Heterocyclic compounds as FGFR inhibitors and their applications

Abstract

This invention provides a class of heterocyclic compounds as FGFR inhibitors, specifically disclosing compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts, pharmaceutical compositions comprising them, and their use in the preparation of medicaments for treating cancer.

Description

[Technical Field]

[0001] This invention belongs to the field of pharmaceutical technology, and relates to heterocyclic compounds of FGFR inhibitors, their preparation methods, and applications. [Cross-reference to related applications]

[0002] This application claims the benefit and priority of the following two Chinese invention patent applications, the entire contents of which are incorporated herein by reference:

[0003] Patent application No. 202110380922.X, filed with the China National Intellectual Property Administration on April 3, 2021; and

[0004] Patent application No. 202210224490.8, filed with the China Intellectual Property Office on March 7, 2022. [Previous Technology]

[0005] FGFR (Fibroblast Growth Factor Receptor) is a transmembrane receptor-type tyrosine kinase. The family mainly includes four members: FGFR1, 2, 3, and 4. After FGFR binds to its ligand FGF (Fibroblast growth factor), it causes receptor dimerization, leading to phosphorylation of tyrosine residues in the kinase domain and activation of the receptor. Subsequently, activated FGFR further activates downstream signaling pathways such as RAS / RAF, PI3K / AKT, JAK / STAT, and PLCγ, participating in the regulation of multiple processes including cell proliferation, apoptosis, migration, repair of damaged tissues, and angiogenesis. Under normal physiological conditions, the FGFR signaling pathway is strictly regulated and remains at a weak activation level. However, excessive activation often leads to the occurrence and development of tumors. The molecular mechanisms of abnormal FGFR activation mainly 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 cholangiocarcinoma (14%), and FGFR2 gene mutation occurs in endometrial cancer (12-14%). FGFR3 gene abnormalities are most common 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 (incidence not reported); the second most common is myeloma, with 15-20% of myeloma patients having FGFR3 gene translocations. Some of these FGFR gene abnormalities have been shown to be associated with poor patient prognosis.

[0006] Given the importance of the FGFR signaling pathway in tumor treatment, targeted therapy against the FGFR signaling pathway has become a research hotspot in the field of tumor treatment in recent years. This patent application discovers a class of heterocyclic compounds that can selectively inhibit FGFR proteins, such as FGFR2, and have a killing effect on related tumor cells. [Summary of the Invention]

[0007] This invention provides a class of heterocyclic compounds, their stereoisomers, and pharmaceutically acceptable salts. These compounds can inhibit the activity of FGFRs, thereby affecting their biological function.

[0008] Specifically, the present invention provides a compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (I)

[0009] X and Z are each independently selected from CR9 or N;

[0010] W is selected from O or C (=O);

[0011] Y is selected from C(=O), NHC(=O), C(=O)NH, N(CH3) or bonds;

[0012] Ring A is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclic group;

[0013] Ring B is selected from C6-C10 aryl, 5-10 heteroaryl or C3-C10 cyclic hydrocarbon group;

[0014] E is selected from C3-C10 cyclic hydrocarbon group, C6-C10 aryl group, 3-12-membered heterocyclic group or 5-12-membered heteroaryl group, wherein the C3-C10 cyclic hydrocarbon group, C6-C10 aryl group, 3-12-membered heterocyclic group or 5-12-membered heteroaryl group is optionally substituted by one or more R1a;

[0015] R1a is independently selected from halogen, CN, NH2, OH, C1-C6 alkyl, C3-C8 cyclic hydrocarbon, 3-6 membered heterocyclic group, C1-C6 alkoxy, -S(=O)-C1-C4 alkyl, -S(=O)2-C1-C4 alkyl, -S(=O)(=NR8a)R8b, -N=S(=O)R8aR8b, -NR8aR8b, -C(=O)NR8aR8b or -NR7C(=O)R8b, wherein the C1-C6 alkyl, C3-C8 cyclic hydrocarbon, 3-6 membered heterocyclic group, C1-C6 alkoxy, -S(=O)-C1-C4 alkyl or -S(=O)2-C1-C4 alkyl is optionally substituted by one or more groups independently selected from halogen, OH, C1-C3 alkoxy or CN;

[0016] R1 is selected from -CN, -(CH2)qCN, -C≡CR5, -C(=O)C≡CR5, -C(=O)CR6=C(R5)2, -R7C(=O)CH=C(R5)2, -NHC(=O)CR6=C(R5)2, -R7NHC(=O)CH=C(R5)2, -NHC(=O)C≡CR5, -S(=O)CR6=C(R5)2, -S(=O)2CR6=C(R5)2, -NHS(=O)CR6=C(R5)2, -NHS(=O)2CR6=C(R5)2, -NR6C(=O)CR6=C(R5)2 or NHC(=O)R5;

[0017] R5 is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cyclic hydrocarbon, 3-12 membered heterocyclic group or C6-C10 aryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cyclic hydrocarbon, 3-12 membered heterocyclic group or C6-C10 aryl is optionally substituted by one or more R5a;

[0018] R5a is independently selected from halogens, CN, N(R5b)2, OH, NO2, C3-C8 cycloalkyl groups or 3-12 membered heterocyclic groups;

[0019] R5b is independently selected from H or C1-C6 alkyl groups;

[0020] R6 is selected from H, CN, halogens, or C1-C6 alkyl groups;

[0021] R7 is selected from C1-C6 alkylene groups, C3-C8 cycloalkylene groups, or 3-12 membered heterocyclic groups;

[0022] R2 is selected from H, NH2, C1-C6 alkyl, OH or halogen;

[0023] R3 is independently selected from halogens, CN, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy or C3-8 cycloalkyl;

[0024] R4 is independently selected from halogen, CN, NH2, OH, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-10 membered heterocyclic group, -C(=O)R8a, -C(=O)OR8a, -NR8aR8b, -C(=O)NR8aR8b or -NR7C(=O)R8b, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 3-10 membered heterocyclic group is optionally substituted by one or more R4a;

[0025] R4a is independently selected from halogens, CN, NH2, OH or C1-C6 alkyl groups;

[0026] R8a and R8b are each independently selected from H, halogen, CN, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0027] R9 is selected from H, CN, OH, NH2, -NHR10, -NH-C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl, wherein the C1-C6 alkyl, -NH-C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl is optionally substituted by one or more R10;

[0028] R10 is independently selected from halogen, NH2, C3-C8 cycloalkyl, 3-10 heterocyclic, C6-C10 aryl or 5-10 heteroaryl, wherein the NH2, C3-C8 cycloalkyl, 3-10 heterocyclic, C6-C10 aryl or 5-10 heteroaryl is optionally substituted by one or more R11;

[0029] R11 is independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C3-C8 cycloalkyl or 3-10 heterocyclic group, wherein the C1-C6 alkyl, C3-C8 cycloalkyl or 3-10 heterocyclic group is optionally substituted by C1-C6 alkyl, halogen, OH, -NH-C1-C6 alkyl, -N(C1-C6 alkyl)2;

[0030] n and m are each independently selected from 0, 1, 2 or 3;

[0031] q is selected from 1, 2 or 3.

[0032] In some embodiments, ring A is selected from 5-10 member heteroaryl groups.

[0033] In some embodiments, ring A is selected from 5-6 member heteroaryl groups.

[0034] In some embodiments, ring A is selected from 5-6 membered heteroaryl or 5-6 membered heterocyclic group.

[0035] In some embodiments, ring A is selected from pyrimidinyl, pyridinyl or tetrahydropyrroleyl.

[0036] In some embodiments, ring A is selected from pyrimidinyl or tetrahydropyrroleyl.

[0037] In some embodiments, ring A is selected from pyridinyl or pyrimidinyl.

[0038] In some embodiments, ring A is selected from pyrimidine groups.

[0039] In some embodiments, ring B is selected from C6-C10 aryl or 5-10 heteroaryl.

[0040] In some embodiments, ring B is selected from C6-C10 aryl or C3-C10 cyclic hydrocarbon groups.

[0041] In some embodiments, cyclo B is selected from phenyl or cyclohexenyl.

[0042] In some embodiments, ring B is selected from phenyl.

[0043] In some implementations, W is selected from O.

[0044] In some embodiments, Y is selected from C(=O), NHC(=O), C(=O)NH or bond.

[0045] In some embodiments, Y is selected from N(CH3) or bond.

[0046] In some implementations, Z is selected from CR9.

[0047] In some embodiments, E is selected from C3-C6 cyclic hydrocarbon group, C6-C10 aryl group, 3-10 heterocyclic group or 5-10 heteroaryl group, wherein the C3-C6 cyclic hydrocarbon group, C6-C10 aryl group, 3-10 heterocyclic group or 5-10 heteroaryl group is optionally substituted by R1a.

[0048] In some embodiments, E is selected from C6-C10 aryl, 3-10 heterocyclic or 5-10 heteroaryl, wherein the C6-C10 aryl, 3-10 heterocyclic or 5-10 heteroaryl is optionally replaced by R1a.

[0049] In some embodiments, E is selected from C6-C10 aryl, 3-10 heterocyclic or 5-6 heteroaryl, wherein the C6-C10 aryl, 3-10 heterocyclic or 5-6 heteroaryl is optionally replaced by R1a.

[0050] In some embodiments, E is selected from the following groups optionally substituted with R1a: phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, pyrroloyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothiopheneyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, tetrahydropyrroloyl, tetrahydropyridyl, piridyl, piridinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2-pyridoneyl, 2-piridoneyl, azacyclobutyl, 1,4-diazacycloheptyl, bicyclo[1.1] .1] Pentyl, 2,7-diazaspirocyclic[4.4] Nonyl, 2,8-diazaspirocyclic[4.5] Decyl, 2,7-diazaspirocyclic[3.5] Nonyl, 2,6-diazaspirocyclic[3.5] Nonyl, 2,6-diazaspirocyclic[3.3] Heptyl, 2,6-diazaspirocyclic[3.4] Octyl, 2,5-diazaspirocyclic[3.4] Octyl, 4,7-diazaspirocyclic[2.5] Octyl, 2,5-diazabicyclo[2.2.1] Heptyl, 5,8-diazaspirocyclic[3.5] Nonyl, 3,8-diazabicyclo[3.2.1] Octyl or dihydropyrrole.

[0051] In some embodiments, E is selected from the following groups optionally substituted by R1a: phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, furanyl, thiopheneyl, pyrroloyl, pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothiopheneyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, tetrahydropyrroloyl, tetrahydropyridyl, piridyl, piridinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl Alkenyl, 2-pyridone, 2-piperazinone, aziridine, 1,4-diazaspiroheptanyl, bicyclo[1,1,1]pentyl, 2,7-diazaspiro[4.4]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl or 2,5-diazaspiro[3.4]octyl.

[0052] In some embodiments, E is selected from the following groups optionally substituted by R1a: phenyl, pyridinyl, thiopheneyl, pyrazolyl, imidazolyl, azacyclobutyl, tetrahydropyrroleyl, piridinyl, piridinyl, tetrahydropyridinyl, cyclohexyl, cyclohexenyl, morpholinyl, 2-piridinoneyl, 2-pyridinoneyl, 1,4-diazaspirocyclic heptyl, bicyclo[1,1,1]pentyl, 2,7-diazaspirocyclic[4.4]nonyl, 2,8-diazaspirocyclic[4.5]decyl, 2,7-diazaspirocyclic[3.5]nonyl, 2,6-diazaspirocyclic[3.5]nonyl, 2,6-diazaspirocyclic[3.3]heptyl, 2,6-diazaspirocyclic[3.4]octyl, 2,5-diazaspirocyclic[3.4] Octyl, 4,7-diazaspirocyclo[2.5]octyl, 2,5-diazabicyclo[2,2,1]heptyl, 5,8-diazaspirocyclo[3.5]nonyl, 3,8-diazabicyclo[3,2,1]octyl or dihydropyrrole.

[0053] In some embodiments, E is selected from the following groups optionally substituted by R1a: phenyl, pyridinyl, thiophene, pyrazolyl, imidazolyl, aziridine, tetrahydropyrroleyl, piridinyl, piridinyl, tetrahydropyridinyl, cyclohexyl, cyclohexenyl, morpholinyl, 2-piridinoneyl, 2-pyridinoneyl, 1,4-diazaspiroheptanyl, bicyclo[1,1,1]pentyl, 2,7-diazaspiro[4.4]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, or 2,5-diazaspiro[3.4]octyl.

[0054] In some embodiments, R1a is independently selected from halogen, CN, NH2, OH, C1-C6 alkyl, C3-C8 cyclic hydrocarbon, 3-6 membered heterocyclic group, C1-C6 alkoxy, -S(=O)-C1-C4 alkyl, -S(=O)2-C1-C4 alkyl, -S(=O)(=NR8a)R8b, -N=S(=O)R8aR8b, -NR8aR8b, -C(=O)NR8aR8b or -NR7C(=O)R8b, wherein the C1-C6 alkyl, C3-C8 cyclic hydrocarbon, 3-6 membered heterocyclic group, C1-C6 alkoxy, -S(=O)-C1-C4 alkyl or -S(=O)2-C1-C4 alkyl is optionally substituted by one or more groups independently selected from halogen, OH or C1-C3 alkoxy.

[0055] In some embodiments, R1a is independently selected from halogen, CN, NH2, OH, -NR8aR8b, C1-C6 alkyl, C3-C8 cyclic hydrocarbon, 3-6 membered heterocyclic group, C1-C6 alkoxy, wherein the C1-C6 alkyl, C3-C8 cyclic hydrocarbon, 3-6 membered heterocyclic group, C1-C6 alkoxy is optionally substituted by one or more groups independently selected from halogen, OH or C1-C3 alkoxy.

[0056] In some embodiments, R1a is independently selected from halogen, CN, NH2, OH, C1-C6 alkyl, C3-C8 cyclic hydrocarbon, 3-6 membered heterocyclic group, C1-C6 alkoxy, wherein the C1-C6 alkyl, C3-C8 cyclic hydrocarbon, 3-6 membered heterocyclic group, C1-C6 alkoxy is optionally substituted by one or more groups independently selected from halogen, OH or C1-C3 alkoxy.

[0057] In some embodiments, R1a is independently selected from halogen, -NR8aR8b, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl is optionally substituted by one or more groups independently selected from halogen, OH, CN or C1-C3 alkoxy.

[0058] In some embodiments, R1a is independently selected from C1-C6 alkyl or C1-C6 alkoxy.

[0059] In some embodiments, R1a is independently selected from Cl, F, CH3, -OCH3, CF3, -N(CH3)2 or CH2CN.

[0060] In some embodiments, R1a is independently selected from CH3 or -OCH3.

[0061] In some embodiments, R1 is selected from -CN, -(CH2)qCN, -C≡CH, -C(=O)C≡CR5, -C(=O)CR6=C(R5)2, -R7C(=O)CH=C(R5)2, -NHC(=O)CR6=C(R5)2, -R7NHC(=O)CH=C(R5)2, -NHC(=O)C≡CR5, -S(=O)CR6=C(R5)2, -S(=O)2CR6=C(R5)2, -NHS(=O)CR6=C(R5)2 or -NHS(=O)2CR6=C(R5)2.

[0062] In some embodiments, R1 is selected from -C≡CR5, -C(=O)C≡CR5, -C(=O)CR6=C(R5)2, -R7C(=O)CH=C(R5)2, -NHC(=O)CR6=C(R5)2, -R7NHC(=O)CH=C(R5)2, -NHC(=O)C≡CR5, -S(=O)CR6=C(R5)2, -S(=O)2CR6=C(R5)2, -NHS(=O)CR6=C(R5)2, -NHS(=O)2CR6=C(R5)2, -NR6C(=O)CR6=C(R5)2 or NHC(=O)R5.

[0063] In some embodiments, R1 is selected from -CN, -(CH2)qCN, -C≡CR5, -C(=O)C≡CR5, -C(=O)CR6=C(R5)2, -R7C(=O)CH=C(R5)2, -NHC(=O)CR6=C(R5)2, -R7NHC(=O)CH=C(R5)2, -NHC(=O)C≡CR5, -NHS(=O)2CR6=C(R5)2, -NR6C(=O)CR6=C(R5)2 or NHC(=O)R5.

[0064] In some embodiments, R1 is selected from -(CH2)qCN, -C≡CH, -C(=O)C≡CR5, -C(=O)CR6=C(R5)2, -R7C(=O)CH=C(R5)2, -NHC(=O)CR6=C(R5)2, -R7NHC(=O)CH=C(R5)2, -NHC(=O)C≡CR5 or -NHS(=O)2CR6=C(R5)2.

[0065] In some embodiments, R1 is selected from -C≡CR5, -C(=O)C≡CR5, -C(=O)CR6=C(R5)2, -R7C(=O)CH=C(R5)2, -NHC(=O)CR6=C(R5)2, -R7NHC(=O)CH=C(R5)2, -NHC(=O)C≡CR5, -NHS(=O)2CR6=C(R5)2, -NR6C(=O)CR6=C(R5)2 or NHC(=O)R5.

[0066] In some embodiments, R6 is selected from H, F, Cl, CN or CH3.

[0067] In some embodiments, R6 is selected from H, F, CN or CH3.

[0068] In some embodiments, R5 is independently selected from H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3-C6 cycloalkyl is optionally substituted by one or more R5a.

[0069] In some embodiments, R5 is independently selected from H or C1-C3 alkyl groups, wherein the C1-C3 alkyl groups are optionally substituted by one or more R5a.

[0070] In some embodiments, R5a is independently selected from halogen, CN, N(R5b)2 or 3-12 membered heterocyclic groups.

[0071] In some embodiments, R5a is independently selected from halogens, CN, N(R5b)2 or 3-6 membered heterocyclic groups.

[0072] In some embodiments, R5a is independently selected from N(R5b)2 or 3-6 membered heterocyclic groups.

[0073] In some embodiments, R5a is independently selected from halogen, CN, N(CH3)2, guanidinyl or morpholinyl.

[0074] In some embodiments, R5a is independently selected from N(R5b)2, piracetamyl or morpholinyl.

[0075] In some embodiments, R5b is independently selected from C1-C6 alkyl groups.

