the cancer is, for example, gastric cancer and bladder cancer.

[0158] The compounds disclosed herein have one or more of the following beneficial effects:

[0159] The heterocyclic compound or stereoisomer thereof or pharmaceutically acceptable salt provided by the present disclosure can selectively inhibit FGFR protein, such as FGFR2 or FGFR3, and has a killing effect on related tumor cells;

[0160] The heterocyclic compounds, stereoisomers, or pharmaceutically acceptable salts thereof provided herein have good inhibitory activity against FGFR, particularly FGFR3. Compared to FGFR1 and / or FGFR2, the heterocyclic compounds, stereoisomers, or pharmaceutically acceptable salts provided herein have higher selectivity for FGFR3.

[0161] The heterocyclic compound provided by the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has good inhibitory activity against tumor cells (eg, JMSU-1 cells, SNU16 cells, RT112 cells).

[0162] The heterocyclic compounds provided by the present disclosure, or stereoisomers thereof, or pharmaceutically acceptable salts thereof have good pharmacokinetic properties, for example, good plasma clearance.

[0163] Definitions and Explanations of Terms

[0164] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0165] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge and dotted wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0166] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0167] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0168] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0169] Indicates the attachment site on a substituent.

[0170] In the ring Indicates that the corresponding ring is aromatic.

[0171] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0172] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0173] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0174] In the embodiments of the present disclosure, the substituent "X" is optionally substituted by a substituent "Y", which means that the substituent "X" is optionally substituted by one or more (e.g., 1, 2, 3 or 4) substituents "Y", and the options of each substituent "Y" are independent of each other. For example, "the C1-C6 alkyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally substituted by R 1a "Substituted" means that the C1-C6 alkyl, C2-C6 alkynyl or C3-C6 cycloalkyl are each optionally substituted with one or more R 1a Replace, and each R 1a The options are independent.

[0175] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0176] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. L in 1 When selected from "C1-C3 alkylene-O", L 1 You can connect rings Q and R from left to right. 1 Constitute "ring Q-C1-C3 alkylene-OR 1 ", you can also connect rings Q and R from right to left 1 Constitute the "ring QO-C1-C3 alkylene-R 1”.

[0177] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R 5 Substitution can occur at any position on the benzene ring.

[0178] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0179] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight or branched, and typically has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. 10 The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl , 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" may be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" may be understood to mean a straight-chain or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0180] The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl groups, typically having 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6"Haloalkyl" refers to a C 1-6 Alkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, and the like.

[0181] The term "alkoxy" refers to a radical derived from a straight-chain or branched alcohol group by the loss of a hydrogen atom from a hydroxyl group, and can be understood as "alkyloxy" or "alkyl-O-," typically having 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-." The "C1-C6 alkoxy" group may further include a "C1-C3 alkoxy group."

[0182] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond, typically having 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. 10 "Alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 "Alkenyl" is preferably "C2-C6 alkenyl", further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0183] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. 10 "Alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 "Alkynyl" may include "C2-C6 alkynyl". "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、-CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 The term "alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH).

[0184] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring, a 3- to 8-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, a 5- to 6-membered ring, or a 3- to 6-membered ring. The term "C3-C 10 "Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl" or "C3-C8 cycloalkyl". The term "C3-C6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0185] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spirocyclic or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "3-10 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in its ring atoms. The term "4-10 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned ring atoms. The term "4-10 membered heterocyclyl" may contain 1, 2 or 3 heteroatoms independently selected from N, O or S. "4-10 membered heterocyclyl" includes "4-9 membered heterocyclyl", "6-9 membered heterocyclyl", "4-7 membered heterocyclyl" or "4-6 membered heterocyclyl", each of which independently contains 1, 2 or 3 heteroatoms independently selected from N, O or S, or each of which independently contains 1, 2 or 3 N atoms. “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic group include but are not limited to diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Examples of heterocyclic groups include but are not limited to Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7 membered heterocyclic group, specific examples of which include but are not limited to dihydroisoquinolinyl. "4-10 membered heterocyclic group" may include "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc., and "4-7 membered heterocyclic group" may further include "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0186] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 20 "Aryl" is understood to be an aromatic radical having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 The term "C6-C 20 "Aryl" may contain "C6-C 10 Aryl".

[0187] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having aromatic character, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1, 2 or 3, preferably 1-2, heteroatoms independently selected from N, O and S.

[0188] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine or iodine. The term "treating" means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0189] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0190] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0191] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0192] The term "therapeutically effective amount" means

[0193] An amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.

[0194] The amount of a compound of the disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0195] The term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal can be a human.

[0196] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0197] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid addition salts or base addition salts, including salts formed between a compound and an inorganic acid or organic acid, and salts formed between a compound and an inorganic base or an organic base.

[0198] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0199] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0200] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0201] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0202] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0203] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0204] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0205] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0206] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0207] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0208] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0209] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.01 mg / kg to 200 mg / kg body weight per day in single or divided doses. DETAILED DESCRIPTION

[0210] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and used without further purification.

[0211] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0212] Unless otherwise stated, % refers to wt%.

[0213] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0214] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6(ppm). NMR measurements are performed in solvents such as deuterated dimethyl sulfoxide, deuterated chloroform, and deuterated methanol, with tetramethylsilane (TMS) as the internal standard. "IC50" refers to the inhibitory concentration (IC50), which is the concentration at which half of the maximum inhibitory effect is achieved.

[0215] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio is the volume ratio of each solvent. For example, "the elution phase is a petroleum ether mixed solvent containing 16 to 18% ethyl acetate" means that during the elution process, the volume ratio of ethyl acetate to petroleum ether in the mixed eluent is 16:84 to 18:82; or the elution phase is a "water mixed solvent containing 5 to 95% acetonitrile" means that during the elution process, the volume ratio of acetonitrile to water in the mixed eluent is 5:95 to 95:5.

[0216] Abbreviations:

[0217] PD-132: dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II); DME: ethylene glycol dimethyl ether; TEA: triethylamine; MeCN: acetonitrile; Boc2O: di-tert-butyl dicarbonate; DMF: N,N-dimethylformamide; DCM: dichloromethane; Dioxane: dioxane; NaBH3CN: sodium cyanoborohydride; MeOH: methanol; NaOMe: sodium methoxide; DMA: N,N-dimethylformamide; NDM : dodecylmercaptan; DIAD: diisopropyl azodicarboxylate; THF: tetrahydrofuran; B2Pin2: bis(diphenylphosphino)ferrocenepalladium(II) dichloride; Pd(dppf)Cl2: bis(diphenylphosphino)ferrocenepalladium(II) dichloride; KOAc: potassium acetate or potassium acetate; NCS: N-chlorosuccinimide; PPTS: pyridine p-toluenesulfonate; CHCl3: chloroform; DIEA or DIPEA: N,N-diisopropylethylamine; n-BuOH: n-butanol; NIS : N-iodosuccinimide; Xphos: 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Xphos-Pd-G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II); DCE: 1,2-dichloroethane; MsCl: methanesulfonyl chloride; HATU: 2-(7-azabenzene) 4: tetrakis(triphenylphosphine)palladium; TBAF: tetrabutylammonium fluoride; CuI: cuprous iodide; Toluene: toluene; TMS: trimethylsilyl; TBS: tert-butyldimethylsilyl; PPh3: triphenylphosphine; TFA: trifluoroacetic acid; Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1-biphenyl; DMSO: dimethyl sulfoxide.

[0218] Intermediate 1

[0219] Step 1: Synthesis of 3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-methyl tert-butyl ester (A3)

[0220] 3-Bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-methyl tert-butyl ester A1 (10 g, 33.1 mmol), potassium carbonate (4.6 g, 33.1 mmol), dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (1.1 g, 1.65 mmol), trimethylboroxane A2 (8.30 g, 66.2 mmol) were dissolved in ethylene glycol dimethyl ether (10 mL). The reaction solution was stirred at 60 ° C for 4 hours. After the reaction was completed, water (20 mL) was added thereto, and the mixture was extracted with ethyl acetate (10 mL * 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 12g Flash silica gel column, gradient 0-15% tetrahydrofuran / petroleum ether, flow rate 60 mL / min) to give the title compound A3 (7 g, 2.94 mmol, yield: 89%).

[0221] 1H NMR (400MHz, DMSO-d6) δ = 7.24 (s, 1H), 4.49 (s, 2H), 4.03 (t, J = 5.4Hz, 2H), 3.77 (t, J = 5.4Hz, 2H), 1.93 (s, 3H), 1.44 (s, 9H)

[0222] MS m / z(ESI):=238.2[M+H] +

[0223] Step 2: Synthesis of 2-bromo-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-methyl tert-butyl ester (Int-1)

[0224] Compound A3 (2 g, 8.48 mmol) and ferric chloride (683.5 mg, 7 mmol) were dissolved in acetonitrile (35 mL). The reaction solution was stirred at 0 ° C for 0.5 hours, and liquid bromine (6.7 g, 42.1 mmol) was slowly added dropwise thereto. After reacting for 1 hour, an aqueous solution of sodium sulfite (20 mL) was added thereto. After stirring for 0.5 hours, triethylamine (10 mL) and di-tert-butyl dicarbonate (10 mL) were added thereto. After the reaction was completed for 1 hour, water (50 mL) was added thereto, and the mixture was extracted with ethyl acetate (50 mL * 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 12g Flash silica gel column, gradient 0-10% tetrahydrofuran / petroleum ether, flow rate 60 mL / min) to give the title compound Int-1 (979 mg, 3.1 mmol, yield: 36%). 1 H NMR (400MHz, DMSO-d6) δ = 4.50 (s, 2H), 4.03 (t, J = 5.5Hz, 2H), 3.84–3.75 (m, 2H), 1.87 (s, 3H), 1.48–1.41 (m, 9H)

[0225] MS m / z(ESI):=315.9 / 317.9[M+H] +

[0226] Intermediate 2

[0227] Step 1: Synthesis of ethyl 3-bromo-1-(2-(tert-butoxycarbonylamino)ethyl)-4-methylpyrazole-5-carboxylate (B3)

[0228] 3-Bromo-4-methyl-1H-pyrazole-5-carboxylic acid ethyl ester B1 (2.31 g, 10 mmol), N-Boc-bromoethylamine B2 (2.68 g, 12 mmol), and cesium carbonate (3.9 g, 12 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was stirred at 25 ° C for 3 hours. After the reaction was completed, water (50 mL) was added thereto, and ethyl acetate (50 mL * 3 times) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-40% tetrahydrofuran / petroleum ether, flow rate: 80 mL / min) to obtain the title compound B3 (2.75 g, 7.32 mmol, yield: 73%). MS m / z (ESI): = 376.1 [M+H]+

[0229] Step 2: Synthesis of ethyl 1-(2-aminoethyl)-3-bromo-4-methylpyrazole-5-carboxylate hydrochloride (B4)

[0230] Compound B3 (2.75 g, 7.32 mmol) was dissolved in dichloromethane (10 mL). Dioxane hydrochloride (4 M, 10 mL) was added at room temperature. The reaction mixture was stirred at 25°C for 6 hours. After completion of the reaction, the organic phase was filtered and concentrated under reduced pressure (0.01 MPa) to remove the solvent, yielding the title compound B4 (2.26 g, 7.31 mmol, yield: 99%).

[0231] MS m / z (ESI): = 276.3 [M+H] +

[0232] Step 3: Synthesis of ethyl 3-bromo-1-(2-(1-(tert-butoxycarbonyl)azetidine-3-amino)ethyl)-4-methylpyrazole-5-carboxylate (B6)

[0233] Compound B4 (1 g, 3.2 mmol), 1-Boc-3-azetidinone B5 (1.09 g, 6.4 mmol), and sodium cyanoborohydride (0.65 g, 9.6 mmol) were dissolved in methanol (10 mL). The reaction solution was stirred at 25 ° C for 16 hours. After the reaction was completed, water (50 mL) was added thereto, and ethyl acetate (50 mL * 3 times) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-40% tetrahydrofuran / petroleum ether, flow rate: 80 mL / min) to give the title compound B6 (1.07 g, 2.5 mmol, yield: 78%).

[0234] MS m / z(ESI):=431.2[M+H] +

[0235] Step 4: Synthesis of tert-butyl 3-(2-bromo-3-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H-yl)azetidine-1-carboxylate (Int-2)

[0236] Compound B6 (1.07 g, 2.5 mmol) and sodium methoxide (0.45 g, 7.5 mmol) were dissolved in methanol (10 mL). The reaction solution was stirred at 25 ° C for 6 hours. After the reaction was completed, water (50 mL) was added thereto, and the mixture was extracted with ethyl acetate (50 mL * 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-60% tetrahydrofuran / petroleum ether, flow rate 80 mL / min) to give the title compound Int-2 (0.81 g, 2.1 mmol, yield: 84%).

[0237] MS m / z(ESI):=385.3[M+H] +

[0238] Intermediate 3

[0239] Step 1: Synthesis of 6-bromopyrazolo[1,5-a]pyridin-4-ol (C2)

[0240] Compound C1 (25 g, 110.10 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (130 mL). A sodium hydroxide (4.40 g, 110.10 mmol, 1.0 eq) / water (8 mL) solution was added. The reaction system was heated to 30°C, followed by the addition of dodecylmercaptan (33.43 g, 165.16 mmol, 1.5 eq). The mixture was stirred at 60°C for 6 hours. After completion of the reaction, the reaction mixture was diluted with water (300 mL), and aqueous hydrochloric acid was added until the pH was <7. The residue was then filtered to obtain a residue. The filtrate was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a concentrate. The concentrate and the filter residue were purified by silica gel column (eluting phase was a mixed solvent of petroleum ether containing 30-50% tetrahydrofuran) to give the title compound 6-bromopyrazolo[1,5-a]pyridine-4-ol C2 (20 g, 93.88 mmol, yield: 85%) as a white solid.

[0241] MS (ESI+) m / z = 213.0 [M+H] + .

[0242] 1 H NMR (400MHz, DMSO-d6) δ=11.06(s,1H),8.55(s,1H),7.91(d,J=2.2Hz,1H),6.69(d,J=1.7Hz,1H),6.56(d,J=1.1Hz,1H)

[0243] Step 2: Synthesis of 6-bromo-4-(2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine (C4)

[0244] Compound C2 (10 g, 46.94 mmol, 1.0 eq), compound C3 (15.29 g, 56.33 mmol, 1.2 eq), and triphenylphosphine (18.47 g, 70.41 mmol, 1.5 eq) were dissolved in tetrahydrofuran (200 mL). The reaction system was cooled to 0°C, and diisopropyl azodicarboxylate (11.39 g, 56.33 mmol, 1.2 eq) was added. The mixture was stirred at 0°C for 6 hours. After the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain a concentrate. The concentrate was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-5% tetrahydrofuran) to obtain the title compound C4 (9 g, 19.30 mmol, yield: 41%) as a white solid.

[0245] MS (ESI+) m / z = 466.2 [M+H] + .

[0246] 1 H NMR (400MHz, DMSO-d6) δ = 8.66 (s, 1H), 8.62 (d, J = 2.9Hz, 1H), 7.99 (d, J = 2.2Hz, 1H), 7.77 (dt, J = 3.0, 8.7Hz, 1H), 7.63 (dd,J=4.6,8.8Hz,1H),6.74(s,2H),5.76(t,J=4.8Hz,1H),4.14–4.10(m,2H),0.79(s,9H),0.03(s,3H),-0.03(s,3H)

[0247] Step 3: Synthesis of 4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (C5)

[0248] Compound C4 (9 g, 19.30 mmol, 1.0 eq), bis(trifluoromethyl)benzoyl borate (14.70 g, 57.89 mmol, 3 eq), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (700 mg, 964.80 μmol, 0.05 eq), and potassium acetate (3.79 g, 38.59 mmol, 2 eq) were mixed in dioxane (90 mL). The mixture was stirred at 70°C under a nitrogen atmosphere for 6 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-15% tetrahydrofuran) to obtain the crude title compound C5 (10.5 g, 19 mmol, yield: 98%) as a red colloid.

[0249] MS (ESI+) m / z = 513.3 [M+H] +

[0250] 1 H NMR (400MHz, DMSO-d6) δ=8.62(d,J=2.9Hz,1H),8.35(s,1H),8.05(d,J=2.0Hz,1H),7.74(dt,J=2.9,8.7Hz,1H),7.57(dd,J=4.5,8.7Hz,1H ),6.72(d,J=2.2Hz,1H),6.57(s,1H),5.68–5.64(m,1H),4.16–4.05(m,2H),1.28(d,J=2.9Hz,12H),0.80(s,9H),0.04(s,3H),-0.03(s,3H)

[0251] Step 4: Synthesis of 4-(2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (Int-3)

[0252] Compound C5 (10 g, 19.47 mmol, 1.0 eq), N-chlorosuccinimide (2.60 g, 19.47 mmol, 1.0 eq), and pyridine p-toluenesulfonate (489.40 mg, 1.95 mmol, 0.1 eq) were dissolved in chloroform (150 mL), and the mixture was stirred at 40°C for 5 hours. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain a concentrate, which was diluted with ethyl acetate (500 mL) and washed with water (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried in petroleum ether (100 mL) at 20°C for 0.5 hours to obtain the title compound Int-3 (9 g, 16.43 mmol, yield: 84%) as a gray solid.

[0253] MS (ESI+) m / z = 548.3 [M+H] +

[0254] 1 H NMR (400MHz, DMSO-d6) δ=8.62(d,J=2.9Hz,1H),8.30(s,1H),8.15(s,1H),7.79(dt,J=2.4,8.9Hz,1H),7.65(dd,J=4.4,8.6 Hz,1H),6.69(s,1H),5.71(dd,J=2.9,5.5Hz,1H),4.18–4.03(m,2H),1.29(s,12H),0.76(s,9H),-0.02(s,3H),-0.11(s,3H)

[0255] Intermediate 4

[0256] Step 1: Synthesis of ethyl 3-bromo-1-(2-(1-(tert-butoxycarbonyl)pyrrolidine-3-amino)ethyl)-4-methylpyrazole-5-carboxylate (D2)

[0257] Compound B4 (1 g, 3.2 mmol), 1-tert-butyloxycarbonyl-3-pyrrolidone D1 (1.2 g, 6.4 mmol), and sodium cyanoborohydride (0.65 g, 9.6 mmol) were dissolved in methanol (10 mL). The reaction solution was stirred at 25 ° C for 12 hours. After the reaction was completed, water (50 mL) was added thereto, and the mixture was extracted with ethyl acetate (50 mL * 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-40% tetrahydrofuran / petroleum ether, flow rate 80 mL / min) to give the title compound D2 (1.02 g, 2.3 mmol, yield: 72%).

[0258] MS m / z(ESI):=445.3[M+H] +

[0259] Step 2: Synthesis of tert-butyl 3-(2-bromo-3-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)yl)pyrrolidine-1-carboxylate (Int-4)

[0260] Compound D2 (1.02 g, 2.3 mmol) and sodium methoxide (0.38 g, 7.0 mmol) were dissolved in methanol (10 mL). The reaction solution was stirred at 25 ° C for 6 hours. After the reaction was completed, water (50 mL) was added thereto, and the mixture was extracted with ethyl acetate (50 mL * 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-60% tetrahydrofuran / petroleum ether, flow rate 80 mL / min) to give the title compound Int-4 (0.74 g, 1.85 mmol, yield: 80%).

[0261] MS m / z(ESI):=399.1[M+H] +

[0262] Intermediate 5

[0263] Step 1: Synthesis of ethyl 3-bromo-4-chloropyrazole-5-carboxylate (E2)

[0264] 3-Bromo-1H-pyrazole-5-carboxylic acid ethyl ester E1 (2.18 g, 10 mmol) and N-chlorosuccinimide (1.6 g, 12 mmol) were dissolved in dichloromethane (10 mL). The reaction solution was stirred at 40 ° C for 6 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. Water (50 mL) was added thereto, and ethyl acetate (50 mL * 3 times) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-60% tetrahydrofuran / petroleum ether, flow rate, 80 mL / min) to give the title compound E2 (2.09 g, 8.3 mmol, yield: 83%). MS m / z (ESI): = 252.9 [M+H] +

[0265] Step 2: Synthesis of ethyl 3-bromo-1-(2-(tert-butoxycarbonyl)amino)ethyl)-4-chloro-1H-pyrazole-5-carboxylate (E3)

[0266] Compound E2 (2.01 g, 8.0 mmol), N-Boc-bromoethylamine B2 (2.68 g, 12 mmol), and cesium carbonate (3.9 g, 12 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction solution was stirred at 25 ° C for 3 hours. After the reaction was completed, water (50 mL) was added thereto, and the mixture was extracted with ethyl acetate (50 mL * 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-40% tetrahydrofuran / petroleum ether, flow rate: 80 mL / min) to give the title compound E3 (2.41 g, 6.1 mmol, yield: 76.2%).

[0267] MS m / z(ESI):=396.1[M+H] +

[0268] Step 3: Synthesis of ethyl 1-(2-aminoethyl)-3-bromo-4-chloropyrazole-5-carboxylate hydrochloride (E4)

[0269] Compound E3 (2.41 g, 6.1 mmol) was dissolved in dichloromethane (10 mL). Dioxane hydrochloride (4 M, 10 mL) was added at room temperature. The reaction mixture was stirred at 25°C for 6 hours. After completion of the reaction, the organic phase was filtered and concentrated under reduced pressure (0.01 MPa) to remove the solvent, yielding the title compound E4 (1.95 g, 5.9 mmol, yield: 96%).

[0270] MS m / z(ESI):=296.1[M+H] +

[0271] Step 4: Synthesis of 2-bromo-3-chloro-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)one (E5)

[0272] Compound E4 (1.0 g, 3.01 mmol) and sodium methoxide (0.45 g, 7.5 mmol) were dissolved in methanol (10 mL). The reaction mixture was stirred at 25°C for 6 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent, water (50 mL) was added thereto, and ethyl acetate (50 mL*3 times) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-60% tetrahydrofuran / petroleum ether, flow rate: 80 mL / min) to give the title compound E5 (0.57 g, 2.3 mmol, yield: 76.4%).

[0273] MS m / z(ESI):=250.1[M+H] +

[0274] Step 5: Synthesis of tert-butyl 2-bromo-3-chloro-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (Int-5)

[0275] Compound E5 (0.57 g, 2.3 mmol) was dissolved in tetrahydrofuran (10 mL). Borane tetrahydrofuran (1 M, 10 mL) was added to the reaction solution, and the reaction solution was stirred at 50 ° C for 6 hours. After the reaction, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent, and the residue was dissolved in dichloromethane (20 mL). Boc anhydride (1.0 g, 4.6 mmol) and N, N-diisopropylethylamine (593 mg, 4.6 mmol) were added and stirred at room temperature for 2 hours. After the reaction, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent, and water (50 mL) was added thereto. It was extracted with ethyl acetate (50 mL * 3 times), the organic phases were combined, and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-60% tetrahydrofuran / petroleum ether, flow rate: 80 mL / min) to give the title compound Int-5 (603 mg, 1.8 mmol, yield: 78.2%).

[0276] MS m / z(ESI):=336.1[M+H] +

[0277] Example 1 7-(7-(1-cyanopyrrolidin-3-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 1)

[0278] Step 1: 5,7-dichloroimidazo[1,2-a]pyridine (1B)

[0279] 2-Amino-4,6-dichloropyridine compound 1A (3.5 g, 22 mmol, 1 eq), chloroacetaldehyde (8 g, 44 mmol, 2 eq, 40% aqueous solution), and sodium bicarbonate (5.5 g, 66 mmol, 3 eq) were dissolved in n-butanol (50 mL) and stirred at 80°C for 16 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and water (100 mL) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 16-18% ethyl acetate) to obtain the title compound 1B as a white solid (2.8 g, 15 mmol, yield: 67%).