[0076] In some embodiments, R5b is independently selected from CH3.

[0077] In some embodiments, R7 is selected from C1-C6 alkylene, C3-C6 cycloalkylene or 3-6 heterocyclic groups.

[0078] In some embodiments, R7 is selected from the following groups: -CH2-, -CH(CH3)-, -C(CH3)2-, or.

[0079] In some embodiments, R7 is selected from the following groups: -CH2-, -CH(CH3)-, -C(CH3)2-, or.

[0080] In some embodiments, R1 is selected from the following groups: , ...

[0081] In some embodiments, R1 is selected from the following groups: , , , , , , , , , , , , , , , , , , , , or.

[0082] In some embodiments, R2 is selected from H, NH2, CH3, OH or halogens.

[0083] In some embodiments, R2 is selected from H, NH2, CH3 or halogen.

[0084] In some embodiments, R2 is selected from H, NH2 or halogen.

[0085] In some embodiments, R2 is selected from H or NH2.

[0086] In some embodiments, R3 is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkyl groups.

[0087] In some embodiments, R3 is independently selected from halogens or C1-C6 alkoxy groups.

[0088] In some embodiments, R3 is selected from F and -OCH3.

[0089] In some embodiments, R3 is selected from halogens.

[0090] In some implementations, R3 is selected from F.

[0091] In some implementations, m is selected from 0 or 1.

[0092] In some embodiments, R4 is independently selected from halogens, CN, NH2, OH, NO2, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-10 heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3-10 heterocyclic groups are optionally substituted by one or more R4a.

[0093] In some embodiments, R4 is independently selected from CN, halogen, C1-C6 alkyl or C1-C6 alkoxy.

[0094] In some embodiments, R4 is independently selected from halogens, C1-C6 alkyl groups, or C1-C6 alkoxy groups.

[0095] In some embodiments, R4 is independently selected from CN or C1-C6 alkyl groups.

[0096] In some embodiments, R4 is independently selected from CN or CH3.

[0097] In some embodiments, R4 is independently selected from C1-C6 alkyl groups.

[0098] In some embodiments, R4 is independently selected from CH3.

[0099] In some implementations, n is selected from 0 or 1.

[0100] In some embodiments, R9 is selected from H, NH2, -NHR10, -NH-C1-C6 alkyl or C1-C6 alkyl, wherein the C1-C6 alkyl or -NH-C1-C6 alkyl is optionally substituted by one or more R10.

[0101] In some embodiments, R9 is selected from H, CN, OH, NH2, -NHR10 or -NH-C1-C6 alkyl, wherein the -NH-C1-C6 alkyl is optionally substituted by one or more R10.

[0102] In some embodiments, R10 is independently selected from halogens, NH2, C3-C8 cycloalkyl or 3-10 heterocyclic groups, wherein the NH2, C3-C8 cycloalkyl or 3-10 heterocyclic group is optionally substituted by one or more R11.

[0103] In some embodiments, R10 is independently selected from halogen, NH2, C3-C6 cycloalkyl, 5-6 heterocyclic, C6-C10 aryl or 5-6 heteroaryl, wherein the NH2, C3-C6 cycloalkyl, 5-6 heterocyclic, C6-C10 aryl or 5-6 heteroaryl is optionally substituted by one or more R11.

[0104] In some embodiments, R10 is independently selected from NH2, C3-C6 cycloalkyl, 5-6 membered heterocyclic, C6-C10 aryl or 5-6 membered heteroaryl, wherein the NH2, C3-C6 cycloalkyl, 5-6 membered heterocyclic, C6-C10 aryl or 5-6 membered heteroaryl is optionally substituted by one or more R11.

[0105] In some embodiments, R10 is independently selected from NH2, 3-10-membered heterocyclic group, C6-C10 aryl or 5-10-membered heteroaryl, wherein the NH2, 3-10-membered heterocyclic group, C6-C10 aryl or 5-10-membered heteroaryl is optionally replaced by one or more R11.

[0106] In some embodiments, R10 is independently selected from the following groups that are optionally substituted by one or more R11: pyrazolyl, NH2, phenyl, pyridyl, pyrroleyl, tetrahydropyrroleyl or morpholinyl.

[0107] In some embodiments, R11 is independently selected from C1-C6 alkyl, halogen, C1-C3 alkoxy, C3-C6 cycloalkyl or 5-6 membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl or 5-6 membered heterocyclic group is optionally substituted with C1-C6 alkyl, halogen, OH, -NH-C1-C6 alkyl or -N(C1-C6 alkyl)2.

[0108] In some embodiments, R11 is independently selected from the following groups optionally substituted with C1-C6 alkyl, halogen, OH, -NH-C1-C6 alkyl, or -N(C1-C6 alkyl)2: methyl, ethyl, tetrahydropyrrolyl, piperidinyl, -OCH3, F, piperazinyl, cyclopropyl, or isopropyl.

[0109] In some embodiments, R11 is independently selected from the following groups optionally substituted with methyl, ethyl, OH, -N(CH3)2 or F: methyl, ethyl, tetrahydropyrrolyl, piperidinyl, -OCH3, F, piperazinyl, cyclopropyl or isopropyl.

[0110] In some embodiments, R11 is independently selected from C1-C6 alkyl groups.

[0111] In some embodiments, R9 is selected from the following groups: H, CN, OH, NH2, etc.

[0112] In some embodiments, the compound represented by formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound represented by formula (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (II)

[0113] Where rings A, X, Y, Z, E, R1, R2, R3, R4, n, and m are defined as above. It should be understood that in claim 14 relating to formula (II), when claim 14 refers to the preceding claim x, rings A, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (II) are defined as in claim x. For example, when claim 14 refers to claim 1, rings A, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (II) are defined as in claim 1; when claim 14 refers to claim 2, rings A, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (II) are defined as in claim 2, and so on.

[0114] In some embodiments, the compound represented by formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound represented by formula (III), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (III)

[0115] Where rings B, X, Y, Z, E, R1, R2, R3, R4, n, and m are as defined above. It should be understood that in claim 15 relating to formula (III), when claim 15 refers to the preceding claim x, rings B, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (III) are as defined in claim x. For example, when claim 15 refers to the preceding claim 1, rings B, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (III) are as defined in claim 1; when claim 15 refers to the preceding claim 2, rings B, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (III) are as defined in claim 2, and so on.

[0116] In some embodiments, the compound represented by formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound represented by formula (IV), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (IV).

[0117] Where X, Y, Z, E, R1, R2, R3, R4, n, and m are defined as above.

[0118] It should be understood that in claim 16 relating to formula (IV), when claim 16 refers to the preceding claim x, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (IV) are as defined in claim x. For example, when claim 16 refers to the preceding claim 1, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (IV) are as defined in claim 1; when claim 16 refers to the preceding claim 2, X, Y, Z, E, R1, R2, R3, R4, n, and m in formula (IV) are as defined in claim 2, and so on.

[0119] In some embodiments, the compound represented by formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound represented by formula (V), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (V)

[0120] Where rings A, B, Y, W, E, R1, R2, R3, R4, n, and m are defined as above.

[0121] It should be understood that in claim 17 relating to formula (V), when claim 17 refers to the preceding claim x, rings A, B, Y, W, E, R1, R2, R3, R4, n, and m in formula (V) are as defined in claim x. For example, when claim 17 refers to the preceding claim 1, rings A, B, Y, W, E, R1, R2, R3, R4, n, and m in formula (V) are as defined in claim 1; when claim 17 refers to the preceding claim 2, rings A, B, Y, W, E, R1, R2, R3, R4, n, and m in formula (V) are as defined in claim 2, and so on.

[0122] In some embodiments, the compound represented by formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or stereoisomers thereof or pharmaceutically acceptable salts: or.

[0123] Furthermore, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0124] Furthermore, the present invention 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 the preparation of a medicament for the prevention or treatment of diseases related to FGFR.

[0125] Furthermore, the present invention 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 the prevention or treatment of diseases related to FGFR.

[0126] Further, the present invention relates to a compound of formula (I) for the prevention or treatment of diseases associated with FGFR, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0127] The present invention also relates to a method for preventing or treating diseases associated with FGFR, the method comprising administering a therapeutically effective dose of a compound of formula (I) of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a pharmaceutical preparation comprising a compound of formula (I) of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0128] Furthermore, the diseases associated with FGFR are selected from cancer.

[0129] In some embodiments of this application, the cancer is, for example, a solid tumor, such as gastric cancer.

[0130] On the other hand, the present invention provides the use of a compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of cancer.

[0131] On the other hand, the present invention provides the use of a compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of cancer.

[0132] On the other hand, the present invention provides a compound of formula (I) for the prevention or treatment of cancer, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0133] On the other hand, the present invention provides a method for treating cancerous diseases in mammals, comprising administering to a mammal, preferably a human, a therapeutically effective amount of a compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Implementation Method

[0134] Term Definitions and Explanations

[0135] Unless otherwise stated, the definitions of groups and terms recorded in this specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the embodiments, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should fall within the scope of this specification.

[0136] In this article, “” represents a connection site.

[0137] In this article, double arrows “” or multiple arrows “” or “” in the synthetic route indicate multi-step reactions.

[0138] The term “pharmaceutical acceptable salt” means a pharmaceutically acceptable non-toxic acid or base salt, including inorganic acids and bases, and organic acids and bases.

[0139] The compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of the present invention.

[0140] The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, the absolute configuration of a stereocenter is indicated by wedge-shaped and dashed lines. When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, they include E and Z geometric isomers unless otherwise specified. Similarly, all tautomers are included within the scope of this invention.

[0141] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

[0142] The term “stereoisomer” refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.

[0143] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer usually produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical properties. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of compounds.

[0144] The term "pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0145] The term “substituted” means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo substitution will not occur on the aromatic group.

[0146] The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0147] The term “C1-C6 alkyl” should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, 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-C3 alkyl” should be understood to refer to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms.

[0148] The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-", wherein the alkyl group is as defined above. The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C6 alkoxy" may include the range of "C1-C3 alkoxy", etc.

[0149] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0150] The term “haloalkyl” is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term “C1-C6 haloalkyl” means a C1-C6 alkyl group as defined above that is substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl, etc.

[0151] The term “haloalkoxy” is intended to include both monohaloalkoxy and polyhaloalkoxy, wherein a halogen is substituted on the alkyl moiety of the alkoxy group. For example, the term “C1-C6 haloalkoxy” means a C1-C6 alkoxy group as defined above that is substituted with one or more halogens.

[0152] The term "C3-C10 cycloalkyl group" should be understood to refer to a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. This includes C3-C10 cycloalkyl groups and C3-C10 partially saturated cycloalkyl groups (e.g., cycloalkenyl, cycloynyl, etc.). The term "C3-C10 cycloalkyl group" refers to a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene. C3-C10 partially saturated cycloalkyl groups refer to a partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl. According to the present invention, the bicyclic hydrocarbon ring includes a bridged ring, a spiro ring, or a fused ring structure. The term "C3-C8 cyclic hydrocarbon group" should be understood to refer to a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 8 atoms, including C3-C8 cycloalkyl and C3-C8 partially saturated cyclic hydrocarbon groups; the term "C3-C8 cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms. The term "C3-C6 cyclic hydrocarbon group" should be understood to refer to a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 atoms, including C3-C6 cycloalkyl and C3-C6 partially saturated cyclic hydrocarbon groups; the term "C3-C6 cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms.

[0153] The term “C6-C10 aryl” should be understood as a monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms, particularly a ring having 6 carbon atoms (“C6 aryl”), such as phenyl; or a ring having 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl; or a ring having 10 carbon atoms (“C10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0154] The term “3-12 membered heterocyclic group” should be understood as a saturated or partially unsaturated monocyclic or bicyclic ring having 3-12 ring atoms. The bicyclic ring includes bridged rings, spirocyclic rings, and fused rings. The “heterocyclic” in the heterocyclic group includes, but is not limited to, atoms and / or groups of atoms independently selected from N, O, S, C(=O), C(=S), S(=O), S(O)2, and the number of heteroatoms can be, for example, 1-6 (e.g., 1, 2, 3, 4, 5, or 6). Specifically, the heterocyclic group can be monocyclic, including but not limited to: 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piridinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piridinyl, 2-piridinoneyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazinolo-2(1H)-yl rings. The ring may be partially unsaturated, meaning it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl; or it may be benzofused, such as, but not limited to, dihydroisoquinolinyl. The term "3-8 membered heterocyclic group" should be understood as a saturated or partially unsaturated monocyclic or bicyclic ring having 3-8 ring atoms. The term "3-6 membered heterocyclic group" should be understood as a saturated or partially unsaturated monocyclic or bicyclic ring having 3-6 ring atoms.

[0155] The term “5-12 heteroaryl” should be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems, particularly 5, 6, 9, or 10 ring atoms, and in each case may be benzofused. The “heteroaryl” in the term means that the aromatic ring includes, but is not limited to, atoms and / or groups of atoms independently selected from N, O, S, C(=O), C(=S), S(=O), S(O)2, and the number of heteroatoms may be, for example, 1-6 (e.g., 1, 2, 3, 4, 5, or 6). Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrileyl, inazinyl, purinyl, etc., and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridineyl, zoazolyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, or etc.

[0156] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0157] (i) Suppress the disease or disease state, that is, curb its development;

[0158] (ii) To alleviate a disease or disease state, even if the disease or disease state subsides.

[0159] The term “therapeutic effective amount” means (i) the amount of the compound of the present invention used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present invention constituting a “therapeutic effective amount” varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by those skilled in the art based on their own knowledge and the disclosure of this invention.

[0160] The term "individual" includes both 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; domesticated 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 may be a human.

[0161] The term "excipient" refers to a pharmaceutically acceptable inert component. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression. Typical examples of "pharmaceutically acceptable carriers" suitable for the above formulations include sugars, starches, cellulose and their derivatives, which are commonly used excipients in pharmaceutical formulations.

[0162] The term "pharmaceuticalally acceptable excipient" refers to those excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0163] The words “comprise”, “comprise” or “comprise” and their English variants such as comprises or comprising should be understood in an open, non-exclusive sense, that is, “including but not limited to”.

[0164] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0165] The chemical reactions in the specific embodiments of the present invention are carried out in a suitable solvent, which must be suitable for the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0166] Detailed Implementation

[0167] The following embodiments describe the technical solution of the invention in detail, but the scope of protection of the invention includes, but is not limited to, these embodiments.

[0168] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift was 10⁻⁶ (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0169] Abbreviations:

[0170] DMAP: 4-Dimethylaminopyridine; Et3N or TEA: Triethylamine; THF: Tetrahydrofuran; MeCN or ACN: Acetonitrile; 18-crown-6 or 18-crown-6: 1,4,7,10,13,16-Hexaoxane; Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphine)ferrocene]palladium dichloride; dioxane: Dioxane; Pd(PPh4)3: Tetra(triphenylphosphine)palladium; DIEA or DIPEA: N, N-Diisopropylethylamine; DMF: N,N-Dimethylmethylmethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; NMP: N-methylpyrrolidone; BOP-Cl: bis(2-oxo-3-oxazolyl)phosphine chloride; Pyridine: pyridine; Pd(OAc)2: palladium acetate; S-phos: 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; DCM: dichloromethane; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; TCHP: tricyclohexylphosphine; TFA: trifluoroacetic acid; LiHMDS: lithium hexamethyldisilamide; TsCl: p-toluenesulfonate; MeAC: acetic acid; TBAF: tetrabutylammonium fluoride; TsOH: p-toluenesulfonic acid; LAH: lithium aluminum hydride.

[0171] Example 1

[0172] N-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)propenylated amide (1)

[0173] Step 1 N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)propenylated amide (1B)

[0174] 4,4,5,5-Tetramethyl-2-(4-aminophenyl)-1,3,2-dioxoboropentane (5.0 g, 23 mmol, 1 eq), 4-dimethylaminopyridine (0.70 g, 5.7 mmol, 0.25 eq), and triethylamine (4.6 g, 46 mmol, 6.3 mL, 2 eq) were dissolved in tetrahydrofuran (50 mL). Acrylamide chloride (2.5 g, 27 mmol, 2.2 mL, 1.2 eq) in tetrahydrofuran (5 mL) was slowly added dropwise at 0°C. The resulting mixture was stirred at 20°C for 5 hours. The solvent was removed by vacuum distillation, and water (100 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (100 mL × 3 times). The organic phases were mixed, washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluting phase was a mixture of petroleum ether and ethyl acetate containing 16–18%) to give a white solid, title compound 1B (2.3 g, 8.3 mmol, yield: 36%).

[0175] 1H NMR (400 MHz, DMSO-d6): δ= 10.24 (s, 1H), 7.73 - 7.66 (m, 2H), 7.65 - 7.59 (m, 2H), 6.50 - 6.39 (m, 1H), 6.31 - 6.22 (m, 1H), 5.77 (d,J= 10.8 Hz, 1H), 1.28 (s, 12H).

[0176] Second step: 2-(4-bromo-2-fluorophenoxy)-4-methylpyrimidine (1E)

[0177] 4-Bromo-2-fluorophenol (5.0 g, 26 mmol, 1.0 eq) and 2-chloro-4-methylpyrimidine (3.7 g, 29 mmol, 1.1 eq) were dissolved in acetonitrile (30 mL), and potassium carbonate (7.2 g, 52 mmol, 2.0 eq) and 18-crown-6 (0.69 g, 2.6 mmol, 0.10 eq) were added. The resulting mixture was stirred at 85°C for 12 hours, cooled, and then extracted with water (100 mL) and ethyl acetate (100 mL × 3 times). The resulting organic phases were mixed, washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (elution phase was a mixture of petroleum ether and ethyl acetate containing 0-15% ethyl acetate) to give a white solid, title compound 1E (7.2 g, yield: 97%).

[0178] 1H NMR (400 MHz, CDC13): δ= 8.35 (d,J= 5.2 Hz, 1H), 7.42 - 7.28 (m, 2H), 7.22 - 7.10 (m, 1H), 6.95 (d,J= 5.2 Hz, 1H), 2.50 (s, 3H).