[0280] MS (ESI+) m / z = 187.2 [M+H] + .

[0281] Step 2: 5,7-dichloro-3-iodoimidazo[1,2-a]pyridine (1C)

[0282] 5,7-Dichloroimidazo[1,2-a]pyridine (1.86 g, 10 mmol, 1.0 eq) and N-iodosuccinimide (2.7 g, 12 mmol, 1.2 eq) were dissolved in dichloromethane (30 mL). The reaction mixture was stirred at 25°C for 2 hours, then cooled, water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 3). The resulting organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-15% ethyl acetate) to obtain the title compound 1C (2.84 g, 9.1 mmol, yield: 91%) as a white solid.

[0283] MS (ESI+) m / z = 312.9 [M+H] + .

[0284] Step 3: 5,7-dichloroimidazo[1,2-a]pyridine-3-carbonitrile (1D)

[0285] Compound 1C (1.6 g, 5 mmol, 1.0 eq) and cuprous cyanide (1.8 g, 20 mmol, 4 eq) were mixed in N,N-dimethylformamide (10 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 3 hours. Water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 1D (731 mg, 3.45 mmol, yield: 69%) as a light yellow solid.

[0286] MS (ESI+) m / z = 212.2 [M+H] + .

[0287] Step 4: 7-chloro-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (1E)

[0288] Compound 1N (735 mg, 5.2 mmol, 1.5 eq) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (415 mg, 10.35 mmol, 3 eq) was added at 0°C. After stirring for 30 minutes, 1D (731 mg, 3.45 mmol, 1.0 eq) was added and the reaction mixture was allowed to react for 3 hours. Aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was filtered, and the organic phase was evaporated under reduced pressure to remove the solvent. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 1E (765 mg, 2.42 mmol, yield: 70%) as a light yellow solid.

[0289] MS (ESI+) m / z = 317.3 [M+H] + .

[0290] Step 5: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (1F)

[0291] Compound 1E (100 mg, 0.315 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (118 mg, 0.46 mmol, 1.5 eq), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (13 mg, 0.03 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium (28 mg, 0.03 mmol, 0.2 eq), and potassium acetate (130 mg, 1.5 mmol, 5 eq) were mixed in dioxane (3 mL). The mixture was stirred at 90°C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was filtered and dried to give the title compound 1F (160 mg, crude product).

[0292] MS (ESI+) m / z = 409.2 [M+H] + .

[0293] Step 6: 2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (1G)

[0294] Compound 1F (160 mg, 1.0 eq), compound 1O (237 mg, 0.65 mmol, 2 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (47 mg, 0.06 mmol, 0.2 eq), and potassium carbonate (195 mg, 1.5 mmol, 5 eq) were mixed in dioxane (5 mL) and water (1 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 1G (98 mg, 0.18 mmol, yield: 61%) as a light yellow solid.

[0295] MS (ESI+) m / z = 518.2 [M+H] + .

[0296] Step 7: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (1H)

[0297] Compound 1G (98 mg, 0.18 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 1H (50.2 mg, 0.12 mmol, yield: 67%) as a yellow solid.

[0298] MS (ESI+) m / z = 418.2 [M+H] + .

[0299] Step 8: tert-Butyl 3-(2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyrrolidine-1-carboxylate (1I)

[0300] Compounds 1H (50.2 mg, 0.12 mmol, 1.0 eq) and 1P (45 mg, 0.24 mmol, 2.0 eq) were dissolved in dichloromethane (1 mL). Sodium triacetoxyborohydride (51 mg, 0.24 mmol, 2.0 eq) was added to the mixture under a nitrogen atmosphere at 25°C and stirred for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 1I (58.7 mg, 0.1 mmol, yield: 83%) as a yellow solid.

[0301] MS (ESI+) m / z = 587.3 [M+H] + .

[0302] Step 9: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(3-methyl-7-pyrrolidin-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (1J)

[0303] Compound 1I (58.7 mg, 0.1 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 1J (48.6 mg, 0.1 mmol, yield: 100%) as a yellow solid.

[0304] MS (ESI+) m / z = 487.2 [M+H] + .

[0305] Step 10: 7-(7-(1-cyanopyrrolidin-3-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 1)

[0306] Compound 1J (10 mg, 0.02 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (10 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 0.2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 1 as a white solid (5.1 mg, 0.01 mmol, yield: 50%).

[0307] MS (ESI+) m / z = 512.2 [M+H] + .

[0308] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.39(s,1H),7.83–7.78(m,1H),7.73–7.70 (m,1H),7.44(d,J=1.3Hz,1H),6.73(s,1H),6.02–5.98(m,1H),3.88–3.85(m,2H),3.73–3. 70(m,1H),3.66–3.61(m,2H),3.54–3.49(m,1H),3.42–3.36(m,2H),3.30–3.25(m,1H),3. 20–3.14(m,1H),2.95–2.87(m,2H),2.30(s,3H),1.87–1.82(m,1H),1.77(d,J=6.4Hz,3H).

[0309] The synthesis method of intermediate 1O is as follows:

[0310] The first step is tert-butyl 3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (1L)

[0311] Compound 1K (906 mg, 3 mmol, 1.0 eq), methylboronic acid (1.08 g, 18 mmol, 6 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (235 mg, 0.3 mmol, 0.1 eq), and potassium carbonate (2.07 g, 15 mmol, 5 eq) were mixed in dioxane (20 mL) and water (4 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 20-100% ethyl acetate) to obtain the title compound 1L as a white solid (463 mg, 1.95 mmol, yield: 65%).

[0312] MS (ESI+) m / z = 238.2 [M+H] + .

[0313] Step 2: 2-iodo-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (1O)

[0314] Compound 1L (463 mg, 1.95 mmol, 1.0 eq) and N-iodosuccinimide (483 mg, 2.15 mmol, 1.1 eq) were dissolved in 1,2-dichloroethane (10 mL). The reaction mixture was stirred at 90°C for 3 hours, then cooled, water (100 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The resulting organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-40% ethyl acetate) to obtain the title compound 1O (517 mg, 1.42 mmol, yield: 73%) as a white solid.

[0315] MS (ESI+) m / z = 364.1 [M+H] + .

[0316] Example 2 7-(7-(1-acryloylpyrrolidin-3-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 2)

[0317] Compound 1J (10 mg, 0.02 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 0.2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 2 as a white solid (4.3 mg, 0.008 mmol, yield: 40%).

[0318] MS (ESI+) m / z = 541.2 [M+H] + .

[0319] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.39(s,1H),7.83–7.77(m,1H),7.73–7.70(m,1H) ,7.44(s,1H),6.74(s,1H),6.69–6.56(m,1H),6.17–6.12(m,1H),6.04–5.97(m,1H),5.70–5.65(m ,1H),3.92–3.86(m,2H),3.84–3.73(m,2H),3.71–3.67(m,1H),3.64–3.53(m,2H),3.40–3.35(m, 2H),3.22–3.15(m,1H),2.99–2.90(m,2H),2.30(s,3H),1.94–1.85(m,1H),1.77(d,J=6.5Hz,3H).

[0320] Example 3 7-(7-acryloyl-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 3)

[0321] Compound 1H (10 mg, 0.025 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 3 as a white solid (5.6 mg, 0.012 mmol, yield: 51%).

[0322] MS (ESI+) m / z = 472.2 [M+H] + .

[0323] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.40(s,1H),7.83–7.79(m,1H ),7.74–7.71(m,1H),7.45(d,J=1.3Hz,1H),6.95(dd,J=16.6,10.6Hz,1H),6 .74(s,1H),6.20(dd,J=16.7,2.3Hz,1H),6.06–5.98(m,1H),5.82–5.74(m,1 H),4.89–4.70(m,2H),4.10–3.90(m,4H),2.31(s,3H),1.78(d,J=6.4Hz,3H).

[0324] Example 4 2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carbonitrile (Compound 4)

[0325] Compound 1H (10 mg, 0.025 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (10.6 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 4 (4.7 mg, 0.01 mmol, yield: 46%) as a white solid.

[0326] MS (ESI+) m / z = 443.3 [M+H] + .

[0327] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.8Hz,1H),8.40(s,1H),7.84–7.80(m,1H),7.75–7.71(m,1H),7.46(d,J=1.3Hz,1H),6.73( d,J=1.4Hz,1H),6.02(q,J=6.4Hz,1H),4.55(s,2H),4.06–4.01(m,2H),3.75–3.71(m,2H),2.32(s,3H),1.77(d,J=6.4Hz,3H).

[0328] Example 5 2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (Compound 5)

[0329] The first step: 2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (5A)

[0330] Compound 1F (408 mg, 1.0 mmol, 1.0 eq), compound Int-1 (316 mg, 1.0 mmol, 1 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (90 mg, 0.1 mmol, 0.1 eq), and potassium carbonate (690 mg, 5 mmol, 5 eq) were mixed in dioxane (10 mL) and water (2 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 5A (405 mg, 0.78 mmol, yield: 78%) as a light yellow solid.

[0331] MS (ESI+) m / z = 518.3 [M+H] + .

[0332] Step 2: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (5B)

[0333] Compound 5A (405 mg, 0.78 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 5B (302 mg, 0.72 mmol, yield: 93%) as a yellow solid.

[0334] MS (ESI+) m / z = 418.1 [M+H] + .

[0335] Step 3: 2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (Compound 5)

[0336] Compound 5B (10 mg, 0.025 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (10.6 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 5 as a white solid (5.9 mg, 0.013 mmol, yield: 58%).

[0337] MS (ESI+) m / z = 443.3 [M+H] + .

[0338] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=2.8Hz,1H),8.45(s,1H),7.83–7.79(m,1H),7.75–7.71(m,1H),7.52(d,J=1.3Hz,1H),6.75( d,J=1.3Hz,1H),6.03(q,J=6.4Hz,1H),4.58(s,2H),4.26–4.21(m,2H),3.79–3.73(m,2H),2.04(s,3H),1.78(d,J=6.4Hz,3H).

[0339] Example 6 7-(5-acryloyl-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 6)

[0340] Compound 5B (10 mg, 0.025 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 6 (6.1 mg, 0.013 mmol, yield: 57%) as a white solid.

[0341] MS (ESI+) m / z = 472.2 [M+H] + .

[0342] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.8Hz,1H),8.45(s,1H),7.83–7.71(m,2H ),7.52(s,1H),7.06–6.89(m,1H),6.75(s,1H),6.21(d,J=17.1Hz,1H),6.03 (d,J=6.5Hz,1H),5.79(dd,J=1.9,10.4Hz,1H),4.86(s,1H),4.77–4.67(m,1 H),4.23–4.11(m,2H),4.11–4.00(m,2H),2.09(s,3H),1.78(d,J=6.4Hz,3H)

[0343] Example 7 7-(3,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 7)

[0344] Compound 5B (10 mg, 0.025 mmol, 1.0 eq) and potassium carbonate (13 mg, 0.1 mmol, 5.0 eq) were dissolved in N,N-dimethylformamide (1 mL). Iodomethane (15 mg, 0.1 mmol, 5.0 eq) was added and stirred for 2 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, eluting with 5%-75% acetonitrile-water) to afford the title compound 7 (3.4 mg, 0.013 mmol, yield: 34%) as a white solid.

[0345] MS (ESI+) m / z = 432.1 [M+H] + .

[0346] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.8Hz,1H),8.43(s,1H),7.83–7.77(m,1H),7.75–7.70(m,1H),7.49(d,J=1.2Hz,1H),6.76(d,J=1.3H z,1H),6.02(q,J=6.4Hz,1H),4.09(t,J=5.6Hz,2H),3.52(s,2H),2.83(t,J=5.6Hz,2H),2.41(s,3H),2.03(s,3H),1.78(d,J=6.4Hz,3H).

[0347] Example 8 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-isopropyl-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 8)

[0348] Compound 5B (10 mg, 0.025 mmol, 1.0 eq) and acetone (26 mg, 0.5 mmol, 25.0 eq) were dissolved in dichloromethane (1 mL). Sodium acetate borohydride (22 mg, 0.1 mmol, 5.0 eq) was added and stirred for 2 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, eluting with 5%-75% acetonitrile-water) to afford the title compound 8 as a white solid (5.5 mg, 0.012 mmol, yield: 52%).

[0349] MS (ESI+) m / z = 460.1 [M+H] + .

[0350] 1 H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.8Hz,1H),8.43(s,1H),7.85–7.78(m, 1H),7.75–7.70(m,1H),7.49(d,J=1.2Hz,1H),6.75(d,J=1.4Hz,1H),6.02( q,J=6.4Hz,1H),4.06(t,J=5.5Hz,2H),3.63(s,2H),2.98–2.92(m,1H),2. 93–2.88(m,2H),2.04(s,3H),1.78(d,J=6.4Hz,3H),1.07(d,J=6.5Hz,6H).

[0351] Example 9 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(3-methyl-5-methylsulfonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 9)

[0352] Compound 5B (10 mg, 0.023 mmol, 1.0 eq) and triethylamine (10 mg, 0.1 mmol, 5.0 eq) were dissolved in N,N-dimethylformamide (1 mL). Methanesulfonyl chloride (12 mg, 0.1 mmol, 5.0 eq) was added and stirred for 1 hour. The reaction mixture was evaporated under reduced pressure to remove the solvent, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, eluting with 5%-75% acetonitrile-water) to afford the title compound 7 (5.4 mg, 0.011 mmol, yield: 48%) as a white solid.

[0353] MS (ESI+) m / z = 496.1 [M+H] + .

[0354] 1 H NMR (400MHz, DMSO-d6) δ = 8.61 (d, J = 2.8Hz, 1H), 8.46 (s, 1H), 7.85–7.78 (m, 1H), 7.76–7.71 (m, 1H), 7.53 (s, 1H), 6.76 (s, 1H), 6 .04(q,J=6.3Hz,1H),4.45(s,2H),4.23(t,J=5.4Hz,2H),3.70(t,J=5.5Hz,2H),3.08(s,3H),2.08(s,3H),1.78(d,J=6.5Hz,3H)

[0355] Example 10 2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (Compound 10)

[0356] Step 1: 2-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (10A)

[0357] Compound Int-3 (547 mg, 1.0 mmol, 1.0 eq), Int-1 (316 mg, 1.0 mmol, 1.0 eq), dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II) (36 mg, 50 μmol, 0.05 eq), and potassium carbonate (280 mg, 2.0 mmol, 2 eq) were mixed in dioxane (5 mL) and water (0.5 mL). The mixture was stirred at 70°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 10A (480 mg, 0.73 mmol, yield: 73%) as a yellow solid.

[0358] MS (ESI+) m / z = 657.2 [M+H] + .

[0359] Step 2: 2-(3-chloro-6-(3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (10B)

[0360] Compound 10A (480 mg, 0.73 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 10B (310 mg, 0.70 mmol, yield: 95%) as a yellow solid.

[0361] MS (ESI+) m / z = 443.1 [M+H] + .

[0362] Step 3: 2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbonitrile (Compound 10)

[0363] Compound 10B (10 mg, 0.023 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (10.6 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 10 as a white solid (4.2 mg, 0.008 mmol, yield: 39%).

[0364] MS (ESI+) m / z = 468.3 [M+H] + .

[0365] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.9Hz,1H),8.35–8.33(m,1H),8.10(s,1H),7.78–7.74(m,1H),7.61(dd,J=8.8,4.5Hz,1H),6.85(s,1 H),5.59(t,J=5.2Hz,1H),5.14(t,J=5.7Hz,1H),4.57(s,2H),4.21(t,J=5.5Hz,2H),3.95–3.91(m,2H),3.77–3.72(m,2H),1.98(s,3H).

[0366] Example 11 1-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one (Compound 11)

[0367] Compound 10B (10 mg, 0.023 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 11 (4.8 mg, 0.01 mmol, yield: 42%) as a white solid.

[0368] MS (ESI+) m / z = 497.1 [M+H] + .

[0369] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.9Hz,1H),8.33(d,J=1.0Hz,1H),8.09(s,1H),7.76(td,J=8.7,2.9Hz,1H),7.61(dd,J=8.8,4.5Hz,1H),6.85(s ,1H),6.25–6.17(m,1H),5.80–5.75(m,1H),5.62–5.57(m,1H),5.19(s,1 H),4.80–4.75(m,3H),4.11–4.02(m,4H),3.95–3.92(m,2H),2.02(s,3H).

[0370] Example 12 1-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)prop-2-en-1-one (Compound 12)

[0371] Step 1: 2-(4-(2-((tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (12A)

[0372] Compound Int-3 (547 mg, 1.0 mmol, 1.0 eq), 1O (363 mg, 1.0 mmol, 1.0 eq), dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II) (36 mg, 50 μmol, 0.05 eq), and potassium carbonate (280 mg, 2.0 mmol, 2 eq) were mixed in dioxane (5 mL) and water (0.5 mL). The mixture was stirred at 70°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 12A (492 mg, 0.75 mmol, 75% yield) as a yellow solid.

[0373] MS (ESI+) m / z = 657.2 [M+H] + .

[0374] Step 2: 2-(3-chloro-6-(3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (12B)

[0375] Compound 12A (492 mg, 0.75 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 12B (300 mg, 0.68 mmol, yield: 91%) as a yellow solid.

[0376] MS (ESI+) m / z = 443.1 [M+H] + .

[0377] Step 3: 1-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)prop-2-en-1-one (Compound 12)

[0378] Compound 12B (10 mg, 0.023 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 12 as a white solid (4.7 mg, 0.009 mmol, yield: 41%).

[0379] MS (ESI+) m / z = 497.3 [M+H] + .

[0380] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.8Hz,1H),8.27(d,J=1.0Hz,1H),8.04 (s,1H),7.78–7.74(m,1H),7.63–7.58(m,1H),6.96–6.92(m,1H),6.84(s, 1H),6.23–6.19(m,1H),5.79–5.74(m,1H),5.58(s,1H),5.15(t,J=5.7Hz, 1H),4.89–4.70(m,2H),4.08–3.98(m,2H),3.95–3.90(m,4H),2.23(s,3H).

[0381] Example 13 2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carbonitrile (Compound 13)

[0382] Compound 12B (10 mg, 0.023 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (10.6 mg, 0.1 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 13 as a white solid (5.3 mg, 0.011 mmol, yield: 49%).

[0383] MS (ESI+) m / z = 468.1 [M+H] + .

[0384] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.8Hz,1H),8.28(d,J=0.9Hz,1H),8.04(s,1H),7.78–7.74(m,1H),7.63–7.58(m,1H),6.83(s,1H),5 .58(t,J=5.2Hz,1H),5.14(t,J=5.7Hz,1H),4.54(s,2H),4.01(t,J=5.5Hz,2H),3.92(t,J=5.4Hz,2H),3.77–3.68(m,2H),2.24(s,3H).

[0385] Example 14 7-(5-but-2-ynyl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 14)

[0386] Compound 5B (10 mg, 0.023 mmol, 1.0 eq), 2-butynoic acid (2 mg, 0.2 mmol, 10.0 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol, 3.0 eq), and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 5.0 eq) were dissolved in dichloromethane (2 mL). The mixture was stirred for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 14 as a white solid (3.6 mg, 0.011 mmol, yield: 32%).

[0387] MS (ESI+) m / z = 484.2 [M+H] + .

[0388] 1H NMR(400MHz, DMSO-d6)δ8.60(d,J=2.8Hz,1H),8.45(d,J=1.4Hz,1H),7.82–7.78(m,1H),7.75–7.71(m,1H),7.53–7.48(m,1H),6.75(s,1H), 6.03(q,J=6.4Hz,1H),4.92–4.88(m,1H),4.69–4.65(m,1H),4.29–4.1 5(m,3H),4.14–4.10(m,1H),2.13–2.04(m,6H),1.78(d,J=6.4Hz,3H).

[0389] Example 15 7-(7-(1-cyanoazetidin-3-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 15)

[0390] The first step: tert-butyl 3-(2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl(-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)azetidine-1-carboxylate (15A)

[0391] Compound 1H (83 mg, 0.2 mmol, 1.0 eq), 1-Boc-3-azetidinone (68 mg, 0.4 mmol, 2.0 eq), and sodium cyanoborohydride (63 mg, 1 mmol, 5 eq) were dissolved in methanol (5 mL). The mixture was stirred at 25°C for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 15A (97 mg, 0.17 mmol, 85% yield) as a yellow solid.

[0392] MS (ESI+) m / z = 573.2 [M+H] + .

[0393] Step 2: 7-(7-azetidin-3-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (15B)

[0394] Compound 15A (97 mg, 0.17 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 15B (66 mg, 0.14 mmol, yield: 82%) as a yellow solid.

[0395] MS (ESI+) m / z = 473.1 [M+H] + .

[0396] Step 3: 7-(7-(1-cyanoazetidin-3-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 15)

[0397] Compound 15B (20 mg, 0.042 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.3 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (22 mg, 0.21 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 15 as a white solid (12 mg, 0.024 mmol, yield: 57%).

[0398] MS (ESI+) m / z = 498.2 [M+H] + .

[0399] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.39(s,1H),7.82–7.78(m,1H) ,7.73–7.69(m,1H),7.44(d,J=1.2Hz,1H),6.73(d,J=1.3Hz,1H),6.00(q,J=6. 4Hz,1H),4.26–4.22(m,2H),4.15–4.10(m,2H),3.89(t,J=5.5Hz,2H),3.59(s, 2H),3.56–3.52(m,1H),2.85–2.81(m,2H),2.31(s,3H),1.77(d,J=6.4Hz,3H).

[0400] Example 16 7-(7-(1-acryloylazetidin-3-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 16)

[0401] Compound 15B (20 mg, 0.042 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.3 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 2.3 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 16 (14 mg, 0.027 mmol, yield: 63%) as a white solid.

[0402] MS (ESI+) m / z = 527.3 [M+H] + .

[0403] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.9Hz,1H),8.39(s,1H),7.82–7.78(m,1H),7.73–7.69(m,1H),7 .44(d,J=1.2Hz,1H),6.74(d,J=1.3Hz,1H),6.33–6.29(m,1H),6.14–6.08(m,1H),6.03–5.98(m,1H ),5.71–5.66(m,1H),4.35–4.30(m,1H),4.17–4.12(m,1H),4.07–3.98(m,1H),3.94–3.85(m,2H),3 .86–3.81(m,1H),3.61(s,2H),3.45(s,1H),2.89–2.81(m,2H),2.31(s,3H),1.77(d,J=6.4Hz,3H).

[0404] Example 17 7-(5-(1-acryloylazetidin-3-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 17)

[0405] First step: tert-butyl 3-(2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidine-1-carboxylate (17A)

[0406] Compound 5B (83 mg, 0.2 mmol, 1.0 eq), 1-Boc-3-azetidinone (68 mg, 0.4 mmol, 2.0 eq), and sodium cyanoborohydride (63 mg, 1 mmol, 5 eq) were dissolved in methanol (5 mL). The mixture was stirred at 25°C for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 15A (86 mg, 0.15 mmol, yield: 75%) as a yellow solid.

[0407] MS (ESI+) m / z = 573.2 [M+H] + .

[0408] Step 2: 7-(5-(azetidin-3-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (17B)

[0409] Compound 17A (86 mg, 0.15 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 17B (57 mg, 0.12 mmol, 80% yield) as a yellow solid.

[0410] MS (ESI+) m / z = 473.2 [M+H] + .

[0411] Step 3: 7-(5-(1-acryloylazetidin-3-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 17)

[0412] Compound 17B (20 mg, 0.042 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.3 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 2.3 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 0.5 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 17 as a white solid (15.5 mg, 0.029 mmol, yield: 70%).

[0413] MS (ESI+) m / z = 527.3 [M+H] + .