[0179] Step 3 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenoxy)-4-methylpyrimidine (1G)

[0180] Compound 1E (4.7 g, 17 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxoboronylcyclopentane) (5.1 g, 20 mmol, 1.2 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.2 g, 1.7 mmol, 0.1 eq), and potassium acetate (4.9 g, 50 mmol, 3 eq) were mixed in dioxane (100 mL). The mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. Acetonitrile (100 mL) was added to the mixture, and the mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated to give a black solid, which was the title compound 1G (10 g, crude product).

[0181] MS (ESI+) m / z = 331.0[M+H].

[0182] Step 4: 6-Chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-amine (1I)

[0183] 6-Chloro-5-iodo-4-aminopyrimidine (1.7 g, 6.7 mmol, 1.0 eq), compound 1G (2.2 g, 6.7 mmol, 1.0 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.49 g, 0.67 mmol, 0.10 eq), and potassium phosphate (2.8 g, 13 mmol, 2.0 eq) were mixed in dioxane (40 mL) and water (4 mL). The resulting mixture was stirred at 85°C under a nitrogen atmosphere for 2 hours. The solvent was removed by vacuum distillation of the yellow reaction solution, and the residue was purified by silica gel column chromatography (eluting phase was a mixture of petroleum ether and ethyl acetate containing 33–100% ethyl acetate) to give a pale yellow solid, title compound 1I (1.10 g, yield: 50%).

[0184] 1H NMR (400 MHz, DMSO-d6): δ= 8.49 (d, J = 5.2 Hz, 1H), 8.23 ​​(s, 1H), 7.48 (t,J= 8.4 Hz, 1H), 7.37 (d,J= 11.2 Hz, 1H), 7.21 (d,J= 5.2 Hz, 1H), 7.17 (d,J= 8.0 Hz, 1H), 2.45 (s, 3H).

[0185] Step 5: N-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)propenylated amide (1)

[0186] Compound 1I (0.24 g, 0.72 mmol, 1.0 eq), compound 1B (0.19 g, 0.72 mmol, 1.0 eq), tetraphenylphosphine palladium (84 mg, 0.073 mmol, 0.10 eq), and potassium carbonate (0.20 g, 1.5 mmol, 2.0 eq) were mixed in dioxane (10 mL) and water (1 mL). The resulting mixture was stirred at 85°C under a nitrogen atmosphere for 18 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3 times). The resulting organic phases were mixed, washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by preparative chromatography and lyophilized to give a white solid, title compound 1 (0.15 g, yield: 46%).

[0187] MS (ESI+) m / z = 443.1[M+H].

[0188] 1H NMR (400 MHz, DMSO-d6): δ = 10.20 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 8.4 Hz, 1H), 7.29 - 7.14 (m, 4H), 7.00 (dd,J1= 8.4 Hz,J2= 1.2 Hz, 1H), 6.74 - 6.29 (m, 3H), 6.29 - 6.19 (m, 1H), 5.76 (dd,J1= 10.0 Hz,J2= 2.0 Hz, 1H), 2.43 (s, 3H).

[0189] Example 2

[0190] N-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)methpropenylated amide (2)

[0191] Step 1 N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)phenyl)methylpropenylamide (2B)

[0192] 4,4,5,5-Tetramethyl-2-(4-aminophenyl)-1,3,2-dioxoboropentan (0.20 g, 0.91 mmol, 1 eq), methacrylic acid (0.16 g, 1.8 mmol, 2.0 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.69 g, 1.8 mmol, 2 eq), and N,N-diisopropylethylamine (0.24 g, 0.18 mmol, 2.0 eq) were dissolved in acetonitrile (50 mL). The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 2 hours. The solvent was removed by vacuum distillation, and water (30 mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (30 mL × 3 times). The organic phases were mixed, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluting phase was a mixture of petroleum ether and ethyl acetate containing 0–50% ethyl acetate) to give a pale yellow solid, title compound 2B (0.20 g, yield: 76%).

[0193] 1H NMR (400 MHz, CDC13): δ= 7.79 (d,J= 8.4 Hz, 2H), 7.59 (d,J= 8.4 Hz, 2H), 5.80 (s, 1H), 5.48 (d,J= 1.2 Hz, 1H), 2.07 (s, 3H), 1.35 (s, 12H)

[0194] Second step: N-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)methpropenylated amide (2)

[0195] Compound 1I (0.030 g, 0.090 mmol, 1.0 eq), compound 2B (0.029 g, 0.099 mmol, 1.0 eq), tetraphenylphosphine palladium (0.010 mg, 9.4 µmol, 0.10 eq), and potassium carbonate (0.025 g, 0.18 mmol, 2.0 eq) were mixed in dioxane (5 mL) and water (0.5 mL). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. A saturated ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3 times). The resulting organic phases were mixed, washed with saturated brine (20 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was preparatively purified by chromatography and lyophilized to give a white solid, title compound 2 (3.9 mg, yield: 9.2%).

[0196] MS (ESI+)m / z= 457.2[M+1].

[0197] 1H NMR (400 MHz, MeOD-d4): δ= 9.50 - 9.40 (m, 2H), 8.61 - 8.56 (m, 2H), 8.37 - 8.30 (m, 3H), 8.19 - 8.14 (m, 2H), 8.12 - 8.08 (m, 1H), 6.79 (s, 1H), 6.52 (s, 1H), 3.51 (s, 3H), 3.02 (s, 3H)

[0198] Example 3

[0199] 6-(6-ethynyl-4-methylpyridin-3-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-amine (3)

[0200] Step 1: 5-Bromo-4-methyl-2-((triisopropylsilyl)ethynyl)pyridine (3C)

[0201] Compound 3A (10 g, 40 mmol, 1.0 eq), compound 3B (7.3 g, 40 mmol, 9.0 mL, 1.0 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.9 g, 4.0 mmol, 0.10 eq), cuprous iodide (0.76 g, 4.0 mmol, 0.10 eq), and triethylamine (8.1 g, 80 mmol, 11 mL, 2.0 eq) were mixed in N,N-dimethylformamide (50 mL). The resulting mixture was stirred at 85°C under a nitrogen atmosphere for 2 hours. A saturated ammonium chloride solution (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 3 times). The resulting organic phases were mixed, washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluting phase was a mixture of petroleum ether and ethyl acetate containing 5–12% ethyl acetate) to give a white solid, title compound 3C (8.5 g, yield: 61%).

[0202] 1H NMR (400 MHz, CDC13): δ= 8.56 - 8.47 (m, 1H), 7.26 (s, 1H), 2.30 (s, 3H), 1.08 - 1.06 (m, 21H)

[0203] Step 2: 4-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-2-((triisopropylsilyl)ethynyl)pyridine (3D)

[0204] Compound 3C (4.0 g, 11 mmol, 1.0 eq), compound 1F (5.8 g, 23 mmol, 2.0 eq), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.83 g, 1.1 mmol, 0.10 eq), and potassium acetate (2.2 g, 23 mmol, 2.0 eq) were mixed in 1,4-dioxane (40 mL). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. The solvent was removed by vacuum distillation, and the residue was purified by C18 reversed-phase silica column chromatography (eluting phase was an aqueous solution containing 20–100% acetonitrile) and lyophilized to give a white solid, title compound 3D (0.80 g, yield: 16%).

[0205] 1H NMR (400 MHz, DMSO-d6): δ= 8.61 (s, 1H), 7.38 (s, 1H), 2.45 (s, 3H), 1.31 (s, 12H), 1.18 - 1.04 (m, 21H)

[0206] Step 3: 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(4-methyl-6-((triisopropylsilyl)ethynyl)pyridin-3-yl)pyrimidin-4-amine (3E)

[0207] Compound 1I (0.060 g, 0.18 mmol, 1.0 eq), compound 3D (0.073 g, 0.18 mmol, 1.0 eq), tetraphenylphosphine palladium (0.021 mg, 18 µmol, 0.10 eq), and potassium carbonate (0.075 g, 0.54 mmol, 3.0 eq) were mixed in dioxane (3 mL) and water (0.3 mL). The resulting mixture was stirred at 85°C under a nitrogen atmosphere for 12 hours. The solvent was removed by vacuum distillation, and the residue was purified by preparative chromatography and lyophilized to give a white solid, title compound 3E (75 mg, yield: 73%).

[0208] 1H NMR (400 MHz, CDC13): δ= 8.59 (s, 1H), 8.26 (d,J= 5.2 Hz, 1H), 8.13 (s, 1H), 7.19 - 7.14 (m, 2H), 6.92 - 6.82 (m, 3H), 5.29 - 5.07 (m, 2H), 2.40 (s, 3H), 2.13 (s, 3H), 1.10 - 1.03 (m, 21H)

[0209] Step 4: 6-(6-ethynyl-4-methylpyridin-3-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-amine (3)

[0210] Compound 3E (70 mg, 0.12 mmol, 1.0 eq) was dissolved in 2 mL of tetrahydrofuran, and triethylamine trihydrofluoride (0.20 g, 1.2 mmol, 0.20 mL, 10 eq) was added. The resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 3 hours. The solvent was removed by vacuum distillation, and the residue was purified by preparative chromatography and lyophilized to give a white solid, title compound 3 (24 mg, yield: 47%).

[0211] MS (ESI+)m / z= 413.1[M+H].

[0212] 1H NMR (400 MHz, DMSO-d6): δ= 8.45 (d,J= 5.2 Hz, 1H), 8.48 (s, 1H), 8.16 (s, 1H), 7.40 (s, 1H), 7.28 - 7.21 (m, 2H), 7.16 (d,J= 5.2 Hz, 1H), 7.04 - 6.45 (m, 3H), 4.29 (s, 1H), 2.38 (s, 3H), 2.14 (s, 3H)

[0213] Example 4

[0214] N-(1-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)propenylated amide (4)

[0215] Step 1: 1-tert-butyloxycarbonyl-4-propenylated aminopyridine (4C)

[0216] 1-tert-butyloxycarbonyl-4-aminoguanidine (3.0 g, 15 mmol, 1.0 eq) and N,N-diisopropylethylamine (3.9 g, 30 mmol, 6.3 mL, 2.0 eq) were dissolved in dichloromethane (40 mL), and a solution of acrylamide chloride (2.0 g, 22 mmol, 1.8 mL, 1.5 eq) in dichloromethane (5 mL) was slowly added dropwise at 0°C. The resulting mixture was stirred at 20°C for 3 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (eluting phase was a mixture of petroleum ether and ethyl acetate containing 0–50% ethyl acetate) to give the white solid title compound 4C (2.5 g, yield: 66%).

[0217] 1H NMR (400 MHz, CDC13): δ= 6.29 (dd,J= 1.3, 16.0Hz, 1H), 6.12 - 6.03 (m, 1H), 5.65 (dd,J= 1.3, 10.4 Hz, 1H), 5.57 (br d,J= 8.0 Hz, 1H), 4.15 - 3.91 (m, 3H), 2.87 (t,J= 12.0 Hz, 2H), 2.00 - 1.87 (m, 2H), 1.46 (s, 9H), 1.39 - 1.30 (m, 2H).

[0218] Step 2 4-Acrylamide aminopyridine hydrochloride (4D)

[0219] Compound 4C (2.0 g, 7.9 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL), and 4M dioxane hydrochloride solution (7.86 mL, 4.0 eq) was slowly added dropwise at 0°C. The resulting mixture was stirred at 20°C for 2 hours. The solvent was removed by vacuum distillation to give solid title compound 4D (2.5 g, crude product).

[0220] 1H NMR (400 MHz, DMSO-d6): δ= 8.30 (d,J= 7.2 Hz, 1H), 6.28 - 6.19 (m, 1H), 6.14 - 6.06 (m, 1H), 5.60 (dd,J= 2.3, 10.0 Hz, 1H), 3.30 - 3.19 (m, 2H), 3.03 - 2.86 (m, 2H), 1.92 (dd,J= 3.0, 13.6 Hz, 2H), 1.72 - 1.56 (m, 2H).

[0221] Step 3 N-(1-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)propenylamide (4)

[0222] Compound 4D (0.50 g, 3.2 mmol, 1 eq), compound 1I (0.11 mg, 0.32 mmol, 0.1 eq), and N,N-diisopropylethylamine (0.84 g, 6.5 mmol, 1.1 mL, 2.0 eq) were dissolved in N-methylpyrrolidone (3 mL). The resulting mixture was microwave-heated at 120°C under a nitrogen atmosphere with stirring for 1 hour. The resulting reaction solution was purified by preparative chromatography (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia)) and lyophilized to give a white solid, title compound 4 (1.6 mg, yield: 1.0%).

[0223] MS (ESI+) m / z = 450.1[M+H].

[0224] 1H NMR (400 MHz, MEOD-d4): δ= 8.43 (d,J= 5.2 Hz, 1H), 8.25 (s, 1H), 7.53 (t,J= 8.2 Hz, 1H), 7.38 (dd,J= 1.8, 10.8 Hz, 1H), 7.30 (d,J= 7.6 Hz, 1H), 7.18 (d,J= 5.2 Hz, 1H), 6.20 (d,J= 6.4 Hz, 2H), 5.64 (t,J= 6.0 Hz, 1H), 4.07 (br d, J = 13.6 Hz, 2H), 3.98 - 3.89 (m, 1H), 3.31 (s, 10H), 3.04 (t,J= 11.6 Hz, 2H), 2.48 (s, 3H), 1.83 (d,J= 10.8 Hz, 2H), 1.46 - 1.36 (m, 2H)

[0225] Example 5

[0226] 1-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl)-2-methylprop-2-en-1-one (5)

[0227] Step 1: 4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (5B)

[0228] Compound 1I (1.1 g, 3.32 mmol, 1.0 eq), compound 5A (1.1 g, 3.5 mmol, 1.1 eq), tetraphenylphosphine palladium (0.24 g, 0.33 mmol, 0.10 eq), and potassium carbonate (1.4 g, 10 mmol, 3.0 eq) were mixed in dioxane (30 mL) and water (3 mL). The resulting mixture was stirred at 85°C under a nitrogen atmosphere for 12 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (elution phase was a mixture of dichloromethane and 0-10% methanol) to give a brown solid, title compound 5B (0.70 g, yield: 44%).

[0229] 1H NMR (400 MHz, CDC13): δ= 8.56 (s, 1H), 8.38 (d,J= 5.2 Hz, 1H), 7.37 (t,J= 8.0 Hz, 1H), 7.17 - 7.06 (m, 2H), 6.96 (d,J= 5.2 Hz, 1H), 5.84 (s, 1H), 5.31 (s, 1H), 5.00 (s, 2H), 3.90 (s, 2H), 3.49 - 3.33 (m, 2H), 2.51 (s, 3H), 1.45 (s, 9H)

[0230] Step 2 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amine hydrochloride (5C)

[0231] Compound 5B (0.20 g, 0.42 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and 4M dioxane hydrochloride solution (1.04 mL, 10 eq) was slowly added dropwise at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The solvent was removed by vacuum distillation to give solid title compound 5C (0.18 g, crude product).

[0232] MS (ESI+) m / z = 378.9[M+H].

[0233] Step 3 1-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl)-2-methylprop-2-en-1-one (5)

[0234] Compound 5C (0.16 g, 0.39 mmol, 1.0 eq) and triethylamine (0.12 g, 1.2 mmol, 0.16 mL, 3.0 eq) were dissolved in dichloromethane (5 mL), and methacrylic acid chloride (42 mg, 0.40 mmol, 1.0 eq) was slowly added dropwise at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The solvent was removed by vacuum distillation, and the residue was preparatively purified (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia)) to give a white solid, title compound 5 (0.070 g, yield: 39%).

[0235] MS (ESI+) m / z = 447.2[M+H].

[0236] 1H NMR (400 MHz, DMSO-d6): δ= 8.46 (d,J= 4.8 Hz, 1H), 8.37 (s, 1H), 7.38 (t,J= 8.2 Hz, 1H), 7.24 (dd,J1= 11.2 Hz, J2= 2.0 Hz, 1H), 7.17 (d,J= 5.2 Hz, 1H), 7.10 (td,J= 8.4, 0.8 Hz, 1H), 6.17 (s, 2H), 5.61 (s, 1H), 5.20 - 5.03 (m, 1H), 4.90 (s, 1H), 3.89 (q,J= 2.8 Hz, 2H), 3.49 (t,J= 5.6 Hz, 2H), 2.43 (s, 3H), 2.22 (d,J= 2.0 Hz, 2H), 1.79 (s, 3H).

[0237] Example 6

[0238] 1-(2-Methylpropenyl)-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidine(6)

[0239] Step 1: 4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidine-1-carboxylic acid tert-butyl ester (6A)

[0240] Compound 5B (0.40 g, 0.84 mmol, 1.0 eq) was dissolved in methanol (20 mL), and 10% palladium on carbon (0.050 g) was added. The resulting mixture was stirred at 30°C for 12 hours under a hydrogen atmosphere. The reaction solution was filtered to remove the palladium on carbon, and the solvent was removed by vacuum distillation. The residue was slurried with a petroleum ether solution containing 10% ethyl acetate and filtered to give solid title compound 6A (0.34 g, yield: 85%).

[0241] 1H NMR (400 MHz, DMSO-d6): δ= 8.51 (d,J= 5.2 Hz, 1H), 8.40 - 8.31 (m, 1H), 7.52 - 7.43 (m, 1H), 7.31 (dd,J= 11.2 Hz, 1.2 Hz, 1H), 7.22 (d,J= 5.2 Hz, 1H), 7.12 (d,J= 8.0 Hz, 1H), 6.24 (s, 2H), 4.18 - 3.81 (m, 4H), 3.17 (s, 1H), 2.44 (s, 3H), 1.70 - 1.59 (m, 2H), 1.53 (d,J= 12.8 Hz, 2H), 1.40 (s, 9H)

[0242] Second step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(piperidin-4-yl)pyrimidin-4-amine hydrochloride (6B)

[0243] Compound 6A (0.30 g, 0.62 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and 4M dioxane hydrochloride solution (1 mL) was slowly added dropwise at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The solvent was removed by vacuum distillation to give solid title compound 6B (0.39 g, crude product).

[0244] MS (ESI+) m / z = 381.2[M+H].

[0245] Step 3 1-(2-Methylpropenyl)-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidine(6)

[0246] Compound 6B (0.39 g, 0.94 mmol, 1.0 eq) and triethylamine (0.28 g, 1.2 mmol, 0.16 mL, 3.0 eq) were dissolved in dichloromethane (5 mL), and methacryl chloride (98 mg, 0.94 mmol, 1.0 eq) was slowly added dropwise at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The solvent was removed by vacuum distillation, and the residue was purified by preparative chromatography (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia)) to give a white solid, title compound 6 (0.075 g, yield: 18%).

[0247] MS (ESI+) m / z = 449.2[M+H].

[0248] 1H NMR (400 MHz, DMSO-d6): δ= 8.51 (d,J= 5.2 Hz, 1H), 8.37 (s, 1H), 7.49 (t,J= 8.4 Hz, 1H), 7.38 - 7.27 (m, 1H), 7.22 (d,J= 5.2 Hz, 1H), 7.13 (d,J= 8.0 Hz, 1H), 6.28 (s, 2H), 5.14 (s, 1H), 4.93 (s, 1H), 4.37 (s, 1H), 3.87 (s, 1H), 2.99 - 2.74 (m, 1H), 2.64 - 2.55 (m, 1H), 2.45 (s, 3H), 1.85 (s, 3H), 1.76 - 1.54 (m, 5H)

[0249] Example 7

[0250] 6-(4-propynylaminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-aminopyrimidine (7)

[0251] Step 1: 6-(4-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-aminopyrimidine (7A)

[0252] Compound 1I (6.0 g, 18.1 mmol), compound 1A (4.0 g, 18.1 mmol), tetraphenylphosphine palladium (2.1 g, 1.81 mmol), and potassium carbonate (5.0 g, 36.2 mmol) were mixed in dioxane (80 mL) and water (8 mL). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction solution was cooled and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (eluting phase was a mixture of dichloromethane and 0-10% methanol) to give a brown solid, title compound 7A (6.0 g, yield: 85%).

[0253] MS (ESI+)m / z= 389.2[M+H].

[0254] 1H NMR (400 MHz, DMSO-d6): δ= 8.56 - 8.46 (m, 1H), 8.38 (s, 1H), 7.69 - 7.49 (m, 1H), 7.35 (t,J= 8.4 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.01 (d,J= 8.4 Hz, 2H), 6.37 (d,J= 8.4 Hz, 2H), 5.33 (s, 2H), 2.44 (s, 3H)

[0255] Second step: 6-(4-propynylaminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-aminopyrimidine (7)

[0256] Compound 7B (54 mg, 0.77 mmol) was dissolved in dichloromethane (5 mL), and bis(2-oxo-3-oxazolyl)phosphine chloride (0.26 g, 1.0 mmol), compound 7A (0.20 g, 0.51 mmol), and N,N-diisopropylethylamine (0.26 g, 2.0 mmol) were slowly added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The solvent was removed by vacuum distillation, and the crude product was purified by preparative chromatography (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia)) to give title compound 7 (23 mg, yield: 10%).

[0257] MS (ESI+)m / z= 441.1[M+H].

[0258] 1H NMR (400 MHz, DMSO-d6): δ= 10.85 (s, 1H), 8.49 (d,J= 5.2 Hz, 1H), 8.45 (s, 1H), 7.47 (d,J= 8.8 Hz, 2H), 7.33 (t,J= 8.4 Hz, 1H), 7.27 - 7.14 (m, 4H), 6.98 (dd,J= 8.4, 1.6 Hz, 1H), 6.52 (s, 2H), 4.43 (s, 1H), 2.42 (s, 3H).

[0259] Example 8

[0260] Following a similar synthetic route and steps as in Example 7, in the second step, replacing raw material 7B with raw material A from the table below can synthesize the following compounds 8-14. serial number Raw material A Compound Structure m / z [M+H] 1 H NMR 8 455.1 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.49 (d,J= 5.2 Hz, 1H), 8.44 (s, 1H), 7.47 (d,J= 8.8 Hz, 2H), 7.33 (t,J= 8.4 Hz, 1H), 7.24 - 7.19 (m, 4H), 6.98 (dd,J= 8.4, 1.2 Hz, 1H), 6.50 (s, 2H), 2.42 (s, 3H), 2.04 (s, 3H). 9 445.2 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.50 (d,J= 5.2 Hz, 1H), 8.45 (s, 1H), 7.47 (d,J= 8.4 Hz, 2H), 7.34 (t,J= 8.4 Hz, 1H), 7.25 - 7.14 (m, 4H), 6.99 (dd,J= 1.2, 8.0 Hz, 1H), 6.48 (s, 2H), 2.43 (s, 3H), 2.30 (q,J= 7.6 Hz, 2H), 1.12 - 1.02 (m, 3H) 10 469.1 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H) , 8.49 (d,J= 5.2 Hz, 1H), 8.45 (s, 1H), 7.46 ( d,J= 8.8 Hz, 2H), 7.32 (t,J= 8.4 Hz, 1H), 7.24-7.20 (m, 4H), 7.00 (d,J= 5.2 Hz, 1H), 6.70 - 6.30 (brs, 2H), 2.44-2.38 (m, 5H), 1.15(t,J= 7.6 Hz, 3H) 11 456.2 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.49 (d,J= 5.2 Hz, 1H), 8.45 (s, 1H), 7.42 (d,J= 8.4 Hz, 2H), 7.32 (t,J= 8.4 Hz, 1H), 7.26 - 7.19 (m, 4H), 6.97 (dd,J= 8.4, 1.2 Hz, 1H), 6.51 (s, 2H), 3.87 (s, 2H), 2.42 (s, 3H) 12 481.1 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.79 (s, 1H), 8.47 (d,J= 5.2 Hz, 1H), 7.58 ( d,J= 8.8 Hz, 2H), 7.38 (t,J= 8.4 Hz, 1H), 7.31 (dd,J= 11.2, 2.0 Hz, 1H), 7.25 (d,J= 8.8 Hz, 2H), 7.20 (d,J= 5.2 Hz, 1H), 7.08 - 7.02 (m, 1H), 2.40 (s, 3H), 1.61 - 1.51 (m, 1H), 1.02 - 0.93 (m, 2H), 0.87 - 0.78 (m, 2H) 13 461.2 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.49 (d,J= 4.8 Hz, 1H), 8.45 (s, 1H), 7.61 (d,J= 8.8 Hz, 2H), 7.33 (t,J= 8.0 Hz, 1H), 7.29 - 7.21 (m, 3H), 7.19 (d,J= 4.8 Hz, 1H), 6.99 (dd,J= 1.2, 8.0 Hz, 1H), 6.52 (s, 2H), 5.78 - 5.62 (m, 1H), 5.42 (dd,J= 3.6, 15.6 Hz, 1H), 2.41 (s, 3H) 14 500.2 1H NMR (400MHz, DMSO-d6) δ 10.09 (s, 1H), 8.49 (d,J= 5.2 Hz, 1H), 8.44 (s, 1H), 7.53 (d,J= 8.8 Hz, 2H), 7.33 (t,J= 8.4 Hz, 1H), 7.27 - 7.16 (m, 4H), 6.98 (dd,J= 1.2, 8.0 Hz, 1H), 6.72 (td,J= 5.6, 15.6 Hz, 1H), 6.63 - 6.31 (m, 2H), 6.24 (d,J= 15.2 Hz, 1H), 3.06 - 3.02 (m, 2H), 2.42 (s, 3H), 2.16 (s, 6H)

[0261] Example 9

[0262] Following a similar synthetic route and steps as in Example 7, in the first step, raw material 1A is replaced by raw material B in the table below, and in the second step, propynic acid 7B is replaced by raw material C to synthesize the corresponding compounds 15-26. serial number Raw material B Raw material C Compound Structure m / z [M+H] 1 HNMR 15 473.1 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 7.29 (s, 1H), 7.24 - 7.11 (m, 4H), 7.11 - 7.00 (m, 1H), 6.84 (s, 1H), 6.56 - 6.32 (m, 3H), 6.29 - 6.18 (m, 1H), 5.82 - 5.68 (m, 1H), 3.43 (s, 3H), 2.36 (s, 3H) 16 443.1 1 H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.46 (t,J= 2.5 Hz, 2H), 7.81 (s, 1H), 7.63 (dd,J= 8.0 , 1.2 Hz, 1H), 7.31 (t,J= 8.3 Hz, 1H), 7.22 (d,J= 1.9 Hz, 1H), 7.24 - 7.15 (m, 1H), 7.11 (t,J= 7.9 Hz, 1H), 6.97 (dd,J = 8.4 , 1.2 Hz, 1H), 6.74 (d,J= 7.9 Hz, 1H), 6.70 - 6.31 (m, 3H), 6.28 - 6.19 (m, 1H), 5.78 - 5.69 (m, 1H), 2.40 (s, 3H) 17 457.1 1 H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.43 (m, 2H), 7.37 - 7.26 (m, 3H), 7.21 (dd,J= 11.2, 1.6 Hz, 1H), 7.18 - 7.13 (m, 3H), 7.04 - 6.99 (m, 1H), 6.60 ( s, 2H), 6.13 - 6.04 (m, 1H), 6.00 - 5.87 (m, 1H), 5.50 - 5.39 (m, 1H), 3.21 (s, 3H), 2.39 (s, 3H). 18 457.2 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.52 - 8.36 (m, 2H), 8.19 (s, 1H), 7.43 (d,J= 1.2 Hz, 1H), 7.35 (dd,J= 8.4, 1.6 Hz, 1H), 7.22 (t,J= 8.4 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.97 - 6.88 (m, 2H), 6.53 ( s, 2H), 6.43 - 6.35 (m, 1H), 6.26 - 6.18 (m, 1H), 5.76 - 5.70 (m, 1H), 2.35 (s, 3H), 2.09 (s, 3H) 19 469.0 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.52 - 8.33 (m, 2H), 7.38 (s, 1H), 7.28 - 7.18 (m, 2H), 7.16 (d,J= 5.2 Hz, 1H), 7.12 (dd,J= 11.2, 1.6 Hz, 1H), 6.91 (d,J= 8.4 Hz, 2H), 6.53 ( s, 2H), 2.36 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H). 20 488.9 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.72 (s, 1H), 8.45 (d,J= 5.2 Hz, 1H), 7.78 (d,J= 1.2 Hz, 1H), 7.45 (dd,J= 8.4, 1.6 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.23 (d,J= 10.8 Hz, 1H), 7.17 (d,J= 5.2 Hz, 1H), 6.99 (d,J= 8.0 Hz, 1H), 2.34 (s, 3H), 2.05 (s, 3H). 21 469.3 1H NMR (400 MHz, DMSO-d6) δ 10.05 ( s, 1H), 8.73 (s, 1H), 8.46 (d,J= 5.2 Hz, 1H), 7.95 ( s, 2H), 7.40 - 7.26 (m, 3H), 7.20 (d,J= 5.2 Hz, 1H), 7.17 (s, 1H), 7.12 (dd,J= 8.4, 1.6 Hz, 1H), 7.03 (dd,J= 8.4, 1.2 Hz, 1H), 2.41 (s, 3H), 2.14 (s, 3H), 2.09 - 1.96 (m, 3H). 22 485.3 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.87 (dd,J= 4.8, 1.2 Hz, 1H), 8.74 (dd,J= 8.4, 1.2 Hz, 1H), 8.51 - 8.42 (m, 2H), 7.75 - 7.62 (m, 1H), 7.35 (t,J= 8.4 Hz, 1H), 7.27 (dd,J= 11.2, 2.0 Hz, 1H), 7.20 (d,J= 5.2 Hz, 1H), 7.02 (dt,J= 8.8, 1.2 Hz, 2H), 6.84 (d,J= 1.6 Hz, 1H), 6.57 ( s, 2H), 3.61 (s, 3H), 2.42 (s, 3H), 2.01 (s, 3H). 23 498.2 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.81 (s, 1H), 8.44 (d,J= 5.2 Hz, 1H), 7.85 ( d,J= 4.4 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.21 (d,J= 5.2 Hz, 1H), 7.14 (dd,J= 8.4, 1.6 Hz, 1H), 7.06 (dd,J= 8.2, 1.2 Hz, 1H), 6.96 (d,J= 1.2 Hz, 1H), 2.47 (s, 6H), 2.42 (s, 3H), 2.02 ( s, 3H). 24 471.4 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.39-8.48 (m, 2H), 8.28 (s, 1H), 7.46 (d,J= 2.0 Hz, 1H), 7.37 (dd,J= 8.4, 2.0 Hz, 1H), 7.23 (t,J= 8.4 Hz, 1H), 7.11-7.17 (m, 2H), 6.89-6.95 (m, 2H), 6.54 (s, 2H), 5.75 (s, 1H), 5.48 (s, 1H), 2.36 (s, 3H), 2.08 (s, 3H), 1.92 (s, 3H) 25 524.4 26 483.1 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.34 (s, 1H), 8.48 - 8.40 (m, 2H), 7.34 (t,J= 8.2 Hz, 1H), 7.27 (dd,J= 11.2, 1.6 Hz, 1H), 7.19 (d,J= 5.2 Hz, 1H), 7.03 (s, 2H), 6.97 (d,J= 8.4 Hz, 1H), 6.50 (s, 2H), 2.42 (s, 3H), 2.08 - 1.94 (m, 9H)

[0263] The synthetic route of compound 23A is as follows:

[0264] Compound 23A can be synthesized using a similar synthetic procedure to that of compound 3D in the second step of Example 3. MS (ESI+) m / z = 263.2 [M+H].

[0265] Example 10

[0266] Following a similar synthetic route and steps as in Example 5, in the first step, 5A is replaced by different raw material D in the table below, and in the third step, methacrylic chloride is replaced by acrylonitrile chloride, to synthesize the corresponding compounds 27-29 in the table below. serial number Raw material D Compound Structure m / z [M+H] 1 HNMR 27 457.1 1H NMR (400 MHz, DMSO-d6) δ = 8.59 (t,J= 5.6 Hz, 1H), 8.48 (d,J= 5.2 Hz, 1H), 8.46 (s, 1H), 7.33 (t,J= 8.4 Hz, 1H), 7.28 - 7.21 (m, 3H), 7.19 (d,J= 5.2 Hz, 1H), 7.12 (d,J= 8.4 Hz, 2H), 6.98 (dd,J= 8.4, 1.6 Hz, 1H), 6.50 (s, 2H), 6.31 - 6.21 (m, 1H), 6.16 - 6.07 (m, 1H), 5.62 (dd,J= 10.0, 2.4 Hz, 1H), 4.32 (d,J= 5.8 Hz, 2H), 2.41 (s, 3H) 28 482.3 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.48 (d,J= 5.2 Hz, 1H), 8.49 (s, 1H), 7.33 (t,J= 8.4 Hz, 1H), 7.26 - 7.19 (m, 4H), 6.99-6.93 (m, 3H), 6.48 (brs, 2H), 6.31 - 6.21 (m, 1H), 6.13 - 6.07 (m, 1H), 5.61 (dd,J= 10.4, 2.4 Hz, 1H), 2.41 (s, 3H), 1.20-1.14 (m, 4H), 29 512.2 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d,J= 5.2 Hz, 1H), 8.42 (s, 1H), 7.36 (t,J= 8.4 Hz, 1H), 7.27 - 7.16 (m, 4H), 7.02 (dd,J= 1.2, 8.4 Hz, 1H), 6.90 - 6.73 (m, 3H), 6.37 (s, 2H), 6.13 (dd,J= 2.4, 16.8 Hz, 1H), 5.78 - 5.63 (m, 1H), 3.66 (d,J= 14.4 Hz, 4H), 3.19 (s, 4H), 2.43 (s, 3H)

[0267] Example 11

[0268] N-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)ethylenesulfonamide (30)

[0269] Compound 7A (150 mg, 0.39 mmol) and pyridine (122 mg, 1.54 mmol) were dissolved in dichloromethane (5 mL), and chloroethylsulfonyl chloride 30A (69 mg, 0.42 mmol) was slowly added dropwise at 0°C. The resulting mixture was stirred at 0°C for 3 hours. The solvent was removed by vacuum distillation, and the crude product was purified by preparative chromatography (Phenomenex Luna C18100*30mm*5um, 5-35% acetonitrile aqueous solution mobile phase) to give title compound 30 (13 mg, yield: 7.3%).

[0270] MS (ESI+)m / z= 479.2[M+H].

[0271] 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.49 (d,J= 5.2 Hz, 1H), 8.43 (s, 1H), 7.32 (t,J= 8.4 Hz, 1H), 7.23 - 7.17 (m, 4H), 7.01 - 6.94 (m, 3H), 6.74 (dd,J= 16.4, 9.6 Hz, 1H), 6.50 (s, 2H), 6.06 (d,J= 16.4 Hz, 1H), 5.97 (d,J= 9.6 Hz, 1H), 2.43 (s, 3H).

[0272] Example 12

[0273] 1-(2-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)prop-2-en-1-one (31)

[0274] Step 1 2-(6-amino-5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (31C)

[0275] Compound 31A (0.50 g, 2.2 mmol), compound 31B (1.1 g, 2.3 mmol), and potassium carbonate (0.61 g, 4.4 mmol) were mixed in dioxane (30 mL). The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 4 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (eluting phase was a mixture of petroleum ether and ethyl acetate containing 25-50% ethyl acetate) to give a pale yellow solid, title compound 31C (1.04 g, yield: 97%).

[0276] MS (ESI+)m / z= 446.3[M+H].

[0277] Second step: 2-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (31D)

[0278] Compound 31C (0.50 g, 0.92 mmol), compound 1G (0.36 g, 1.1 mmol), palladium acetate (10 mg, 46 μmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (38 mg, 92 μmol), and potassium carbonate (0.25 g, 1.84 mmol) were mixed in dioxane (7.5 mL) and water (0.75 mL). The resulting mixture was stirred at 85°C under a nitrogen atmosphere for 12 hours. The solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (eluting phase was a mixture of dichloromethane and 0-10% methanol) to give a brown solid, title compound 31D (60 mg, yield: 12%).