[0414] 1 H NMR(400MHz, DMSO-d6)δ8.59(d,J=2.9Hz,1H),8.44(s,1H),7.82–7.78(m,1H),7.75–7.71(m,1H),7. 50(d,J=1.2Hz,1H),6.75(d,J=1.3Hz,1H),6.33–6.29(m,1H),6.14–6.07(m,1H),6.06–6.00(m,1H), 5.71–5.66(m,1H),4.36–4.31(m,1H),4.20–4.14(m,1H),4.15–4.10(m,2H),4.06–3.99(m,1H),3.91 –3.86(m,1H),3.60(s,2H),3.52–3.45(m,1H),2.89–2.85(m,2H),2.04(s,3H),1.78(d,J=6.4Hz,3H).

[0415] Example 18 7-(5-(1-cyanoazetidin-3-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 18)

[0416] Compound 17B (20 mg, 0.042 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.3 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (22 mg, 0.21 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 18 as a white solid (14.7 mg, 0.029 mmol, yield: 70%).

[0417] MS (ESI+) m / z = 498.2 [M+H] + .

[0418] 1 H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.9Hz,1H),8.44(s,1H),7.83–7.78(m,1H),7.75–7.70(m,1H),7.50(d,J=1.2Hz,1H),6.75(d,J=1.2Hz,1H),6.03 (q,J=6.4Hz,1H),4.27–4.23(m,2H),4.20–4.13(m,2H),4.12–4.08(m,2H) ,3.61–3.54(m,3H),2.88–2.82(m,2H),2.03(s,3H),1.78(d,J=6.4Hz,3H).

[0419] Example 19 7-(5-(1-cyanopyrrolidin-3-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 19)

[0420] The first step: tert-butyl 3-(2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl(-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyrrolidine-1-carboxylate (19A)

[0421] Compound 5B (83 mg, 0.2 mmol, 1.0 eq), 1-tert-butoxycarbonyl-3-pyrrolidone (74 mg, 0.4 mmol, 2.0 eq), and sodium cyanoborohydride (63 mg, 1 mmol, 5 eq) were dissolved in methanol (5 mL). The mixture was stirred at 25°C for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 19A (93.7 mg, 0.16 mmol, 80% yield) as a yellow solid.

[0422] MS (ESI+) m / z = 587.3 [M+H] + .

[0423] Step 2: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(3-methyl-5-pyrrolidin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (19B)

[0424] Compound 19A (93.7 mg, 0.16 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 19B (53.5 mg, 0.11 mmol, yield: 68.7%) as a yellow solid.

[0425] MS (ESI+) m / z = 487.3 [M+H] + .

[0426] Step 3: 7-(5-(1-cyanopyrrolidin-3-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 19)

[0427] Compound 19B (20 mg, 0.041 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.3 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (22 mg, 0.21 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 19 as a white solid (13.3 mg, 0.026 mmol, yield: 63%).

[0428] MS (ESI+) m / z = 512.2 [M+H] + .

[0429] 1 H NMR(400MHz, DMSO-d6)δ=8.64–8.56(m,1H),8.49–8.41(m,1H),7.88–7.78(m,1H),7.75 –7.70(m,1H),7.55–7.47(m,1H),6.78–6.71(m,1H),6.10–5.96(m,1H),4.10(t,J=5.3Hz ,2H),3.74–3.60(m,3H),3.59-3.48(m,1H),3.46–3.37(m,2H),3.24–3.15(m,1H),3.04– 2.87(m,2H),2.21–2.10(m,1H),2.07–2.02(m,3H),1.94–1.84(m,1H),1.82–1.75(m,3H)

[0430] Example 20 7-(5-(1-cyanopiperidin-4-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 20)

[0431] First step: tert-butyl 4-(2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl(-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)piperidine-1-carboxylate (20A)

[0432] Compound 5B (83 mg, 0.2 mmol, 1.0 eq), N-tert-butyloxycarbonyl-4-piperidone (80 mg, 0.4 mmol, 2.0 eq), and sodium cyanoborohydride (63 mg, 1 mmol, 5 eq) were dissolved in methanol (5 mL). The mixture was stirred at 25°C for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 20A (90 mg, 0.15 mmol, yield: 75%) as a yellow solid.

[0433] MS (ESI+) m / z = 601.3 [M+H] + .

[0434] Step 2: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(3-methyl-5-)piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (20B)

[0435] Compound 20A (90 mg, 0.15 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 20B (60 mg, 0.12 mmol, 80% yield) as a yellow solid.

[0436] MS (ESI+) m / z = 501.3 [M+H] + .

[0437] Step 3: 7-(5-(1-cyanopiperidin-4-yl)-3-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 20)

[0438] Compound 20B (23 mg, 0.046 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.3 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (22 mg, 0.21 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 20 (15.6 mg, 0.03 mmol, yield: 64.4%) as a white solid.

[0439] MS (ESI+) m / z = 526.2 [M+H] + .

[0440] 1 H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.8Hz, 1H), 8.44 (s, 1H), 7.84–7.77 (m, 1H), 7.76–7.7 0(m,1H),7.50(d,J=0.9Hz,1H),6.75(s,1H),6.02(q,J=6.3Hz,1H),4.07(t,J=5.3Hz,2H), 3.71(s,2H),3.45(d,J=12.6Hz,2H),3.07(t,J=11.2Hz,2H),2.98(t,J=5.4Hz,2H),2.72– 2.65(m,1H),2.04(s,3H),1.85(d,J=11.4Hz,2H),1.78(d,J=6.4Hz,3H),1.68–1.57(m,2H)

[0441] Example 21 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)azetidine-1-carbonitrile (Compound 21)

[0442] The first step: tert-butyl 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)azetidine-1-carboxylate (21A)

[0443] Compound 12B (88.5 mg, 0.2 mmol, 1.0 eq), 1-Boc-3-azetidinone (68 mg, 0.4 mmol, 2.0 eq), and sodium cyanoborohydride (63 mg, 1 mmol, 5 eq) were dissolved in methanol (5 mL). The mixture was stirred at 25°C for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 21A (83.7 mg, 0.14 mmol, 70% yield) as a yellow solid.

[0444] MS (ESI+) m / z = 598.2 [M+H] + .

[0445] Step 2: 2-(6-(7-azetidin-3-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)-3-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethyl-1-ol (21B)

[0446] Compound 21A (83.7 mg, 0.14 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 21B (50 mg, 0.10 mmol, yield: 71%) as a yellow solid.

[0447] MS (ESI+) m / z = 498.2 [M+H] + .

[0448] Step 3: 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)azetidine-1-carbonitrile (Compound 21)

[0449] Compound 21B (20 mg, 0.04 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.5 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (22 mg, 0.20 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 21 as a white solid (14.1 mg, 0.027 mmol, yield: 67.4%).

[0450] MS (ESI+) m / z = 523.2 [M+H] + .

[0451] 1H NMR (400MHz, DMSO-d6) δ8.59(d,J=2.9Hz,1H),8.25(d,J=1.0Hz,1H),8.03(s,1H ),7.78–7.73(m,1H),7.63–7.58(m,1H),6.83(s,1H),5.57(t,J=5.2Hz,1H),5.1 4(t,J=5.7Hz,1H),4.27–4.21(m,2H),4.15–4.10(m,2H),3.96–3.90(m,2H),3.8 9–3.84(m,2H),3.58(s,2H),3.55–3.50(m,1H),2.83–2.78(m,2H),2.23(s,3H).

[0452] Example 22 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)pyrrolidine-1-carbonitrile (Compound 22)

[0453] The first step: tert-butyl 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyrrolidine-1-carboxylate (22A)

[0454] Compound 12B (176 mg, 0.4 mmol, 1.0 eq), 1-tert-butoxycarbonyl-3-pyrrolidone (185 mg, 1 mmol, 2.5 eq), and sodium cyanoborohydride (126 mg, 2.0 mmol, 5 eq) were dissolved in methanol (10 mL). The mixture was stirred at 25°C for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 22A (201.6 mg, 0.33 mmol, yield: 82.5%) as a yellow solid.

[0455] MS (ESI+) m / z = 612.2 [M+H] + .

[0456] Step 2: 2-(3-chloro-6-(3-methyl-7-pyrrolidin-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (22B)

[0457] Compound 22A (201.6 mg, 0.33 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 22B (153 mg, 0.30 mmol, yield: 91%) as a yellow solid.

[0458] MS (ESI+) m / z = 512.2 [M+H] + .

[0459] Step 3: 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)pyrrolidine-1-carbonitrile (Compound 22)

[0460] Compound 22B (153 mg, 0.30 mmol, 1.0 eq) and N,N-diisopropylethylamine (78 mg, 0.6 mmol, 2.0 eq) were dissolved in dichloromethane (5 mL). Cyanogen bromide (160 mg, 1.5 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 22 as a white solid (112 mg, 0.21 mmol, yield: 70%).

[0461] MS (ESI+) m / z = 537.2 [M+H] + .

[0462] 1H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.9Hz, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.77 (dt, J = 3.0, 8.9Hz, 1 H),7.62(dd,J=4.4,8.9Hz,1H),6.85(s,1H),5.59(t,J=5.2Hz,1H),5.16(t,J=5.7Hz,1H),4.07(br t,J=5.4Hz,2H),3.93(t,J=5.5Hz,2H),3.68–3.61(m,3H),3.53(dt,J=3.2,8.5Hz,2H), 3.23–3.15(m,2H),3.01–2.87(m,2H),2.21–2.09(m,1H),1.98(s,3H),1.93–1.82(m,1H)

[0463] Step 4: 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)pyrrolidine-1-carbonitrile (Compounds 22-1, 22-2, 22-3, 22-4)

[0464] Compound 22 was prepared by chiral separation (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm)); mobile phase: A: carbon dioxide; B: isopropanol (0.1% ammonia solution); B%: 40%-40%; flow rate: 150 ml / min) to obtain two components, one of which was prepared by chiral separation (column: DAICEL CHIRALPKAD (250mm*30mm, 10μm); mobile phase: A: carbon dioxide; B: methanol (0.1% ammonia); B%: 60%-60%; flow rate: 150 ml / min) to obtain compounds 22-1 and 22-2. Another component was prepared by chiral separation (column: Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: A: carbon dioxide; B: methanol (0.1% ammonia); B%: 55%-55%; flow rate: 140 ml / min) to obtain four single-configuration isomers of compounds 22-3 and 22-4.

[0465] 22-1 SFC retention time: 2.510 min

[0466] 1H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.9Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.77 (t, J = 3.1, 8.7Hz, 1H ),7.61(dd,J=4.7,8.5Hz,1H),6.84(s,1H),5.58(t,J=5.2Hz,1H),5.20–5.15(m,1H),3.95–3.91(m ,2H),3.87–3.82(m,2H),3.74–3.59(m,3H),3.52(dt,J=3.2,8.6Hz,1H),3.44–3.38(m,1H),3.20–3 .13(m,1H),2.95–2.86(m,2H),2.65–2.58(m,1H),2.22(s,3H),2.19–2.10(m,1H),1.91–1.78(m,1H)

[0467] MS (ESI+) m / z = 537.3 [M+H] + .

[0468] 22-2 SFC retention time: 4.739 min

[0469] 1 H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.9Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.77 (t, J = 3.0, 8.7Hz, 1H), 7.61 ( dd,J=4.5,8.7Hz,1H),6.84(s,1H),5.58(t,J=5.0Hz,1H),5.17(t,J=5.7Hz,1H),3.95–3.90(m,2H),3.87–3 .82(m,2H),3.73–3.67(m,1H),3.67–3.59(m,2H),3.52(dt,J=3.4,8.6Hz,1H),3.43–3.39(m,1H),3.19–3.1 3(m,1H),2.94–2.86(m,2H),2.71–2.66(m,1H),2.22(s,3H),2.19–2.09(m,1H),1.84(dd,J=8.5,12.4Hz,1H)

[0470] MS (ESI+) m / z = 537.3 [M+H] + .