[0279] MS (ESI+)m / z=522.1[M+H].

[0280] Step 3 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(2,7-diazaspiro[3.5]nonane-2-yl)-4-aminopyrimidine (31E)

[0281] Compound 31D (60 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and 4M dioxane hydrochloride solution (1.0 mL) was slowly added dropwise at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The solvent was removed by vacuum distillation to give solid hydrochloride of title compound 31E (80 mg, crude product).

[0282] MS (ESI+) m / z = 422.1[M+H].

[0283] Step 4 1-(2-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-yl)prop-2-en-1-one (31)

[0284] Compound 31E (32 mg, 75 μmol) and triethylamine (32 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL), and a dichloromethane solution of acrylonitrile chloride 4B (5.8 mg, 64 μmol, 64 μL, 1.0 mol / L) was slowly added dropwise at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The solvent was removed by vacuum distillation, and the residue was purified by preparative chromatography (Phenomenex Luna C18150*25mm*10um, eluent 3%-33% acetonitrile-water (containing 0.1% TFA)) to give a white solid, title compound 31 (11 mg, yield: 30%).

[0285] MS (ESI+) m / z = 476.2[M+H].

[0286] 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d,J= 5.2 Hz, 1H), 7.98 (s, 1H), 7.40 (t,J= 8.4 Hz, 1H), 7.27 (dd,J= 11.2, 1.6 Hz, 1H), 7.18 (d,J= 5.2 Hz, 1H), 7.12 (dd,J= 8.4, 1.2 Hz, 1H), 6.76 (dd,J= 16.4, 10.4 Hz, 1H), 6.05 (dd,J=16.4, 2.4 Hz, 1H), 5.79 (br s, 2H), 5.65 - 5.60 (m, 1H), 3.41 - 3.34 (m, 8H), 2.37 (s, 3H), 1.55 (br s, 4H).

[0287] Example 13

[0288] Following a similar synthetic route and steps as in Example 12, in the first step, by replacing 31A with different raw material E in the table below, compounds 32-43 corresponding to the table below can be synthesized. serial number Raw material E Compound Structure m / z [M+H] 1 HNMR 32 436.2 1H NMR (400 MHz, DMSO-d6) δ = 8.48 (d,J= 5.2 z, 1H), 8.01 (s, 1H), 7.41 (t,J= 8.4Hz, 1H), 7.25 - 7.19 (m, 2H), 7.13 (m, 1H), 6.61 - 6.51 (m, 1H), 6.16 - 6.07 (m, 1H), 5.90 (brs, 2H), 5.65 - 5.60 (m, 1H), 3.48 (s, 4H), 3.24 - 3.19 (m, 4H), 2.40 (s, 3H). 33 436.2 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d,J= 5.2 Hz, 1H), 8.01 (s, 1H), 7.48 - 7.41 (m, 1H), 7.25 - 7.18 (m, 2H), 7.09 (d,J= 8.4 Hz, 1H), 6.58 - 6.47 (m, 1H), 6.15 - 6.05 (m, 1H), 5.68 - 5.58 (m, 3H), 5.53 (dd,J= 7.2, 17.8 Hz, 1H), 4.73 - 4.47 (m, 1H), 3.89 - 3.64 (m, 1H), 3.63 - 3.44 (m, 2H), 3.31 - 3.26 (m, 1H), 3.19 (dd,J= 6.4, 12.4 Hz, 1H), 2.45 (s, 3H), 2.19 - 1.99 (m, 1H), 1.96 - 1.74 (m, 1H) 34 422.2 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d,J= 6.8 Hz, 1H), 8.48 (d,J= 4.8 Hz, 1H), 8.21 (s, 1H), 8.00 (s, 1H), 7.40 (t,J= 8.4 Hz, 1H), 7.25 (dd,J= 1.6, 11.2 Hz, 1H), 7.18 (d,J= 5.2 Hz, 1H), 7.11 (dd,J= 1.2, 8.0 Hz, 1H), 6.20 - 6.10 (m, 1H), 6.09 - 6.01 (m, 1H), 5.84 (s, 2H), 5.59 (dd,J= 2.4, 9.6 Hz, 1H), 4.43 - 4.33 (m, 1H), 3.81 (t,J= 7.6 Hz, 2H), 3.51 - 3.46 (m, 2H), 2.37 (s, 3H) 35 450.2 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd,J= 5.2, 1.6 Hz, 1H), 8.01 (d,J= 4.0 Hz, 1H), 7.43 (dt,J= 8.4, 1.6 Hz, 1H), 7.29 (ddd,J= 11.2, 5.6, 1.6 Hz, 1H), 7.20 (d,J= 5.2 Hz, 1H), 7.15 - 7.09 (m, 1H), 6.67 (dd,J= 16.4, 10.4 Hz, 1H), 6.13 - 5.96 (m, 1H), 5.72 (s, 2H), 5.65 - 5.54 (m, 1H), 3.62 - 3.53 (m, 1H), 3.52 - 3.47 (m, 1H), 3.44 (br t,J= 6.4 Hz, 1H), 3.42 - 3.35 (m, 2H), 3.30 - 3.27 (m, 1H), 3.22 (br t,J= 5.6 Hz, 1H), 3.13 (br t,J= 5.6 Hz, 1H), 2.40 (s, 3H), 1.60 - 1.45 (m, 2H) 36 476.2 1 H NMR ( 400 MHz, DMSO-d6) δ 8.48 (dd,J= 0.4, 4.8 Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.37 (t,J= 8.4 Hz, 1H), 7.29 (dd,J= 2.0, 11.6 Hz, 1H), 7.19 (d,J= 5.2 Hz, 1H), 7.12 (br d,J= 8.0 Hz, 1H), 6.51 (ddd,J= 5.6, 10.4, 16.4 Hz, 1H), 6.10 (td,J= 2.4, 16.8 Hz, 1H), 5.64 -5.60 (m, 3H), 3.65 - 3.49 (m, 2H), 3.48 - 3.40 (m, 1H), 3.37 (d,J= 7.2 Hz, 1H), 3.23 (d,J= 4.4 Hz, 1H), 3.16 - 3.12 (m, 1H), 3.08 (dd,J= 4.8, 10.8 Hz, 2H), 2.40 (s, 3H), 1.88 - 1.62 (m, 4H) 37 476.2 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.05 (s, 1H), 7.43 -7.41 (m, 1H), 7.32 -7.16 (m, 3H), 6.26-6.09 (m, 1H), 6.09-6.05 (m, 1H), 6.04 - 6.02 (m, 2H), 5.65 -5.62 (m, 1H), 3.86 (s, 2H), 3.57 (s, 2H), 3.04 -3.00 (m, 4H), 2.42 (s, 3H), 1.55 -1.53(m, 4H). 38 438.0 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d,J= 5.2 Hz, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.41 (t,J= 8.4 Hz, 1H), 7.26 (dd,J= 1.6, 11.2 Hz, 1H), 7.20 (d,J= 5.2 Hz, 1H), 7.12 (dd,J= 1.2, 8.4 Hz, 1H), 6.26 - 6.16 (m, 1H), 6.11 - 5.99 (m, 1H), 5.82 (s, 2H), 5.63 (dd,J= 2.4, 10.4 Hz, 1H), 4.25 (s, 2H), 3.94 (s, 2H), 3.74 (s, 4H), 2.38 (s, 3H) 39 436.2 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d,J= 5.2 Hz, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.41 (t,J= 8.4 Hz, 1H), 7.28 (dd,J= 2.0, 11.2 Hz, 1H), 7.21 (d,J= 5.2 Hz, 1H), 7.12 (dd,J= 1.2, 8.4 Hz, 1H), 6.24 - 5.96 (m, 2H), 5.79 (s, 2H), 5.61 - 5.50 (m, 1H), 3.75 (d,J= 8.8 Hz, 2H), 3.47 - 3.42 (m, 2H), 2.53 (d,J= 2.0 Hz, 1H), 2.43 (s, 3H), 1.40 (s, 3H) 40 436.2 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d,J= 4.8 Hz, 1H), 8.16 (s, 2H), 7.97 (s, 1H), 7.39 (t,J= 8.4 Hz, 1H), 7.30 - 7.16 (m, 2H), 7.11 (d,J= 7.2 Hz, 1H), 6.24 - 5.96 (m, 2H), 5.75 (s, 2H), 5.56 (dd,J= 2.0, 10.0 Hz, 1H), 3.59 (d,J= 8.0 Hz, 2H), 3.33 (s, 2H), 3.22 (t,J= 5.6 Hz, 2H), 2.62 - 2.55 (m, 1H), 2.40 (s, 3H) 41 486.2 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d,J= 5.2 Hz, 1H), 8.32 (d,J= 9.2 Hz, 1H), 8.10 (s, 1H), 7.46 (t,J= 8.4 Hz, 1H), 7.28 (dd,J= 11.2, 1.2 Hz, 1H), 7.23 - 7.12 (m, 2H), 6.36 - 6.25 (m, 1H), 6.11 (dd,J= 17.2, 2.0 Hz, 3H), 5.65 - 5.58 (m, 1H), 4.44 - 4.27 (m, 1H), 3.89 - 3.75 (m, 1H), 3.54 (d,J= 13.2 Hz, 1H), 3.21 - 3.08 (m, 1H), 2.85 (t,J= 11.2 Hz, 1H), 2.38 (s, 3H), 1.64 - 1.45 (m, 2H) 42 450.2 1H NMR (400 MHz, DMSO-d6)δ8.49 (d,J =5.0 Hz, 1H), 8.06 (s, 1H), 7.43 (t,J =8.3 Hz, 1H), 7.19 (d,J =5.0 Hz, 1H), 6.67 (dd,J =16.5, 10.3 Hz, 1H), 6.15 (dd,J =16.5, 2.5 Hz, 1H), 5.98 (s, 2H), 5.66 (dd,J =10.3, 2.6 Hz, 1H), 4.22 (s, 2H), 3.32 (s, 2H), 3.19 (d,J =13.0 Hz, 2H), 2.36 (s, 3H), 1.12 (s, 6H) 43 464.2 1 H NMR (400 MHz, DMSO-d6)δ8.50 (d,J =5.0 Hz, 1H), 8.10 (s, 1H), 7.47 (t,J =8.3 Hz, 1H), 7.33 (dd,J =11.4, 1.9 Hz, 1H), 7.23 - 7.15 (m, 2H), 6.73 (dd,J =16.6, 10.5 Hz, 1H), 6.10 (s, 1H), 6.04 (s, 2H), 5.64 (dd,J =10.5, 2.4 Hz, 1H), 4.32 (d,J =97.1 Hz, 1H), 3.91 (d,J =102.9 Hz, 1H), 3.44 (dd,J =21.5, 12.9 Hz, 2H), 2.81 (s, 1H), 2.60 (d,J =23.1 Hz, 1H), 2.41 (s, 3H), 0.96 (s, 3H).

[0289] Implementation Example 14

[0290] N-(1-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)azacyclobutyl-3-yl)ethylenesulfonamide (44)

[0291] Following a similar synthetic route and steps as in Example 12, 31A was replaced with 34A in the first step, and acrylonitrile chloride 4B was replaced with 2-chloroethylsulfonyl chloride 30A in the fourth step, to synthesize compound 44.

[0292] MS (ESI+) m / z = 458.1[M+H].

[0293] 1HNMR (400 MHz, DMSO-d6) δ 8.48 (d,J= 5.2 Hz, 1H), 8.24 - 7.72 (m, 2H), 7.41 (t,J= 8.4 Hz, 1H), 7.33 - 7.16 (m, 2H), 7.09 ( d,J= 8.8 Hz, 1H), 6.67 (dd,J= 16.8, 9.6 Hz, 1H), 5.99 (d,J= 16.4 Hz, 1H), 5.91 (d,J= 9.6 Hz, 1H), 5.85 (s, 2H), 3.89 (d,J= 4.8 Hz, 1H), 3.71 (t,J= 8.0 Hz, 2H), 3.56 - 3.45 (m, 2H), 2.41 (s, 3H).

[0294] Example 15

[0295] Using compound 34E as a raw material, the synthesis method of step 2 in Example 7 was adopted, in which 7B was replaced with raw material C in the table below to synthesize the corresponding compounds 45-48. serial number Raw material C Compound Structure m / z [M+H] 1 HNMR 45 420.1 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d,J= 6.8 Hz, 1H), 8.49 (d,J= 5.2 Hz, 1H), 8.37 ( s, 1H), 7.99 (s, 1H), 7.40 (t,J= 8.4 Hz, 1H), 7.24 (dd,J= 11.2, 1.6 Hz, 1H), 7.19 (d,J= 5.2 Hz, 1H), 7.10 (dd,J= 8.4, 1.6 Hz, 1H), 5.83 (s, 2H), 4.38 - 4.27 (m, 1H), 4.16 (s, 1H), 3.76 ( t,J= 7.6 Hz, 2H), 3.50 - 3.47 (m, 2H), 2.39 (s, 3H) 46 434.2 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d,J= 6.8 Hz, 1H), 8.49 (d,J= 5.2 Hz, 1H), 8.16 (s, 1H), 7.44 (t,J= 8.4 Hz, 1H), 7.30 (dd,J= 11.2, 1.6 Hz, 1H), 7.20 (d,J= 5.2 Hz, 1H), 7.15 (dd,J= 8.4, 1.2 Hz, 1H), 6.56 (s, 2H), 4.41 - 4.25 (m, 1H), 3.87 (d,J= 3.6 Hz, 2H), 3.56 (s, 2H), 2.38 (s, 3H), 1.94 (s, 3H)。 47 456.1 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d,J= 6.8 Hz, 1H), 8.49 (d,J= 5.2 Hz, 1H), 8.07 (s, 1H), 7.49 - 6.98 (m, 3H), 6.37 - 6.00 (m, 2H), 5.92 (d,J= 2.0 Hz, 1H), 4.61 - 4.28 (m, 1H), 3.87 - 3.60 (m, 3H), 2.37 (s, 2H) 48 424.2 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d,J= 5.2 Hz, 1H), 8.27 ( d,J= 6.8 Hz, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.40 (t,J= 8.4 Hz, 1H), 7.24 (dd,J= 11.2, 1.2 Hz, 1H), 7.19 (d,J= 5.2 Hz, 1H), 7.10 (dd,J= 8.4, 1.2 Hz, 1H), 5.81 (s, 2H), 4.36 - 4.22 (m, 1H), 3.75 (t,J= 7.6 Hz, 2H), 3.43 (d,J= 2.8 Hz, 2H), 2.38 (s, 3H), 2.02 (q,J= 7.6 Hz, 2H), 0.94 (t,J= 7.6 Hz, 3H)

[0296] Example 16

[0297] Using a similar synthesis method and steps as in Example 1, replace 1H in step 4 with the starting material F in the table below to synthesize the corresponding compounds 49-55. serial number Raw material F Compound Structure m / z [M+H] 1 HNMR 49 442.3 1H NMR(400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.48 (d,J= 5.2 Hz, 1H), 8.04 (d,J= 5.2 Hz, 1H), 7.58 (d,J= 8.4 Hz, 2H), 7.31 (t,J= 8.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.09 (d,J= 8.4 Hz, 2H), 6.97 (dd,J= 1.6, 8.4 Hz, 1H), 6.76 (d,J= 5.6 Hz, 1H), 6.47 - 6.36 (m, 1H), 6.30 - 6.21 (m, 1H), 6.09 (s, 2H), 5.80 - 5.72 (m, 1H), 2.40 (s, 3H) 50 443.2 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.46 (d,J= 5.2 Hz, 1H), 8.32 (s, 1H), 7.61 (d,J= 8.8 Hz, 2H), 7.31 (d,J= 8.8 Hz, 2H), 7.26 (t,J= 8.4 Hz, 1H), 7.18 - 7.13 (m, 2H), 6.95 (d,J= 8.4 Hz, 1H), 6.85 (s, 2H), 6.45-6.39 (m, 1H), 6.30-6.20 (m, 1H), 5.78-5.73 (m, 1H), 2.41 (s, 3H) 51 428.2 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.25 (s, 1H), 8.87 (s, 1H), 8.48 (d,J= 4.8 Hz, 1H), 7.67 (d,J= 8.8 Hz, 2H), 7.44 (s, 1H), 7.42 - 7.36 (m, 3H), 7.20 (d,J= 5.2 Hz, 1H), 7.13 (dd,J= 8.4, 1.2 Hz, 1H), 6.48 - 6.39 (m, 1H), 6.30 - 6.23 (m, 1H), 5.80 - 5.75 (m, 1H), 2.43 (s, 3H) 52 462.1 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.12 (d,J= 8.4 Hz, 1H), 8.50 (d,J= 5.2 Hz, 1H), 8.45 (d,J= 5.2 Hz, 1H), 7.72 (d,J= 8.4 Hz, 1H), 7.62 (d,J= 8.8 Hz, 1H), 7.46 - 7.38 (m, 1H), 7.38 - 7.32 (m, 2H), 7.29 (d,J= 8.4 Hz, 1H), 7.22 - 7.14 (m, 2H), 6.48 - 6.37 (m, 1H), 6.31 - 6.21 (m, 1H), 5.78 (dd,J= 10.0, 1.6 Hz, 1H), 2.42 (s, 1H), 2.44 - 2.37 (m, 1H) 53 458.2 1 H NMR (400 MHz, DMSO-d6) δ10.16 (s, 1H),8.48- 8.47 (d,J= 4.8 Hz, 1H), 7.53 - 7.51 (d,J= 8.0 Hz, 2H), 7.25 - 7.23 (d,J= 8.0 Hz, 1H), 7.19 - 7.17 (m,J= 3.2 Hz, 3H), 6.92 - 6.90 (d,J= 8.4 Hz, 1H), 6.39 - 6.37 (d,J= 10 Hz, 1H), 6.26 - 6.14 (dd,J= 18.4, 16.8 Hz, 1H), 5.76 - 5.73 (d,J= 11.6 Hz, 1H), 2.40 (s, 3H) 54 466.2

[0298] The starting material 54B of compound 54 is synthesized from 54A through the following steps.

[0299] 54A (500 mg, 3.3 mmol) was dissolved in 10 mL of dichloromethane, and iodine chloride (1.6 g, 10 mmol) was slowly added dropwise under a nitrogen atmosphere at 0°C. After reacting the resulting solution at room temperature for 1 hour, the reaction was quenched with 5 mL of saturated sodium sulfite solution, and then extracted with 25 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (elution phase was 0-100% ethyl acetate in petroleum ether) to give compound 54B (410 mg, yield: 45%).

[0300] Example 17

[0301] N-(4-(6-amino-5-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)pyrimidin-4-yl)phenyl)-2-butynylamine (55)

[0302] Step 1: Ethyl 4-(4-amino-6-chloropyrimidin-5-yl)cyclohexyl-3-ene-1-carboxylate (55B)

[0303] 4-Amino-6-chloro-5-iodopyrimidine 1H (2.0 g, 7.8 mmol), compound 55A (2.6 g, 9.4 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.57 g, 0.78 mmol), and potassium carbonate (2.2 g, 16 mmol) were dissolved in dioxane (20 mL) and water (2 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. After cooling, 20 mL of saturated ammonium chloride solution was added, and the mixture was extracted with 40 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluting phase: petroleum ether containing 50% ethyl acetate) to obtain solid compound 55B (1.1 g, yield: 50%).

[0304] 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.56 - 6.28 (m, 2H), 5.67 (s, 1H), 4.16 - 4.03 (m, 2H), 2.99 - 2.57 (m, 1H), 2.41 - 1.87 (m, 6H), 1.20 (t,J= 7.2 Hz, 3H)

[0305] Step 2: Ethyl 4-(4-amino-6-(4-nitrophenyl)pyrimidin-5-yl)cyclohexyl-3-ene-1-carboxylate (55D)

[0306] Compound 55B (1.1 g, 3.9 mmol), 4-nitrophenylboronic acid 55C (0.78 g, 4.7 mmol), tetrakis(triphenylphosphine)palladium (0.45 g, 0.39 mmol), and potassium carbonate (1.1 g, 7.8 mmol) were dissolved in dioxane (15 mL) and water (1.5 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. After cooling, 20 mL of saturated ammonium chloride solution was added, and the mixture was extracted with 40 mL of ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluting phase: petroleum ether containing 50% ethyl acetate) to obtain compound 55D (0.39 g, yield: 27%).

[0307] MS (ESI+) m / z = 368.2[M+H].

[0308] Step 3: Ethyl 4-(4-amino-6-(4-aminophenyl)pyrimidin-5-yl)cyclohexyl-3-ene-1-carboxylate (55E)

[0309] Compound 55D (0.36 g, 1.0 mmol) was dissolved in 10 mL of methanol, and iron powder (0.56 g, 10 mmol) and 2 mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with 40 mL of ethyl acetate. 20 mL of saturated sodium chloride solution was added to the filtrate, and another 20 mL of ethyl acetate was added for extraction. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluting phase: petroleum ether containing 50%-100% ethyl acetate) to obtain solid 55E (0.21 g, yield: 62%).

[0310] MS (ESI+) m / z = 339.2[M+H].

[0311] Step 4: Ethyl 4-(4-amino-6-(4-(-2-butynylamino)phenyl)pyrimidin-5-yl)cyclohexyl-3-ene-1-carboxylate (55g)

[0312] Compound 55E (0.21 g, 0.58 mmol) and N,N-diisopropylethylamine (0.23 g, 1.8 mmol) were dissolved in 3 mL of dichloromethane, and 2-butynedichloro 55F (55 mg, 0.55 mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The resulting reaction solution was concentrated under reduced pressure, and the crude product was purified by C18 reversed-phase chromatography (eluting phase was an aqueous solution containing 5-80% acetonitrile), and the solvent was removed by lyophilization to obtain compound 55G (0.19 g, yield: 81%).

[0313] MS (ESI+) m / z = 405.2[M+H].

[0314] Step 5: 4-(4-amino-6-(4-(-2-butyninylamino)phenyl)pyrimidin-5-yl)cyclohex-3-ene-1-carboxylic acid (55H)

[0315] Compound 55G (0.19 g, 0.47 mmol) and lithium hydroxide (23 mg, 0.95 mmol) were mixed in tetrahydrofuran (2 mL) and water (0.5 mL). After stirring the resulting mixture at room temperature for 1 hour, dry ice (5 g) was added to the reaction solution. The resulting mixture was concentrated under reduced pressure to give crude compound 55H (0.24 g).

[0316] MS (ESI+) m / z = 377.2[M+H].

[0317] Step 6: N-(4-(6-amino-5-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)pyrimidin-4-yl)phenyl)-2-butynylamine (55)

[0318] 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol) was added to a solution of crude 55H (48 mg, approximately 0.1 mmol) in N,N-dimethylformamide (1 mL), followed by the addition of N,N-diisopropylethylamine (39 mg, 0.3 mmol) and (S)-2-cyanopyrrolidine 55I (20 mg, 0.21 mmol). The resulting solution was stirred at room temperature for 2 hours. After filtration, the mixture was purified by preparative high-performance liquid chromatography (Waters Xbridge C18, 20-60% acetonitrile aqueous solution (containing 0.01% ammonia)) to give the title compound 55 (3.6 mg, yield: 7.9%).

[0319] MS (ESI+) m / z = 455.2[M+H].

[0320] 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.31 (s, 1H), 7.62 (d,J= 8.6 Hz, 4H), 6.63 (s, 2H), 5.76 (s, 1H), 4.72 (dt,J= 7.6, 3.9 Hz, 1H), 3.69 (s, 4H), 2.34 - 2.10 (m, 4H), 2.06 (m, 4H), 1.71 (m, 2H), 1.24 (m, 2H), 0.96 (m, 2H).

[0321] Example 18-1

[0322] Following a similar route and steps as in Example 17, the compounds 55A in the first step were replaced with different raw materials G in the table below, 2-butynedichloro 55F was replaced with acrylonitrile chloride 4B in the fourth step, and 55I was replaced with raw material H in the table below in the sixth step, to synthesize the corresponding compounds 56-59 in the table. serial number Raw material G Raw material H Compound Structure m / z [M+H] 1 HNMR 56 414.2 1 H NMR (400 MHz, DMSO+D2O) δ 10.16 (s, 1H), 8.45 (s, 1H), 8.14 (s, 1H), 7.47 (t,J= 7.6 Hz, 4H), 7.19 (dd,J= 8.4, 10.0 Hz, 4H), 6.43 - 6.34 (m, 1H), 6.27 - 6.19 (m, 1H), 5.80 - 5.65 (m, 1H), 3.50 - 3.44 (m, 4H), 2.05 - 1.68 (m, 4H) 57 439.2 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.45 (s, 1H), 7.56 (d,J= 7.6 Hz, 2H), 7.47 (d,J= 8.4 Hz, 2H), 7.24 (d,J= 8.0 Hz, 2H), 7.18 (d,J= 8.4 Hz, 2H), 6.63 - 6.10 (m, 4H), 5.74 (dd,J= 2.0, 10.0 Hz, 1H), 4.87 (t,J= 6.4 Hz, 1H), 3.68 - 3.43 (m, 2H), 2.34 - 2.30 (m, 1H), 2.19 (td,J= 6.0, 12.0 Hz, 1H), 2.06 - 1.85 (m, 2H) 58 418.2 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.49 (d,J= 4.8 Hz, 1H), 8.45 (s, 1H), 7.61 (d,J= 8.8 Hz, 2H), 7.33 (t,J= 8.0 Hz, 1H), 7.29 - 7.21 (m, 3H), 7.19 (d,J= 4.8 Hz, 1H), 6.99 (dd,J= 1.2, 8.0 Hz, 1H), 6.52 (s, 2H), 5.78 - 5.62 (m, 1H), 5.42 (dd,J= 3.6, 15.6 Hz, 1H), 2.41 (s, 3H) 59 443.2 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.31 (s, 1H), 7.73 - 7.64 (m, 4H), 6.45 (dd,J= 10.0, 17.0 Hz, 3H), 6.32 - 6.22 (m, 1H), 5.79 - 5.71 (m, 2H), 4.71 (td,J= 4.0, 7.6 Hz, 1H), 3.79 - 3.41 (m, 2H), 2.83 (s, 1H), 2.31 - 1.89 (m, 8H), 1.79 - 1.60 (m, 2H)

[0323] Example 18-2

[0324] N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (60)

[0325] Step 1: 2,4-Dichloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidine (60B)

[0326] 2,4-Dichloro-5-iodopyrimidine 60A (5.0 g, 18 mmol), compound 1G (6.0 g, 18 mmol), potassium carbonate (5.0 g, 36 mmol), and (diphenylphosphine ferrocene)palladium dichloride (0.70 g, 0.91 mmol) were added to a mixed solvent of dioxane (50 mL) and water (5 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and extracted with 100 mL of ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-2 / 1) to obtain compound 60B (2.9 g, yield: 45%).

[0327] MS (ESI+)m / z= 351.0[M+H].

[0328] Step 2: 2-Chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(3-nitrophenyl)pyrimidine (60D)

[0329] Compound 60B (2.1 g, 6.0 mmol), 3-nitrophenylboronic acid 60C (1.0 g, 6.0 mmol), potassium carbonate (1.7 g, 12.0 mmol), and tetrakis(triphenylphosphine)palladium (0.35 g, 0.30 mmol) were added to a mixed solvent of dioxane (20 mL) and water (2 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 50 mL of ethyl acetate. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1-1 / 1) to obtain compound 60D (1.0 g, yield: 38%).

[0330] MS (ESI+)m / z= 438.1[M+H].

[0331] 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.52 (d,J= 5.2 Hz, 1H), 8.39 - 8.31 (m, 2H), 7.87 (d,J= 8.0 Hz, 1H), 7.79 - 7.71 (m, 1H), 7.53 - 7.43 (m, 2H), 7.30 - 7.20 (m, 2H), 2.48 - 2.44 (m, 3H).

[0332] Step 3: 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(3-nitrophenyl)pyrimidin-2-amine (60F)

[0333] Compound 60D (0.40 g, 0.91 mmol), 1-methyl-1H-pyrazole-4-amine 60E (0.17 g, 1.8 mmol), cesium carbonate (0.88 g, 2.7 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (57 mg, 0.091 mmol), and palladium acetate (20 mg, 0.091 mmol) were added to dioxane (20 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 50 mL of ethyl acetate. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1-0 / 1) to obtain compound 60F (0.20 g, yield: 44%).

[0334] MS (ESI+) m / z = 499.1[M+H].

[0335] Step 4: 4-(3-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (60G)

[0336] Compound 60F (0.18 g, 0.36 mmol) was dissolved in 5 mL of methanol, and iron powder (0.2 g, 3.6 mmol) and 1 mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with 20 mL of ethyl acetate. 10 mL of saturated sodium chloride solution was added to the filtrate, and another 20 mL of ethyl acetate was added for extraction. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by C18 reversed-phase column (mobile phase: 5-80% acetonitrile aqueous solution) and lyophilized to remove the solvent to obtain solid 60G (80 mg, yield: 47%).

[0337] MS (ESI+) m / z = 469.2[M+H].

[0338] Step 5: N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (60)

[0339] Compound 60G (70 mg, 0.15 mmol) and triethylamine (45 mg, 0.45 mmol) were dissolved in dichloromethane (5 mL), and a dichloromethane solution of acrylonitrile chloride 4B (13 mg, 0.15 mmol, 150 μL, 1.0 mol / L) was slowly added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The solvent was removed by vacuum distillation, and the residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10µm, eluent 3%-55% acetonitrile-water) to give a white solid, title compound 60 (20 mg, yield: 26%).

[0340] MS (ESI+) m / z = 523.2[M+H].

[0341] 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.75 (s, 1H), 8.53 (s, 1H), 8.46 (d,J= 4.8 Hz, 1H), 8.43 - 7.80 (m, 2H), 7.60 (s, 1H), 7.53 (s, 1H), 7.33 - 7.20 (m, 3H), 7.18 (d,J= 5.2 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.91 (d,J= 7.6 Hz, 1H), 6.53 - 6.39 (m, 1H), 6.35 - 6.19 (m, 1H), 5.77 (d, J = 11.2 Hz, 1H), 3.84 (s, 3H), 2.41 (s, 3H).

[0342] Example 19

[0343] N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)methylpropenylated amide (61)

[0344] Using compound 60G as a raw material, compound 61 was synthesized by replacing acrylamide 4B with 61A using a similar synthesis method as step 5 in Example 18-2.

[0345] MS (ESI+)m / z= 537.1[M+H].

[0346] 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.76 (s, 1H), 8.52 (s, 1H), 8.46 (d,J= 5.2 Hz, 1H), 8.0 (s, 2H), 7.60 (s, 1H), 7.51 (s, 1H), 7.32 - 7.16 (m, 4H), 7.03 (d,J= 8.0 Hz, 1H), 6.86 (d,J= 6.8 Hz, 1H), 5.82 (s, 1H), 5.54 (s, 1H), 3.85 (s, 3H), 2.41 (s, 3H), 1.96 (s, 3H).

[0347] Example 20

[0348] N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propionic acid (62)

[0349] Using compound 60G as a raw material, compound 62 was synthesized by replacing acrylamide 4B with 62A using a similar synthesis method as step 5 in Example 18-2.

[0350] MS (ESI+)m / z= 525.1[M+H].

[0351] 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.73 (s, 1H), 8.52 (s, 1H), 8.47 (d,J= 5.2 Hz, 1H), 8.09 (s, 2H), 7.52 - 7.51 (m, 1H), 7.52 (s, 1H), 7.36 - 7.13 (m, 4H), 7.02 (d,J= 8.0 Hz, 1H), 6.84 (d,J= 7.2 Hz, 1H), 3.84 (s, 3H), 2.42 (s, 3H), 2.38 - 2.29 (m, 2H), 1.19 - 1.04 (m, 3H).

[0352] Example 21

[0353] 2-Fluoro-N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (63)

[0354] Using compound 60G as the starting material, and employing a similar synthesis method to the second step in Example 7, 7B was replaced with 63A, and bis(2-oxazolyl)phosphine chloride was replaced with 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate. The reaction was carried out at room temperature for 1 hour to synthesize compound 63.

[0355] MS (ESI+)m / z= 541.1[M+H].

[0356] 1H NMR (400 MHz, DMSO-d6) δ 10.44 (d,J= 4.4 Hz, 1H), 9.77 (s, 1H), 8.53 (s, 1H), 8.46 (d,J= 5.2 Hz, 1H), 8.13 (s, 2H), 7.66 (d,J= 7.2 Hz, 1H), 7.53 (s, 1H), 7.34 - 7.15 (m, 4H), 7.09 - 6.90 (m, 2H), 5.83 - 5.63 (m, 1H), 5.45 (dd,J= 3.6, 15.5 Hz, 1H), 3.84 (s, 3H), 2.41 (s, 3H).

[0357] Example 22

[0358] N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2-methylphenyl)propenylamide (64)

[0359] Using similar synthesis steps and methods as in the second step and beyond of Example 18-2, 64A was used to replace 60C to synthesize compound 64.

[0360] MS (ESI+)m / z= 537.2[M+H].

[0361] 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.52 (s, 1H), 8.59 (s, 1H), 8.44 (d,J= 5.2 Hz, 1H), 8.02 - 7.70 (m, 1H), 7.64 - 7.43 (m, 2H), 7.28 - 7.19 (m, 2H), 7.16 (d,J= 5.2 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.94 (d,J= 8.0 Hz, 1H), 6.52 (dd,J= 10.4, 16.6 Hz, 1H), 6.23 (d,J= 17.2 Hz, 1H), 5.73 (d,J= 10.4 Hz, 1H), 3.80 (s, 3H), 2.39 (s, 3H), 1.92 (s, 3H).

[0362] Example 23

[0363] N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)2-methoxyphenyl)propenylamide (65)

[0364] Using similar synthesis steps and methods as in the second step and beyond in Example 18-2, 60C was replaced with 65A to synthesize compound 65.

[0365] MS (ESI+)m / z= 553.2[M+H].

[0366] 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.57 (s, 1H), 8.59 (s, 1H), 8.44 (d,J= 5.2 Hz, 1H), 8.18 ( d,J= 6.3 Hz, 1H), 7.88 ( s, 1H), 7.53 (s, 1H), 7.24 - 7.14 (m, 5H), 6.97 (dd,J= 1.6, 8.4 Hz, 1H), 6.75 (dd,J= 10.0, 17.0 Hz, 1H), 6.25 (dd,J= 1.8, 16.8 Hz, 1H), 5.75 - 5.68 (m, 1H), 3.81 (s, 3H), 3.44 (s, 3H), 2.38 (s, 3H).

[0367] Example 24

[0368] N-(3-(2-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)propenylated amide (66)

[0369] Using similar synthesis steps and methods as in the third step and beyond of Example 18-2, 66A was used to replace 60E to synthesize compound 66.

[0370] MS (ESI+)m / z= 580.3[M+H].

[0371] Example 25

[0372] N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(1-methylpyrrolidine-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (67)

[0373] Using similar synthesis steps and methods as in the third step and beyond of Example 18-2, 60E was replaced with 67A to synthesize compound 67.

[0374] MS (ESI+)m / z= 592.3[M+H].

[0375] 1H NMR (400 MHz, DMSO-d6) δ 10.27 (t,J= 5.2 Hz, 1H), 9.77 (s, 1H), 8.55 (s, 1H), 8.47 (d,J= 5.2 Hz, 1H), 8.22 (s, 1H), 7.67 - 7.59 (m, 1H), 7.57 (s, 1H), 7.32 - 7.21 (m, 3H), 7.19 (d,J= 4.8 Hz, 1H), 7.03 (d,J= 6.8 Hz, 1H), 6.94 (d,J= 8.0 Hz, 1H), 6.52 - 6.40 (m, 1H), 6.33 - 6.24 (m, 1H), 5.78 (d,J= 11.6 Hz, 1H), 4.91 (s, 1H), 2.87 - 2.80 (m, 4H), 2.41 (s, 3H), 2.26 (s, 5H), 2.05 ( d,J= 6.4 Hz, 1H).