[0471] 22-3 SFC retention time: 3.619 min

[0472] 11H NMR (400 MHz, DMSO-d6) δ = 8.60 (d, J = 2.6 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.77 (t, J = 2.9, 8.8 Hz, 1H), 7.61 (dd, J = 4.3, 8.5 Hz, 1H), 6.84 (s, 1H), 5.60–5.55 (m, 1H), 5.20–5.15 (m, 1H), 3.95–3.91 (m, 2H), 3.87–3.83 (m, 2H), 3.73–3.68 (m, 1H), 3.65–3.59 (m, 2H), 3.52 (t, J = 3.6, 8.4 Hz, 1H), 3.44–3.38 (m, 1H), 3.20–3.13 (m, 1H), 2.95–2.85 (m, 2H), 2.69–2.65 (m, 1H), 2.22 (s, 3H), 2.19–2.09 (m, 1H), 1.91–1.78 (m, 1H)

[0473] MS (ESI+) m / z = 537.3 [M+H] + .

[0474] 22-4 SFC retention time: 5.110 min [[ID=##ID=10]]

[0475] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.60 (d, J = 3.1 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.80–7.74 (m, 1H), 7.63–7.58 (m, 1H), 6.84 (s, 1H), 5.60–5.55 (m, 1H), 5.17 (t, J = 6.2 Hz, 1H), 3.95–3.90 (m, 2H), 3.87–3.83 (m, 2H), 3.74–3.68 (m, 1H), 3.67–3.59 (m, 2H), 3.55–3.49 (m, 1H), 3.44–3.38 (m, 1H), 3.20–3.11 (m, 1H), 2.95–2.86 (m, 2H), 2.70–2.66 (m, 1H), 2.22 (s, 3H), 2.20–2.09 (m, 1H), 所1.92–1.78 (m, 1H)

[0476] MS (ESI+) m / z = 537.3 [M+H] + .

[0477] It should be noted that there seems to be an error in the text you provided. In the description of the second 1H NMR data in , the Chinese character "所" is included in the English translation by mistake. It should be removed for a correct translation. The corrected translation for is as follows: 1H NMR (400 MHz, DMSO-d6) δ = 8.60 (d, J = 3.1 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.80–7.74 (m, 1H), 7.63–7.58 (m, 1H), 6.84 (s, 1H), 5.60–5.55 (m, 1H), 5.17 (t, J = 6.2 Hz, 1H), 3.95–3.90 (m, 2H), 3.87–3.83 (m, 2H), 3.74–3.68 (m, 1H), 3.67–3.59 (m, 2H), 3.55–3.49 (m, 1H), 3.44–3.38 (m, 1H), 3.20–3.11 (m, 1H), 2.95–2.86 (m, 2H), 2.70–2.66 (m, 1H), 2.22 (s, 3H), 2.20–2.09 (m, 1H), 1.92–1.78 (m, 1H)Example 23 3-(3-chloro-2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)yl)pyrrolidine-1-carbonitrile (Compound 23)

[0478] Step 1: 2-(4-(2-((tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-3-chloro-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (23A)

[0479] Compounds Int-3 (273.5 mg, 0.5 mmol, 1.0 eq), Int-5 (167.5 mg, 0.5 mmol, 1.0 eq), dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II) (36 mg, 50 μmol, 0.1 eq), and potassium carbonate (280 mg, 2.0 mmol, 4 eq) were mixed in dioxane (5 mL) and water (0.5 mL). The mixture was stirred at 70°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 23A (223 mg, 0.33 mmol, yield: 66%) as a white solid.

[0480] MS (ESI+) m / z = 677.2 [M+H] + .

[0481] Step 2: 2-(3-chloro-6-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethyl-1-ol (23B)

[0482] Compound 23A (223 mg, 0.33 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 23B (139 mg, 0.30 mmol, yield: 90%) as a white liquid.

[0483] MS (ESI+) m / z = 463.1 [M+H] + .

[0484] Step 3: tert-Butyl 3-(3-chloro-2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)yl)pyrrolidine-1-carboxylate (23C)

[0485] Compound 23B (139 mg, 0.3 mmol, 1.0 eq), 1-tert-butoxycarbonyl-3-pyrrolidone (111 mg, 0.6 mmol, 2.0 eq), and sodium cyanoborohydride (95 mg, 1.5 mmol, 5 eq) were dissolved in methanol (5 mL). The mixture was stirred at 25°C for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 23C (139 mg, 0.22 mmol, 80% yield) as a yellow solid.

[0486] MS (ESI+) m / z = 632.3 [M+H] + .

[0487] Step 4: 2-(3-chloro-6-(3-chloro-5-pyrrolidin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (23D)

[0488] Compound 23C (139 mg, 0.22 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 23D (96 mg, 0.18 mmol, yield: 81.8%) as a gray-brown liquid.

[0489] MS (ESI+) m / z = 532.1 [M+H] + .

[0490] Step 5: 3-(3-chloro-2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)yl)pyrrolidine-1-carbonitrile (Compound 23)

[0491] Compound 23D (27 mg, 0.05 mmol, 1.0 eq) and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.3 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (22 mg, 0.20 mmol, 4.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 23 as a white solid (22.8 mg, 0.041 mmol, yield: 82%).

[0492] MS (ESI+) m / z = 557.1 [M+H] + .

[0493] 1 H NMR (400MHz, DMSO-d6) δ=8.65–8.54(m,2H),8.18–8.10(m,1H),7.77(dt,J= 2.9,8.9Hz,1H),7.67–7.55(m,1H),6.95(s,1H),5.58(t,J=5.3Hz,1H),5.1 7(t,J=5.6Hz,1H),4.16–4.11(m,2H),3.96–3.91(m,2H),3.78–3.61(m,5H) ,3.57–3.48(m,2H),3.03–2.96(m,2H),2.18–2.09(m,1H),1.93–1.84(m,1H)

[0494] Example 24 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)pyrrolidine-1-carbonitrile (Compound 24)

[0495] First step: tert-butyl 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)pyrrolidine-1-carboxylate (24A)

[0496] Compound 10B (221 mg, 0.5 mmol, 1.0 eq), 1-tert-butoxycarbonyl-3-pyrrolidone (185 mg, 1 mmol, 2.0 eq), and sodium cyanoborohydride (126 mg, 2.0 mmol, 4 eq) were dissolved in methanol (10 mL). The mixture was stirred at 25°C for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 0-50% tetrahydrofuran) to afford the title compound 24A (257 mg, 0.42 mmol, yield: 84%) as a yellow solid.

[0497] MS (ESI+) m / z = 612.2 [M+H] + .

[0498] Step 2: 2-(3-chloro-6-(3-methyl-5-pyrrolidin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (24B)

[0499] Compound 24A (257 mg, 0.42 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 3 hours. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 24B (194.2 mg, 0.38 mmol, 90% yield) as a yellow solid.

[0500] MS (ESI+) m / z = 511.2 [M+H] + .

[0501] Step 3: 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)pyrrolidine-1-carbonitrile (Compound 24)

[0502] Compound 24B (194 mg, 0.38 mmol, 1.0 eq) and N,N-diisopropylethylamine (99 mg, 0.76 mmol, 2.0 eq) were dissolved in dichloromethane (5 mL). Cyanogen bromide (203 mg, 1.9 mmol, 5.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 2 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 24 as a white solid (145 mg, 0.27 mmol, yield: 71.1%).

[0503] MS (ESI+) m / z = 537.2 [M+H] + .

[0504] Step 4: 3-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)pyrrolidine-1-carbonitrile (Compounds 24-1, 24-2, 24-3, 24-4)

[0505] Compound 24 was prepared by chiral separation (column: DAICEL CHIRALPAK IC (250mm*30mm, 5μm)); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia); B%: 45%-45%; flow rate: 80 ml / min) to obtain two components. One component was prepared by chiral separation (column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm)); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia); B%: 60%-60%; flow rate: 80 ml / min) to obtain compounds 24-1 and 24-2. The other component was prepared by chiral separation (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 60%-60%; flow rate: 80 ml / min) to separate the four single-configuration isomers of compounds 24-3 and 24-4.

[0506] 24-1 SFC retention time: 3.590 min

[0507] 1H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.7Hz, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.76 (dt, J = 2.8, 8.7Hz, 1H) ,7.62(dd,J=4.5,8.6Hz,1H),6.85(s,1H),5.59(t,J=5.3Hz,1H),5.14(t,J=5.8Hz,1H),4.07(t,J=5.4 Hz,2H),3.93(t,J=5.1Hz,2H),3.65(d,J=6.1Hz,3H),3.53(dt,J=3.5,8.8Hz,1H),3.45–3.39( m,1H),3.25–3.15(m,2H),3.02–2.86(m,2H),2.18–2.12(m,1H),1.98(s,3H),1.91–1.84(m,1H)

[0508] MS (ESI+) m / z = 537.2 [M+H] + .

[0509] 24-2 SFC retention time: 4.526 min

[0510] 1 H NMR (400MHz, DMSO-d6)δ=8.60(s,1H),8.32(s,1H),8.09(s,1H),7.82–7.72(m,1H),7.62(d d,J=3.5,7.3Hz,1H),6.85(s,1H),5.59(s,1H),5.19–5.10(m,1H),4.07(s,2H),3.93(s,2H ),3.71–3.59(m,3H),3.53(d,J=1.5Hz,1H),3.41(d,J=7.3Hz,1H),3.26–3.15(m,2H),3.04 –2.85(m,2H),2.21–2.09(m,1H),1.98(s,3H),1.91–1.82(m,1H)MS(ESI+)m / z=537.2[M+H] + .

[0511] 24-3 SFC retention time: 2.401 min

[0512] 1H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.9Hz, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.77 (dt, J = 2.9, 8.8Hz, 1 H),7.62(dd,J=4.3,8.5Hz,1H),6.85(s,1H),5.59(t,J=5.2Hz,1H),5.15(t,J=5.6Hz,1H),4.07(t, J=5.3Hz,2H),3.93(t,J=5.2Hz,2H),3.69–3.61(m,3H),3.53(dt,J=3.5,8.7Hz,2H),3.23–3.16(m, 2H),3.01–2.86(m,2H),2.20–2.10(m,1H),1.98(s,3H),1.93–1.83(m,1H)MS(ESI+)m / z=537.1[M+H] + .

[0513] 24-4 SFC retention time: 3.599 min

[0514] 1 H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.7Hz, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.77 (dt, J = 2.6 ,8.9Hz,1H),7.62(dd,J=4.5,8.8Hz,1H),6.85(s,1H),5.59(t,J=5.1Hz,1H),5.15(t,J=5. 7Hz,1H),4.07(t,J=5.5Hz,2H),3.97–3.91(m,2H),3.68–3.62(m,3H),3.58–3.49(m,2H),3 .23–3.17(m,2H),3.03–2.84(m,2H),2.15(d,J=7.1Hz,1H),1.98(s,3H),1.93–1.81(m,1H)

[0515] MS (ESI+) m / z = 537.2 [M+H] + .

[0516] Example 25 4-(2-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)piperidine-1-carbonitrile

[0517] Compound 25 was synthesized by using a route and steps similar to Example 24, replacing the compound 1-tert-butyloxycarbonyl-3-pyrrolidone in the first step with the compound N-tert-butyloxycarbonyl-4-piperidone.

[0518] MS (ESI+) m / z = 551.3 [M+H] + .