[0376] Example 26

[0377] N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (68)

[0378] Using similar synthesis steps and methods as in the third step and beyond of Example 18-2, 60E was replaced with 68A to synthesize compound 68.

[0379] MS (ESI+)m / z= 605.3[M+H].

[0380] Example 27

[0381] N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (69)

[0382] Step 1: 2,5-Dichloro-4-(4-nitrophenyl)pyrimidine (69B)

[0383] 2,4,5-Trichloropyrimidine 69A (1.8 g, 10 mmol), p-nitrophenylboronic acid 55C (1.7 g, 10 mmol), potassium carbonate (2.8 g, 20 mmol), and (diphenylphosphine ferrocene)palladium dichloride (0.35 g, 0.46 mmol) were added to a mixed solvent of dioxane (20 mL) and water (2 mL). After purging with nitrogen three times, the mixture was stirred at 70 °C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and extracted with 100 mL of ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-2 / 1) to give compound 69B (1.7 g, yield: 63%).

[0384] MS (ESI+)m / z= 270.0[M+H].

[0385] Step 2: 5-Chloro-N-(1-Methyl-1H-pyrazol-4-yl)-4-(4-nitrophenyl)pyrimidine-2-amine (69C)

[0386] Compound 69B (0.24 g, 0.91 mmol), 1-methyl-1H-pyrazole-4-amine 60E (0.17 g, 1.8 mmol), cesium carbonate (0.88 g, 2.7 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (57 mg, 0.091 mmol), and palladium acetate (20 mg, 0.091 mmol) were added to dioxane (20 mL). After purging with nitrogen three times, the mixture was stirred at 100°C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and extracted with 50 mL of ethyl acetate. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1-0 / 1) to give compound 69C (0.20 g, yield: 67%).

[0387] MS (ESI+) m / z = 331.0[M+H].

[0388] Step 3: 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)-4-(4-nitrophenyl)pyrimidin-2-amine (69D)

[0389] Compound 69C (0.20 g, 0.61 mmol), compound 1G (0.20 g, 0.61 mmol), potassium carbonate (170 mg, 1.2 mmol), palladium acetate (13 mg, 0.06 mmol), and tricyclohexylphosphine (34 mg, 0.12 mmol) were added to a mixed solvent of dioxane (20 mL) and water (2 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 50 mL of ethyl acetate. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1-0 / 1) to obtain compound 69D (0.13 g, yield: 41%).

[0390] MS (ESI+)m / z= 499.1[M+H].

[0391] Step 4: 4-(4-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (69E)

[0392] Compound 69D (0.13 g, 0.26 mmol) was dissolved in 5 mL of methanol, and iron powder (0.2 g, 3.6 mmol) and 1 mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with 20 mL of ethyl acetate. 10 mL of saturated sodium chloride solution was added to the filtrate, and another 20 mL of ethyl acetate was added for extraction. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by C18 reversed-phase column (mobile phase: 5-80% acetonitrile aqueous solution) and lyophilized to remove the solvent to obtain solid 69E (42 mg, yield: 34%).

[0393] MS (ESI+) m / z = 469.2[M+H].

[0394] Step 5: N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (69)

[0395] Compound 69E (42 mg, 0.09 mmol) and triethylamine (18 mg, 0.18 mmol) were dissolved in dichloromethane (5 mL), and a dichloromethane solution of acrylonitrile chloride 4B (7.6 mg, 0.085 mmol, 85 μL, 1.0 mol / L) was slowly added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The solvent was removed by vacuum distillation, and the residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10µm, eluent 3%-55% acetonitrile-water) to give a white solid, title compound 69 (18 mg, yield: 38%).

[0396] MS (ESI+) m / z = 523.2[M+H].

[0397] 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.72 (s, 1H), 8.49 (s, 1H), 8.48 (d,J= 5.0 Hz, 1H), 7.92 (s, 1H), 7.67 (d,J= 8.4 Hz, 2H), 7.49 (d,J= 60.8 Hz, 3H), 7.31 (t,J= 8.4 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.19 (d,J= 5.1 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.44 (dd,J= 16.9, 10.1 Hz, 1H), 6.27 (dd,J= 16.9, 2.0 Hz, 1H), 5.78 (dd,J= 10.0, 2.1 Hz, 1H), 3.82 (s, 3H), 2.43 (s, 3H).

[0398] Example 28

[0399] N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (70)

[0400] Using similar synthesis steps and methods as in the third step and beyond of Example 27, 69A was replaced with 70A to synthesize compound 70.

[0401] MS (ESI+)m / z= 537.2[M+H].

[0402] 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.54 (s, 1H), 8.43 (d,J= 5.0 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.48 (s, 1H), 7.24 (t,J= 8.3 Hz, 1H), 7.18 (dd,J= 11.4, 2.0 Hz, 1H), 7.13 (d,J= 5.1 Hz, 1H), 6.95 (d,J= 8.1 Hz, 1H), 6.35 (dd,J= 16.8, 10.1 Hz, 1H), 6.19 (dd,J= 17.0, 2.0 Hz, 1H), 5.70 (dd,J= 10.1, 2.1 Hz, 1H), 3.74 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H).

[0403] Example 29

[0404] N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-amino-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (71)

[0405] Using similar synthesis steps and methods as in the third step and beyond of Example 27, 69A was replaced with 71A to synthesize compound 71.

[0406] MS (ESI+)m / z= 538.2[M+H].

[0407] 1H NMR (400 MHz, DMSO-d6)δ10.22 (s, 1H), 8.50 - 8.48 (m, 1H), 8.19 - 8.08 (m, 1H), 7.74 - 7.51 (m, 4H), 7.33 - 7.25 (m, 3H), 7.20 - 7.19 (m, 2H), 6.98 - 6.96 (m, 1H), 6.69 - 6.66 (m, 2H), 6.45 - 6.38 (m, 1H), 6.28 - 6.23 (m, 1H), 5.57 - 5.76 (m, 1H), 3.80 (s, 3H), 2.42 (s, 3H).

[0408] Example 30

[0409] N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)but-2-ynylamine (72)

[0410] Using compound 69E as a raw material, and employing a method similar to step 5 in Example 27, acrylonitrile chloride 4B was replaced with 2-butynylonitrile chloride 55F to synthesize compound 72.

[0411] MS (ESI+)m / z= 535.2[M+H].

[0412] 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 9.65 (s, 1H), 8.41 (d,J= 5.0 Hz, 2H), 7.85 (s, 1H), 7.57 - 7.44 (m, 3H), 7.32 (s, 2H), 7.23 (t,J= 8.4 Hz, 1H), 7.19 - 7.08 (m, 2H), 6.97 - 6.89 (m, 1H), 3.75 (s, 3H), 2.36 (s, 3H), 1.98 (s, 3H).

[0413] Example 31

[0414] 2-Fluoro-N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylated amide (73)

[0415] Using compound 69E as a starting material, and employing a similar synthesis method to the second step in Example 7, 7B was replaced with 63A, and bis(2-oxazolyl)phosphine chloride was replaced with 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate to synthesize compound 73.

[0416] MS (ESI+)m / z= 541.1[M+H].

[0417] 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.74 (s, 1H), 8.51 (s, 1H), 8.48 (d,J= 5.0 Hz, 1H), 7.92 (s, 1H), 7.74 (d,J= 8.4 Hz, 2H), 7.57 (s, 1H), 7.43 (s, 2H), 7.31 (t,J= 8.4 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.19 (d,J= 5.1 Hz, 1H), 7.01 (dd,J= 8.1, 1.8 Hz, 1H), 5.73 (dd,J= 47.6, 3.7 Hz, 1H), 5.46 (dd,J= 15.6, 3.7 Hz, 1H), 3.82 (s, 3H), 2.43 (s, 3H).

[0418] Example 32

[0419] N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (74)

[0420] Using a similar route and steps as in Example 27, 60E in the second step was replaced with 74A to synthesize compound 74B.

[0421] Compound 74B (27 mg, 0.039 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The solvent and trifluoroacetic acid were removed by concentration under reduced pressure. The crude product was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, eluent 3%-55% acetonitrile-water) to give compound 74 (8.7 mg, yield: 37%).

[0422] MS (ESI+)m / z= 592.3 [M+H].

[0423] Example 33

[0424] 2-Fluoro-N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (75)

[0425] Using a similar route and steps as in Example 27, replacing 60E in the second step with 74A, compound 75B can be synthesized. Compound 75 can then be synthesized from compound 75B through two further reaction steps.

[0426] Step 1: 4-(4-((5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(4-(2-fluoropropenylatedamino)phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (75C)

[0427] Compound 75B (56 mg, 0.088 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (38 mg, 0.10 mmol), and 2-fluoroacrylic acid (18 mg, 0.20 mmol) were mixed in a solution of dichloromethane, followed by the addition of N,N-diisopropylethylamine (39 mg, 0.30 mmol). The resulting solution was stirred at 0°C for 1 hour. The mixture was filtered and purified by C18 reversed-phase chromatography (eluting phase: 20-80% aqueous acetonitrile) to give compound 75C (26 mg, yield: 42%).

[0428] MS (ESI+)m / z= 710.3 [M+H].

[0429] Step 2: 2-Fluoro-N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (75)

[0430] Compound 75C (26 mg, 0.037 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The solvent and trifluoroacetic acid were removed by concentration under reduced pressure. The crude product was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, eluent 3%-55% acetonitrile-water) to give compound 75 (6.1 mg, yield: 27%).

[0431] MS (ESI+)m / z= 610.2 [M+H].

[0432] Example 34

[0433] N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-methylphenyl)propenylamide (76)

[0434] Referring to the synthetic route and method of Example 27, 76A was used instead of 55C to synthesize compound 76.

[0435] MS (ESI+)m / z= 537.2 [M+H].

[0436] 1H NMR (400 MHz, DMSO-d6) δ10.19 (s, 1H), 9.73 (s, 1H), 8.58 (s, 1H), 8.46 (d,J =5.0 Hz, 1H), 7.70 (m, 1H), 7.49 (m, 3H), 7.23 (t,J =8.4 Hz, 1H), 7.15 (m, 2H), 7.12 (dd,J =11.7, 1.8 Hz, 1H), 6.89 (m, 1H), 6.43 (dd,J =17.0, 10.1 Hz, 1H), 6.26 (d,J =18.8 Hz, 1H), 5.76 (d,J =12.0 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H), 2.03 (s, 3H).

[0437] Example 35

[0438] N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-fluorophenyl)propenylamide (77)

[0439] Referring to the synthetic route and method of Example 27, 77A was used instead of 55C to synthesize compound 77.

[0440] MS (ESI+)m / z= 541.2 [M+H].

[0441] 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.20 (s, 1H), 9.07 (d,J= 6.6 Hz, 1H), 8.49 (d,J= 5.0 Hz, 1H), 7.92 (s, 1H), 7.83 – 7.55 (m, 2H), 7.39 (t,J= 8.4 Hz, 1H), 7.32 (dd,J= 11.5, 2.1 Hz, 1H), 7.24 – 7.13 (m, 2H), 5.58 (d,J= 3.5 Hz, 0.5H), 5.46 (d,J= 3.5 Hz, 0.5H), 5.27 (dd,J= 15.6, 3.5 Hz, 1H), 4.58 – 4.51 (m, 1H), 4.12 – 4.00 (m, 2H), 3.86 – 3.74 (m, 2H), 2.42 (s, 3H).

[0442] Example 36

[0443] 2-Fluoro-N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-methylphenyl)propenylamide (78)

[0444] Referring to the synthetic route and method of Example 27, 55C was replaced with 76A, and acrylonitrile chloride 4B was replaced with 2-fluoropropenyl chloride to synthesize compound 78.

[0445] MS (ESI+)m / z= 555.2 [M+H].

[0446] 1H NMR (400 MHz, DMSO-d6) δ10.32 (s, 1H), 9.75 (s, 1H), 8.59 (s, 1H), 8.47 - 8.45 (m, 1H), 7.61 - 7.9 (m, 2H), 7.52 (s, 1H), 7.25 - 7.11 (m, 5H), 6.94 - 6.92 (m, 1H), 5.78 - 5.77 (m, 0.5H), 5.66 - 5.65 (m, 0.5H), 5.47 - 5.42 (m, 1H), 3.80 (s, 3H), 2.40 (s, 3H).

[0447] Example 37

[0448] N-(4-(5-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-2-((1-methyl-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (79)

[0449] Referring to the synthetic route and method of Example 27, 55A was used to replace 1G to synthesize compound 79A. Then, 55G in Example 17 was replaced with compound 79A, and compound 79 was synthesized by following the synthetic steps and methods of steps five and six in Example 17.

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

[0451] 1H NMR (400 MHz, DMSO-d6) δ 10.36 (d,J= 3.5 Hz, 1H), 9.49 (s, 1H), 8.20 (s, 1H), 7.88 (d,J= 4.7 Hz, 1H), 7.84 - 7.70 (m, 4H), 7.52 (s, 1H), 6.54 - 6.38 (m, 1H), 6.35 - 6.20 (m, 1H), 5.86 - 5.73 (m, 2H), 4.73 (ddd,J= 7.4, 5.2, 3.6 Hz, 1H), 3.80 (s, 3H), 3.74 - 3.61 (m, 1H), 3.51 (dt,J= 16.3, 7.6 Hz, 1H), 2.68 (d,J= 9.1 Hz, 1H), 2.41 - 1.63 (m, 10H).

[0452] Example 38

[0453] N-(3-(5-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-2-((1-methyl-1H-pyrazole-4-yl)amino)pyrimidin-4-yl)phenyl)propenylamide (80)

[0454] Referring to the synthetic route and method of Example 18-2, 1G was replaced with 55A to synthesize compound 80A. Then, 55G in Example 17 was replaced with compound 80A, and compound 80 was synthesized by following the synthetic steps and methods of steps five and six in Example 17.

[0455] MS (ESI+)m / z= 523.2 [M+H].

[0456] Example 39

[0457] N-(1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)azacyclobutane-3-yl)propenylated amide (81)

[0458] Step 1 (1-(2-chloro-5-bromopyrimidin-4-yl)azacyclobutane-3-yl)tert-butyl carbamate (81C)

[0459] 2,4-Dichloro-5-bromopyrimidine 81A (2.3 g, 10 mmol), 3-tert-butoxycarbonyl-aminoazacyclobutane 81B (1.7 g, 10 mmol), and N,N-diisopropylethylamine (2.6 g, 20 mmol) were mixed in 25 mL of dioxane. The resulting mixture was stirred at 80 °C for 1 hour and then concentrated under reduced pressure. The crude product 81C (6.6 g, about 10 mmol) was used directly in the next step.

[0460] MS (ESI+)m / z= 363.1, 365.1[M+H].

[0461] Step 2 (1-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)azacyclobutane-3-yl)tert-butyl carbamate (81D)

[0462] Compound 81C (3.3 g, crude, approx. 5.0 mmol), compound 1G (2.0 g, 6.0 mmol), potassium carbonate (2.8 g, 20 mmol), and (diphenylphosphine ferrocene)palladium dichloride (0.38 g, 0.5 mmol) were added to a mixed solvent of dioxane (30 mL) and water (3 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 100 mL of ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-2 / 1) to obtain compound 81D (1.7 g, yield: 71%).

[0463] MS (ESI+)m / z= 487.1[M+H].

[0464] Step 3 (1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)azacyclobutane-3-yl) tert-butyl carbamate (81E)

[0465] Compound 81D (0.49 g, 1.0 mmol), 1-methyl-1H-pyrazole-4-amine 60E (0.17 g, 1.8 mmol), cesium carbonate (0.88 g, 2.7 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (62 mg, 0.10 mmol), and palladium acetate (22 mg, 0.10 mmol) were added to dioxane (20 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 50 mL of ethyl acetate. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1-0 / 1) to obtain compound 81E (0.37 g, yield: 67%).

[0466] MS (ESI+) m / z = 548.2[M+H].

[0467] Step 4: 4-(3-aminoazacyclobutane-1-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (81F)

[0468] Compound 81E (0.37 g, 0.67 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was slowly added at 0°C. The resulting solution was stirred at 0°C for 1 hour, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase C18 column chromatography (eluting phase: 5-75% acetonitrile aqueous solution (containing 8 mmol / L NH3)) to obtain compound 81F (0.26 g, yield: 87%).

[0469] MS (ESI+)m / z= 448.2[M+H].

[0470] Step 5: N-(1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)azacyclobutane-3-yl)propenylated amide (81)

[0471] Compound 81F (45 mg, 0.10 mmol) and triethylamine (20 mg, 0.20 mmol) were dissolved in dichloromethane (2 mL), and a dichloromethane solution of acrylonitrile chloride 4B (9.0 mg, 0.1 mmol, 100 μL, 1.0 mol / L) was slowly added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The solvent was removed by vacuum distillation, and the residue was purified by preparative chromatography (Phenomenex Luna C18150*25mm*10µm, eluent 5%-75% acetonitrile-water) to give a white solid, title compound 81 (26 mg, yield: 52%).

[0472] MS (ESI+) m / z = 502.2[M+H].

[0473] 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.72 (d,J= 6.8 Hz, 1H), 8.49 (d,J= 5.0 Hz, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.39 (t,J= 8.3 Hz, 1H), 7.32 (dd,J= 11.4, 2.0 Hz, 1H), 7.24 - 7.13 (m, 2H), 6.23 - 6.01 (m, 2H), 5.61 (dd,J= 9.6, 2.6 Hz, 1H), 4.51 (d,J= 7.4 Hz, 1H), 4.08 (s, 2H), 3.80 (s, 3H), 3.66 (s, 2H), 2.42 (s, 3H).

[0474] Example 40

[0475] N-(1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)azacyclobutane-3-yl)-2-butynylamine (82)

[0476] Using compound 81F as a raw material, and employing a method similar to step 5 in Example 27, the acrylonitrile chloride 4B was replaced with 2-butynylonitrile chloride 55F to synthesize compound 82.