[0519] 1 H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.9 Hz, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.76 (dt, J = 2.9, 8. 8Hz,1H),7.62(dd,J=4.5,8.8Hz,1H),6.85(s,1H),5.59(s,1H),5.16(s,1H),4.05(t,J=5.3H z,2H),3.93(t,J=5.6Hz,2H),3.70(s,2H),3.45(d,J=12.6Hz,2H),3.07(d,J=11.2Hz,2H),2. 97(t,J=5.3Hz,2H),2.69–2.62(m,1H),1.97(s,3H),1.85(d,J=11.5Hz,2H),1.68–1.56(m,2H)

[0520] Example 26 7-(5-(1-cyanoazetidin-3-yl)-3-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 26)

[0521] First step: tert-butyl 3-(2-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-4-oxo-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)azetidine-1-carboxylate (26A)

[0522] Compound 1F (204 mg, 0.5 mmol, 1.0 eq), compound Int-2 (192 mg, 0.5 mmol, 1 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (45 mg, 0.05 mmol, 0.1 eq), and potassium carbonate (345 mg, 2.5 mmol, 5 eq) were mixed in dioxane (10 mL) and water (2 mL). The mixture was stirred at 85°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 26A (223 mg, 0.38 mmol, yield: 76%) as a white solid.

[0523] MS (ESI+) m / z = 587.3 [M+H] + .

[0524] Step 2: 7-(5-(azetidin-3-yl)-3-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (26B)

[0525] Compound 26A (117 mg, 0.2 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to afford the title compound 26B (53.5 mg, 0.11 mmol, yield: 55%) as a yellow solid.

[0526] MS (ESI+) m / z = 487.2 [M+H] + .

[0527] Step 3: 7-(5-(1-cyanoazetidin-3-yl)-3-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 26)

[0528] Compound 26B (25 mg, 0.05 mmol, 1.0 eq) and N,N-diisopropylethylamine (32.5 mg, 0.25 mmol, 5.0 eq) were dissolved in dichloromethane (1 mL). Cyanogen bromide (32 mg, 0.3 mmol, 6.0 eq) was added to the mixture at 0°C under a nitrogen atmosphere and stirred for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 μm, elution phase: 5%-75% acetonitrile-water) to afford the title compound 26 (15.3 mg, 0.03 mmol, yield: 60%) as a white solid.

[0529] MS (ESI+) m / z = 512.1 [M+H] + .

[0530] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=2.9Hz,1H),8.47(s,1H),7.85–7.80(m,1H),7.76–7.71(m,1H),7.56(d,J=1.2Hz,1H),6.76(d,J=1.3Hz, 1H),6.05(q,J=6.4Hz,1H),5.30–5.18(m,1H),4.48–4.43(m,2H),4.43–4.32(m,4H),4.00–3.91(m,2H),2.38(s,3H),1.79(d,J=6.4Hz,3H).

[0531] Example 27 7-(5-(1-cyanopyrrolidin-3-yl)-3-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 27)

[0532] Compound 27 was synthesized by similar routes and steps to Example 26, replacing Compound Int-2 in the first step with Compound Int-4.

[0533] MS (ESI+) m / z = 526.2 [M+H] + .

[0534] 1H NMR(400MHz,DMSO-d6)δ8.61(d,J=2.9Hz,1H),8.47(s,1H),7.83–7.78(m,1H ),7.76–7.72(m,1H),7.56(d,J=1.3Hz,1H),6.76(s,1H),6.05(q,J=6.4Hz,1 H),5.20-5.14(m,1H),4.47–4.32(m,2H),3.79–3.72(m,2H),3.62–3.54(m,2 H),3.50–3.42(m,2H),2.40(s,3H),2.18–2.02(m,2H),1.78(d,J=6.5Hz,3H).

[0535] Example 28 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-7-(oxetan-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Compound 28)

[0536] Step 1: 7-chloro-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine (28A)

[0537] 1-(5-Fluoropyridin-2-yl)ethan-1-ol (Compound 1N, 846 mg, 6.0 mmol, 1.5 eq) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (480 mg, 12.0 mmol, 3 eq) was added at 0°C. After stirring for 30 minutes, 1B (748 mg, 4.0 mmol, 1.0 eq) was added, and the reaction mixture was allowed to react for 3 hours. Aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was filtered, and the organic phase was evaporated under reduced pressure to remove the solvent. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 28A (920 mg, 3.15 mmol, yield: 79%).

[0538] MS (ESI+) m / z = 292.3 [M+H] + .

[0539] Step 2: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (28B)

[0540] Compound 28A (920 mg, 3.15 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.21 g, 4.73 mmol, 1.5 eq), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (127 mg, 0.32 mmol, 0.1 eq), tris(dibenzylideneacetone)dipalladium (147 mg, 0.16 mmol, 0.05 eq), and potassium acetate (927 mg, 9.46 mmol, 3 eq) were mixed in dioxane (10 mL). The mixture was stirred at 90°C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was filtered and dried to give the title compound 28B (980 mg, crude product).

[0541] MS (ESI+) m / z = 384.2 [M+H] + .

[0542] Step 3: 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (28C)

[0543] Compound 28B (400 mg, 1 mmol, 1.0 eq), compound 1O (726 mg, 2 mmol, 2 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (95 mg, 0.1 mmol, 0.1 eq), and potassium carbonate (650 mg, 5.0 mmol, 5 eq) were mixed in dioxane (5 mL) and water (1 mL). The mixture was stirred at 90°C under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried. The resulting residue was purified on a silica gel column (eluting with a mixture of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 28C (410 mg, 0.83 mmol, yield: 83%).

[0544] MS (ESI+) m / z = 493.2 [M+H] + .

[0545] Step 4: 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (28D)

[0546] Compound 28C (410 mg, 0.83 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and N-iodosuccinimide (358.8 mg, 1.59 mmol, 1.9 eq) was added at room temperature. The mixture was stirred at room temperature for 2 hours and then purified by chromatography (Phenomenex Luna C18 150*25 mm*10 μm, eluting with 5%-80% acetonitrile-water) to obtain the title compound 28D (420.5 mg, 0.68 mmol, yield: 82%).

[0547] MS (ESI+) m / z = 619.2 [M+H] + .

[0548] Step 5: 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester (28E)

[0549] Compound 28D (420.5 mg, 0.68 mmol, 1.0 eq), tetrakis(triphenylphosphine)palladium (75 mg, 0.068 mmol, 0.1 eq), cuprous iodide (25 mg, 0.13 mmol, 0.2 eq), trimethyl(1-propynyl)silane (145 mg, 1.3 mmol, 2 eq), triethylamine (200 mg, 1.92 mmol, 3 eq), and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (3.2 ml, 3.2 mmol, 5 eq) were mixed in toluene (3 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The residue was then dried and purified on a reverse-phase silica gel column (Phenomenex Luna C18 150*25 mm*10 μm, eluting with a water mixture containing 5-90% acetonitrile) to obtain the title compound 28E (282 mg, 0.53 mmol, yield: 78%).

[0550] MS (ESI+) m / z = 531.2 [M+H] + .

[0551] Step 6: 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (28F)

[0552] To a solution of compound 28E (282 mg, 0.53 mmol, 1.0 eq) in dichloromethane (2 mL) was added 2 mL of 4 M hydrochloric acid in dioxane. The mixture was stirred at room temperature for 2 hours and then dried to give the title compound 28F (228 mg, 0.52 mmol, yield: 98%).

[0553] MS (ESI+) m / z = 431.2 [M+H] + .

[0554] Step 7: 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-7-(oxabutane-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Compound 28)

[0555] Compound 28F (43 mg, 0.1 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 1.6 eq), and 3-oxetanone (72 mg, 1 mmol, 10 eq) were mixed in methanol (2 mL), followed by the addition of sodium cyanoborohydride (32 mg, 0.5 mmol, 5 eq). The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The residue was then spin-dried and purified on a reverse-phase silica gel column (Phenomenex Luna C18 150*25 mm*10 μm, eluting with a water mixture containing 5-95% acetonitrile) to afford the title compound 28 (15 mg, 0.032 mmol, yield: 32%).

[0556] MS (ESI+) m / z = 487.2 [M+H] + .

[0557] 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.9Hz,1H),7.85–7.79(m,1H),7.71–7.68(m,1H ),7.67–7.60(m,1H),7.26–7.21(m,1H),6.54–6.49(m,1H),5.83(q,J=6.4Hz,1H), 4.62(t,J=6.6Hz,2H),4.51(t,J=6.1Hz,2H),3.89–3.82(m,2H),3.72–3.68(m,1H) ,3.52(s,2H),2.78–2.72(m,2H),2.28(s,3H),2.11(s,3H),1.73(d,J=6.4Hz,3H).

[0558] Example 29 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (Compound 29)

[0559] Compound 29 was synthesized by similar routes and steps to Example 28, except that compound 10 in the third step was replaced by compound Int-1.

[0560] MS (ESI+) m / z = 487.2 [M+H] + .

[0561] 1 H NMR(400MHz, DMSO-d6)δ8.60(d,J=2.9Hz,1H),7.84–7.78(m,1H),7.73–7.66( m,2H),7.33–7.27(m,1H),6.56–6.50(m,1H),5.87(q,J=6.4Hz,1H),4.63(t,J= 6.6Hz,2H),4.53(t,J=6.1Hz,2H),4.10(t,J=5.5Hz,2H),3.76–3.70(m,1H),3. 52(s,2H),2.84–2.75(m,2H),2.11(s,3H),2.02(s,3H),1.74(d,J=6.4Hz,3H).

[0562] Example 30 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-7-(1-(oxetan-3-yl)pyrrolidin-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Compound 30)

[0563] Step 1: tert-Butyl 3-(2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyrrolidine-1-carboxylate (Compound 30A)

[0564] Compound 28F (129 mg, 0.3 mmol, 1.0 eq), acetic acid (30 mg, 0.48 mmol, 1.6 eq), and 1-tert-butoxycarbonyl-3-pyrrolidone (555 mg, 3 mmol, 10 eq) were mixed in methanol (2 mL), followed by the addition of sodium cyanoborohydride (100 mg, 1.5 mmol, 5 eq). The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The residue was then spin-dried and purified on a reverse-phase silica gel column (Phenomenex Luna C18 150*25 mm*10 μm, eluting with a water mixture containing 5-95% acetonitrile) to afford the title compound 30A (110 mg, 0.18 mmol, yield: 61%).

[0565] MS (ESI+) m / z = 600.2 [M+H]+.

[0566] Step 2: 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-7-(pyrrolidin-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (30B)

[0567] To a solution of compound 30A (110 mg, 0.18 mmol, 1.0 eq) in dichloromethane (2 mL) was added 2 mL of 4 M hydrochloric acid in dioxane. The mixture was stirred at room temperature for 2 hours and then dried to give the title compound 30B (85 mg, 0.17 mmol, yield: 94%).

[0568] MS (ESI+) m / z = 500.2 [M+H] + .

[0569] Step 3: 2-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-3-methyl-7-(1-(oxabutane-3-yl)pyrrolidin-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (Compound 30)

[0570] Compound 30B (50 mg, 0.1 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 1.6 eq), and 3-oxetanone (72 mg, 1 mmol, 10 eq) were mixed in methanol (2 mL), followed by the addition of sodium cyanoborohydride (32 mg, 0.5 mmol, 5 eq). The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. The residue was then spin-dried and purified on a reverse-phase silica gel column (Phenomenex Luna C18 150*25 mm*10 μm, eluting with a water mixture containing 5-95% acetonitrile) to afford the title compound 30 (23 mg, 0.041 mmol, yield: 41%).

[0571] MS (ESI+) m / z = 556.3 [M+H]+.

[0572] 1 H NMR(400MHz,DMSO-d6)δ8.61(d,J=2.9Hz,1H),7.85–7.81(m,2H),7.72–7.68(m,1H ),7.33(s,1H),6.58(s,1H),5.91–5.86(m,1H),4.77–4.71(m,2H),4.70–4.66(m,2H ),3.95–3.90(m,2H),3.81–3.76(m,3H),2.99–2.95(m,2H),2.34–2.32(m,1H),2.3 1(s,3H),2.12(s,3H),2.02–1.98(m,4H),1.76(d,J=6.4Hz,3H),1.49–1.44(m,2H).

[0573] Biological evaluation

[0574] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0575] Test Example 1: FGFR enzyme inhibition experiment of the disclosed compounds

[0576] The test samples were dissolved in DMSO to prepare a 10 mM storage solution and stored at -30°C.

[0577] The enzyme reaction was performed using enzyme reaction kits produced by Promega (FGFR1 Kit Catalog No. V2991, FGFR2 Kit Catalog No. V4060, FGFR3 Kit Catalog No. VA7459, reaction substrate was Poly E4Y1) according to the manufacturer's recommended method. The reaction product was detected using the ADP detection kit (ADP-Glo TMKinase Assay, Catalog No. V9101).

[0578] A 5 μL reaction system contained 0.4 ng / μL FGFR1 kinase (or 1.4 ng / μL FGFR2 kinase, or 1 ng / μL FGFR3 kinase), 0.2 μg / μL Poly E4Y1, 5 μM ATP (both Poly E4Y1 and ATP were obtained from a Promega enzyme reaction kit), and a serial dilution of the test compound (starting at 10,000 nM, followed by 3× serial dilutions, 10 concentrations). The final DMSO concentration in the reaction system was 1%. Reactions were performed in 384-well plates (PerkinElmer, Cat. 6007290), with all assays performed in duplicate. In these systems, ATP (from a Promega enzyme reaction kit) was added to initiate the reaction. The 384-well plate was incubated at 25°C for 60 minutes, followed by the addition of 5 μL ADP-Glo ​​(from an ADP assay kit) and the reaction at 25°C for 40 minutes. Then, 10 μL assay buffer was added and the reaction was continued at 25°C for 30 minutes. After the reaction, luminescence values ​​were measured using PerkinElmer Envision. Luminescence values ​​represent the amount of ADP generated. The inhibition rate of kinase activity was calculated using high signal (luminescence value with enzyme added but no inhibitor), low signal (luminescence value without enzyme), and sample signal (luminescence value with enzyme added and inhibitor added). The half-maximal inhibitory concentration (IC) was calculated using XLfit2.0 software (ID Business Solutions Ltd). 50 ).

[0579] Inhibition rate % = ((high Lum-sample Lum) / (high Lum-low Lum)) × 100%. The in vitro activity of the disclosed example compounds on the wild-type FGFR3 / 2 / 1 enzyme was determined by the above test. Compared with FGFR1 and / or FGFR2, the disclosed example compounds have higher selectivity for FGFR3. The measured IC 50 See Table 1 for values.

[0580] Table 1

[0581] Test Example 2: Experiment on the inhibition of cell proliferation by the disclosed compounds

[0582] The test samples were dissolved in DMSO to prepare a 10 mM stock solution and stored at -30°C. During the assay, the compound was diluted 10-fold in serum-free medium containing 5% DMSO to the assay concentration.

[0583] The cells SNU16 were purchased from ATCC (American Type Culture Collection, USA, catalog number CRL-5974), JMSU-1 cells were purchased from DSMZ, and RT112 cells were purchased from DSMZ. IMDM culture medium was purchased from Gibco (Cat. No. 12440-061), culture medium 1640 was purchased from Gibco (Cat. No. 12634-010), and serum was purchased from Gibco (Cat. No. 10099-141C). Luminescent Cell Viability Assay (CTG) was purchased from Promega (Cat. No. G7570).

[0584] Cells in the logarithmic growth phase were seeded in a 96-well cell culture plate with a volume of 100 μL. Cultured overnight at 37°C in an incubator containing 5% carbon dioxide. The next day, 10 μL / well gradient dilutions (starting concentration: 5000 nM, 3× gradient dilutions, 10 concentration points) of the test compound were added, and 10 μL / well serum-free culture medium containing 5% DMSO was added to the control group instead of the drug diluent. The final concentration of DMSO was 0.5%. Incubated in the incubator for 72 hours. Add 50 μL / well CTG reagent. Incubated at 37°C in a carbon dioxide incubator for 40 minutes, and the light absorbance at 450 nm was read on the Perkinelmer Envision. The inhibition rate of the compound on cell growth was calculated according to the following formula, and the half-maximal proliferation inhibition concentration (GI) of the drug was calculated using XLFit2.0 software. 50 ).

[0585] Inhibition rate (%) = [1-([OD 450 ] 化合物 -[OD 450 ] 背景 ) / ([OD 450 ] 细胞 -[OD 450 ] 背景 )]×100%

[0586] Among them: [OD 450 ] 化合物 Represents the absorbance value of compound-treated wells;

[0587] [OD 450 ] 细胞represents the light absorption value of the cell wells in which DMSO was used instead of the compound on day 3;

[0588] [OD 450 ] 背景 represents the light absorbance value of the cell wells in which DMSO was used instead of the compound on day 0;

[0589] The compounds disclosed herein were tested in the cell proliferation assay using the above test, and the GI values ​​were 50 See Table 2 for values.

[0590] Table 2

Claims

1. A compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in, X1 and X2 are independently selected from N or C; Y1 and Y2 are independently selected from N or CR 6 ; Z is selected from O, S, NH or a bond; R 6 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl or C3-C6 cycloalkyl; R 1 Selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C 10 Aryl or 5-6 membered heteroaryl is optionally replaced by R 1a replace; R 1a Selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 Aryl or 5-6 membered heteroaryl, the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclic, C6-C 10 Aryl or 5-6 membered heteroaryl is optionally replaced by R 1b replace; R 1b is selected from halogen, OH, C1-C6 alkyl or C1-C6 alkoxy; R 2 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally replaced by R 2a replace; R 2a is selected from halogen, OH, NH2, C1-C6 alkyl or C1-C6 alkoxy, wherein the OH, NH2, C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; R 3 is selected from H, CN, OH, halogen, C1-C6 alkyl or C1-C6 alkoxy; Ring A is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; Ring C is selected from C3-C6 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl or not present, the C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R c replace; Every R a 、R c independently selected from halogen, CN, OH, NH2, -S(=O)-C1-C4 alkyl, -S(=O)2-C1-C4 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl; L is selected from a bond, -CH2-, -C(=O)-, -NHC(=O)-, C3-C6 carbocycle, 4-6 membered heterocycle, C6-C 10 Aromatic ring or 5-6 membered heteroaromatic ring; W is selected from H, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, 4-6 membered heterocyclic group, CN, -C(=O)CR 4 =C(R 5 )2, -C(=O)C≡CR 5 、-NHC(=O)CR 4 =C(R 5 )2, -NHC(=O)C≡CR 5 、-S(=O)CR 4 =C(R 5 )2、-S(=O)2CR 4 =C(R 5 )2, -NHS(=O)CR 4 =C(R 5 )2 or -NHS(=O)2CR 4 =C(R 5 )2; R 4 Selected from H, CN, halogen or C1-C6 alkyl; Every R 5 independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 4-10 membered heterocyclyl is optionally replaced by R 5a replace; R 5a Independently selected from halogen, CN, OH, NH2, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2, C3-C8 cycloalkyl or 4-6 membered heterocyclyl; R 8 、R 9 、R 10 Independently selected from H, halogen, OH, NH2, =O, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; R 11 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or absent; or R 8 、R 11 The atoms to which it is attached together form a C3-C6 cycloalkyl group; One or more hydrogen atoms of the compound are optionally deuterium atoms.

2. The compound of formula (I) according to claim 1, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein: R 8 、R 9 、R 10 All are H; Or, R 8 =O, R 11 Does not exist, R 9 、R 10 Both are H.

3. The compound of formula (I) according to claim 1 or 2, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein: At least one of X1 or X2 is N; Alternatively, X1 is N and X2 is C; Alternatively, X1 is C and X2 is N.

4. The compound of formula (I) according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: At least one of Y1 or Y2 is N; Or, Y1 is N and Y2 is CR 6 ; Alternatively, Y1 is CR 6 , Y2 is N.

5. The compound of formula (I) according to any one of claims 1 to 4, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Z is O.

6. The compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 6 Selected from H, C1-C6 alkyl or C3-C6 cycloalkyl; Or, R 6 Selected from halogen, C1-C6 alkyl or C3-C6 cycloalkyl; Or, R 6 Selected from C1-C6 alkyl or C3-C6 cycloalkyl.

7. The compound of formula (I) according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from H, CN, OH, NH2, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C3-C6 cycloalkyl is optionally replaced by R 1a replace; Or, R 1 is selected from CN, OH, halogen, C1-C6 alkyl, C2-C6 alkynyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkynyl or C3-C6 cycloalkyl is optionally replaced by R 1a replace; Or, R 1 is selected from CN, halogen or C2-C6 alkynyl, the C2-C6 alkynyl being optionally replaced by R 1a replace; Optionally, R 1a is selected from halogen, OH, C1-C6 alkyl or C1-C6 alkoxy.

8. The compound of formula (I) according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from CN, OH, NH2, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 2a replace; Or, R 2 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R 2a replace. Optionally, R 2a is selected from halogen, OH or NH2.

9. The compound of formula (I) according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R a replace; Alternatively, Ring A is selected from 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally replaced by R a replace; Alternatively, Ring A is selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl being optionally replaced by R a replace; Alternatively, Ring A is selected from pyridyl, said pyridyl being optionally substituted by R a replace; Optionally, R a It is a halogen.

10. The compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from 4-10 membered heterocyclic groups or is absent, wherein the 4-10 membered heterocyclic groups are optionally replaced by R c replace; Alternatively, ring C is selected from a 4-10 membered heterocyclic group, wherein the 4-10 membered heterocyclic group is optionally replaced by R c replace; Alternatively, ring C is selected from a 4-7 membered heterocyclic group, wherein the 4-7 membered heterocyclic group is optionally replaced by R c replace; Optionally, R c Selected from halogen or C1-C6 alkyl.

11. The compound of formula (I) according to any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 11 Selected from H or absent; or R 11 、R 8 The atoms to which it is attached together form a cyclopropyl group.

12. The compound of formula (I) according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: W is selected from C1-C6 alkyl, -S(=O)2C1-C6 alkyl, CN, -C(=O)CR 4 =C(R 5 )2, -C(=O)C≡CR 5 、-NHC(=O)CR 4 =C(R 5 )2, -NHC(=O)C≡CR 5 、-S(=O)CR 4 =C(R 5 )2、-S(=O)2CR 4 =C(R 5 )2, -NHS(=O)CR 4 =C(R 5 )2 or -NHS(=O)2CR 4 =C(R 5 )2; Alternatively, W is selected from CN, -C(=O)CR 4 =C(R 5 )2, -C(=O)C≡CR 5 、-NHC(=O)CR 4 =C(R 5 )2, -NHC(=O)C≡CR 5 、-S(=O)CR 4 =C(R 5 )2、-S(=O)2CR 4 =C(R 5 )2, -NHS(=O)CR 4 =C(R 5 )2 or -NHS(=O)2CR 4 =C(R 5 )2; Alternatively, W is selected from H, C1-C6 alkyl, -S(=O)2C1-C6 alkyl, 4-6 membered heterocyclic group, CN, -C(=O)CR 4 =C(R 5 )2 or -C(=O)C≡CR 5 ; Alternatively, W is selected from CN or -C(=O)CR 4 =C(R 5 )2.

13. The compound of formula (I) according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: L is selected from a bond or -C(=O)-.

14. The compound of formula (I) according to any one of claims 1 to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (II) or its stereoisomer or its pharmaceutically acceptable salt: Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, W are as defined in any one of claims 1-13.

15. The compound of formula (I) according to any one of claims 1 to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (III) or its stereoisomer or its pharmaceutically acceptable salt: Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, W are as defined in any one of claims 1-13.

16. The compound of formula (I) according to any one of claims 1 to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (IV-b) or its stereoisomer or its pharmaceutically acceptable salt: Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, W, R 8 、R 9 、R 10 、R 11 As defined in any one of claims 1 to 13.

17. The compound of formula (I) according to any one of claims 1 to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (V) or its stereoisomer or its pharmaceutically acceptable salt: Among them, ring A, ring C, R 1 、R 2 、R 3 、R 6 , Z, L, W are as defined in any one of claims 1-13.

18. The compound of formula (I) according to claim 1, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein: The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:

19. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. Use of the compound of formula (I) according to any one of claims 1 to 18, or its stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a medicament for preventing or treating a disease mediated by FGFR.

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