[0477] MS (ESI+)m / z= 514.2[M+H].

[0478] 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 9.05 (d,J= 6.7 Hz, 1H), 8.42 (d,J= 5.0 Hz, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.42 (s, 1H), 7.31 (t,J= 8.4 Hz, 1H), 7.24 (dd,J= 11.5, 2.1 Hz, 1H), 7.14 - 7.06 (m, 2H), 4.37 (s, 1H), 4.07 - 3.82 (m, 2H), 3.73 (s, 3H), 3.67 - 3.44 (m, 2H), 2.35 (s, 3H), 1.88 (s, 3H).

[0479] Example 41

[0480] 2-Fluoro-N-(1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)azacyclobutane-3-yl)propenylated amide (83)

[0481] Compound 81F (40 mg, 0.088 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (38 mg, 0.10 mmol), and 2-fluoroacrylate 63A (18 mg, 0.20 mmol) were mixed in a solution of dichloromethane, followed by the addition of N,N-diisopropylethylamine (39 mg, 0.30 mmol). The resulting solution was stirred at 0°C for 1 hour. The mixture was filtered and purified by C18 reversed-phase chromatography (eluting phase: 20-70% aqueous acetonitrile) to give compound 83 (21 mg, yield: 46%).

[0482] MS (ESI+)m / z= 520.2[M+H].

[0483] 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.07 (d,J= 6.9 Hz, 1H), 8.48 (d,J= 5.0 Hz, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.39 (t,J= 8.4 Hz, 1H), 7.31 (dd,J= 11.4, 2.0 Hz, 1H), 7.23 - 7.13 (m, 2H), 5.52 (dd,J= 47.9, 3.5 Hz, 1H), 5.27 (dd,J= 15.6, 3.5 Hz, 1H), 4.58 (d,J= 7.4 Hz, 1H), 4.06 (s, 2H), 3.94 - 3.46 (m, 5H), 2.42 (s, 3H).

[0484] Example 42

[0485] Following a similar route and steps as in Example 39, replacing compound 81B in the first step with raw material I from the table below will synthesize compounds 84-117. Following a similar route and steps as in Example 39, when replacing compound 81B in the first step with 118A and 119A from raw material I to synthesize compounds 118-119 from the table, the concentration of trifluoroacetic acid in the reaction solution needs to be increased to 50% in the fourth step. serial number Raw material I Compound Structure m / z [M+H] 1 HNMR 84 528.2 1H NMR (400 MHz, DMSO-d6)δ9.26 (s, 1H), 8.55 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 7.23 (s, 2H), 6.27 (s, 1H), 6.11 (s, 1H), 5.69 (s, 1H), 4.40 (s, 2H), 4.10 (s, 6H), 3.87 (s, 3H), 2.50 (s, 3H). 85 516.2 1H NMR (400 MHz, DMSO-d6)δ9.08 (s, 1H), 8.49 (d,J =4.0 Hz, 1H), 8.33 - 8.31 (m, 1N), 7.87 (s, 1H), 7.81 (s, 1H), 7.52 (s, 1H), 7.38 - 7.30 (m, 2H), 7.20 - 7.15 (m, 2H), 6.68 (s, 1H), 6.23 - 6.16 (m, 1H), 6.10 - 6.05 (m, 1H), 5.60 - 5.57 (m, 1H), 4.32 - 4.25 (m, 1H), 3.80 (s, 3H), 3.48 - 3.42 (m, 2H), 3.12 - 2.99 (m, 2H), 2.42 (s, 3H), 2.03 - 1.97 (m, 2H). 86 516.2 1H NMR (400 MHz, DMSO-d6)δ9.08 (s, 1H), 8.48 (d,J =4.0 Hz, 1H), 8.32 - 8.30 (m, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 7.37 - 7.29 (m, 2H), 7.20 - 7.14 (m, 2H), 6.22 - 6.15 (m, 1H), 6.09 - 6.05 (m, 1H), 5.59 - 5.56 (m, 1H), 4.31 - 4.25 (m, 1H), 3.79 (s, 3H), 3.49 - 3.41 (m, 2H), 3.10 - 3.03 (m, 2H),2.42 (s, 3H), 2.07 - 1.96 (m, 2H). 87 530.2 1H NMR (400 MHz, DMSO-d6)δ9.51 (s, 1H), 8.49 (d,J =8.0 Hz, 1H), 8.10 (d,J =8.0 Hz, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.54 (s, 1H), 7.49 - 7.41 (m, 2H), 7.34 - 7.31 (m, 1H), 6.22 - 6.16 (m, 1H), 6.10 - 6.05 (m, 1H), 5.59 - 5.56 (m, 1H), 3.90 - 3.76 (m, 6H), 3.04 - 2.93 (m, 2H), 2.42 (s, 3H), 2.04 - 1.96 (m, 2H), 1.80 - 1.75 (m, 2H). 88 530.2 1H NMR (400 MHz, DMSO-d6)δ9.20 (s, 1H), 8.53 - 8.41 (m, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.47 (s, 1H), 7.44 - 7.33 (m, 2H), 7.24 (dt,J =8.4, 2.7 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 6.58 (ddd,J =27.6, 16.8, 10.4 Hz, 1H), 6.14 (ddd,J =16.9, 6.2, 2.5 Hz, 1H), 5.66 (ddd,J =13.7, 10.4, 2.4 Hz, 1H), 4.83 - 4.61 (m, 1H), 3.95 - 3.67 (m, 4H), 3.54 - 3.42 (m, 1H), 3.32 - 3.19 (m, 1H), 2.60 (s, 3H), 2.42 (s, 3H), 2.21 - 1.93 (m, 2H). 89 542.2 1 H NMR (400 MHz, DMSO-d6)δ9.18 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 7.90 (d,J =2.2 Hz, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.42 - 7.28 (m, 2H), 7.25 - 7.11 (m, 2H), 6.52 (dt,J =16.8, 10.0 Hz, 1H), 6.11 (dt,J =16.9, 3.0 Hz, 1H), 5.65 (ddd,J =10.4, 4.4, 2.5 Hz, 1H), 3.79 (s, 4H), 3.72 (s, 2H), 3.59 - 3.48 (m, 2H), 2.40 (s, 3H), 2.06 (dt,J =37.8, 6.9 Hz, 2H). 90 516.2 1H NMR (400 MHz, DMSO-d6)δ9.30 (s, 1H), 8.50 (d,J =4.0 Hz, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 7.50- 7.48 (m, 2H), 7.45 - 7.33 (m, 2H), 7.21 (d,J =4.0 Hz, 1H), 6.84 - 6.77 (m, 1H), 6.15- 6.10 (m, 1H), 5.70 - 5.67 (m, 1H), 3.82 (s, 3H), 3.67 - 3.51 (m, 4H), 3.30 -3.27 (m, 4H), 2.44 (s, 3H). 91 530.2 1 H NMR (400 MHz, DMSO-d6)δ9.20 (s, 1H), 8.53 - 8.41 (m, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.47 (s, 1H), 7.44 - 7.33 (m, 2H), 7.24 (dt,J =8.4, 2.7 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 6.58 (ddd,J =27.6, 16.8, 10.4 Hz, 1H), 6.14 (ddd,J =16.9, 6.2, 2.5 Hz, 1H), 5.66 (ddd,J =13.7, 10.4, 2.4 Hz, 1H), 4.83 - 4.61 (m, 1H), 3.95 - 3.67 (m, 4H), 3.54 - 3.42 (m, 1H), 3.32 - 3.19 (m, 1H), 2.60 (s, 3H), 2.42 (s, 3H), 2.21 - 1.93 (m, 2H). 92 516.2 93 530.2 1H NMR (400 MHz, DMSO-d6)δ9.27 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.48 (d,J =10.5 Hz, 2H), 7.42 (t,J =8.3 Hz, 1H), 7.34 (d,J =8.5 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 6.81 (ddd,J =28.2, 16.5, 10.3 Hz, 1H), 6.14 (dd,J =16.6, 8.2 Hz, 1H), 5.74 - 5.62 (m, 1H), 4.41 - 3.85 (m, 4H), 3.82 (s, 3H), 3.58 - 3.43 (m, 1H), 3.20 - 2.77 (m, 3H), 2.43 (s, 3H), 1.01 (d,J =6.5 Hz, 3H). 94 542.2 1 H NMR (400 MHz, DMSO-d6)δ9.25 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 7.50 (s, 1H), 7.46 - 7.33 (m, 2H), 7.30 - 7.22 (m, 1H), 7.20 (d,J =5.0 Hz, 1H), 6.73 (dd,J =16.7, 10.3 Hz, 1H), 6.18 (dd,J =16.7, 2.4 Hz, 1H), 5.69 (dd,J =10.3, 2.3 Hz, 1H), 4.55 (s, 2H), 3.82 (s, 3H), 3.68 - 3.53 (m, 2H), 2.96 (d,J =12.4 Hz, 1H), 2.86 (d,J =12.6 Hz, 1H), 2.43 (s, 3H), 1.94 - 1.58 (m, 4H). 95 556.3 1H NMR (400 MHz, DMSO-d6)δ9.15 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 7.88 (s, 1H), 7.81 (d,J =9.4 Hz, 1H), 7.51 (s, 1H), 7.40 - 7.28 (m, 2H), 7.24 - 7.13 (m, 2H), 6.79 (dd,J =16.7, 10.5 Hz, 1H), 6.06 (dd,J =16.7, 2.5 Hz, 1H), 5.64 (dd,J =10.4, 2.5 Hz, 1H), 3.80 (s, 3H), 3.70 - 3.51 (m, 4H), 3.50 - 3.37 (m, 4H), 2.41 (s, 3H), 1.72 - 1.55 (m, 4H). 96 555.2 1 H NMR (400 MHz, DMSO-d6)δ9.34 (s, 1H), 8.50 (d,J =5.0 Hz, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 7.54 - 7.46 (m, 2H), 7.43 (d,J =8.2 Hz, 1H), 7.34 (dd,J =8.3, 2.0 Hz, 1H), 7.21 (d,J =5.1 Hz, 1H), 6.84 (d,J =17.8 Hz, 1H), 6.16 (d,J =16.5 Hz, 1H), 5.74 (s, 1H), 5.02 - 4.73 (m, 1H), 4.40 - 4.11 (m, 1H), 3.82 (s, 3H), 3.72 - 3.40 (m, 2H), 3.22 - 2.85 (m, 3H), 2.84 - 2.60 (m, 2H), 2.44 (s, 3H). 97 556.3 1H NMR (400 MHz, DMSO-d6)δ9.26 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 7.45 (dd,J =11.7, 2.0 Hz, 1H), 7.40 (t,J =8.3 Hz, 1H), 7.32 (dd,J =8.2, 2.0 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 6.29 (dd,J =17.0, 10.3 Hz, 1H), 6.08 (dd,J =17.0, 2.4 Hz, 1H), 5.65 (dd,J =10.2, 2.4 Hz, 1H), 3.93 (s, 2H), 3.80 (s, 3H), 3.64 (s, 2H), 3.21 (s, 4H), 2.42 (s, 3H), 1.70 (s, 4H). 98 530.2 1 H NMR (400 MHz, DMSO-d6)δ9.30 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.50 (s, 1H), 7.47 - 7.39 (m, 2H), 7.32 - 7.26 (m, 1H), 7.20 (d,J =5.0 Hz, 1H), 6.77 (dd,J =16.6, 10.5 Hz, 1H), 6.11 (d,J =16.6 Hz, 1H), 5.67 (d,J =10.5 Hz, 1H), 4.71 - 4.23 (m, 2H), 3.82 (s, 3H), 3.70 - 3.48 (m, 2H), 3.16 - 2.90 (m, 2H), 2.90 - 2.72 (m, 1H), 2.43 (s, 3H), 1.09 (d,J =6.6 Hz, 3H). 99 544.3 1H NMR (400 MHz, DMSO-d6)δ9.20 (s, 1H), 8.42 (d,J =5.0 Hz, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 7.41 - 7.35 m, 3H), 7.24 - 7.22 (m, 1H), 7.13 (d,J =5.0 Hz, 1H), 6.75 - 6.60 (m, 1H), 6.05 (dd,J =16.6, 2.4 Hz, 1H), 5.60 (dd,J =11.0, 8.6 Hz, 1H), 4.23 - 3.89 (m, 2H), 3.74 (s, 3H), 3.65 - 3.38 (m, 2H), 2.35 (s, 3H), 1.05 - 1.01 m, 3H), 0.94 (d,J =6.5 Hz, 3H). 100 542.2 1 H NMR (400 MHz, DMSO-d6)δ9.25 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.48 (s, 1H), 7.47 - 7.37 (m, 2H), 7.29 (dd,J =8.4, 2.0 Hz, 1H), 7.20 (d,J =5.0 Hz, 1H), 6.84 (s, 1H), 6.11 (dd,J =16.8, 2.3 Hz, 1H), 5.69 (d,J =10.5 Hz, 1H), 3.81 (s, 3H), 3.77 - 3.46 (m, 2H), 3.32 - 3.09 (m, 4H), 2.43 (s, 3H), 1.07 - 0.68 (m, 4H). 101 528.2 1H NMR (400 MHz, DMSO-d6)δ9.17 (s, 1H), 8.49 (t,J =4.7 Hz, 1H), 7.90 (d,J =8.6 Hz, 1H), 7.78 (s, 1H), 7.49 (d,J =8.2 Hz, 1H), 7.40 - 7.29 (m, 2H), 7.20 (d,J =5.0 Hz, 1H), 7.16 (d,J =8.2 Hz, 1H), 6.72 - 6.32 (m, 1H), 6.09 (dt,J =16.8, 2.6 Hz, 1H), 5.68 - 5.55 (m, 1H), 3.75 - 3.55 (m, 2H), 3.45 - 3.37 (m, 1H), 3.30 - 3.17 (m, 1H), 2.75 - 2.63 (m, 1H), 2.44 (s, 3H), 1.90 (dt,J =27.2, 14.2 Hz, 2H). 102 530.2 1 H NMR (400 MHz, DMSO-d6)δ9.22 (s, 1H), 8.43 d,J =5.0 Hz, 1H), 7.96 (s, 1H),7.75 - 7.68 (m, 1H), 7.49 - 7.36 (m, 3H), 7.23 (d,J =8.1 Hz, 1H), 7.14 (d,J =4.8 Hz, 1H), 6.73 - 6.66 (m, 1H), 6.07 - 6.02 (m, 1H), 5.62 - 5.59 (m, 1H), 3.75 (s, 3H), 3.59 -3.49 (m, 2H), 3.09 - 2.89 (m, 2H), 2.73 - 2.53 (m, 2H), 2.36 (s, 3H), 1.96 - 1.91 (m, 1H), 1.02 (d,J =5.7 Hz, 3H). 103 544.3 1H NMR (400 MHz, DMSO-d6)δ9.21 (s, 1H), 8.43 (d,J =5.0 Hz, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.42 - 7.35 m, 3H), 7.25 - 7.23 (m, 1H), 7.14 (d,J =5.0 Hz, 1H), 6.76 - 6.60 (m, 1H), 6.06 (dd,J =16.6, 2.4 Hz, 1H), 5.61 (dd,J =11.0, 8.6 Hz, 1H), 4.24 - 3.89 (m, 2H), 3.75 (s, 3H), 3.66 - 3.38 (m, 2H), 2.36 (s, 3H), 1.05 - 1.01 m, 3H), 0.95 (d,J =6.5 Hz, 3H). 104 556.3 1 H NMR (400 MHz, DMSO-d6)δ9.24 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 8.01 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 7.48 - 7.38 (m, 2H), 7.28 (d,J =9.8 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H),6.67 - 6.58 (m, 1H), 6.07 (dd,J =16.7, 2.1 Hz, 1H), 5.63 dd,J =16.7, 2.1 Hz, 1H), 3.81 (s, 3H), 3.49 (s, 2H), 3.41 (s, 2H), 3.18 (s, 2H), 2.42 (s, 3H), 2.34 - 2.26 (m, 2H), 2.01 - 1.96 m, 2H), 1.71 - 1.62 (s, 1H), 1.48 - 1.38 (m, 1H). 105 530.2 1H NMR (400 MHz, DMSO-d6)δ9.27 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.47 (d,J =10.7 Hz, 2H), 7.41 (t,J =8.3 Hz, 1H), 7.33 (d,J =8.6 Hz, 1H), 7.20 (d,J =5.0 Hz, 1H), 6.80 (ddd,J =28.8, 16.7, 10.4 Hz, 1H), 6.13 (dd,J =16.9, 8.3 Hz, 1H), 5.68 (dd,J =10.3, 2.4 Hz, 1H), 4.33 (d,J =12.7 Hz, 1H), 4.15 (d,J =16.9 Hz, 1H), 4.08 - 3.94 (m, 1H), 3.81 (s, 3H), 3.53 (d,J =14.1 Hz, 1H), 3.22 - 2.96 (m, 2H), 2.95 - 2.76 (m, 1H), 2.42 (s, 3H), 1.01 (d,J =6.5 Hz, 3H). 106 542.2 1 H NMR (400 MHz, DMSO-d6)δ9.10 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H), 7.39 - 7.26 (m, 2H), 7.20 (d,J =5.1 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.28 (dd,J =17.0, 10.3 Hz, 1H), 6.08 (dd,J =17.0, 2.3 Hz, 1H), 5.65 (dd,J =10.3, 2.3 Hz, 1H), 4.11 (q,J =8.7 Hz, 2H), 3.82 (s, 2H), 3.80 (s, 3H), 3.42 (s, 2H), 3.25 (s, 2H), 2.42 (s, 3H), 2.05 (d,J =5.6 Hz, 2H). 107 544.3 1 H NMR (400 MHz, DMSO-d6)δ9.17 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.47 (s, 1H), 7.42 - 7.29 (m, 2H), 7.25 - 7.14 (m, 2H), 6.68 (s, 1H), 6.09 (dd,J =16.6, 2.4 Hz, 1H), 5.64 (dd,J =10.4, 2.4 Hz, 1H), 4.14 (d,J =69.8 Hz, 3H), 3.80 (s, 3H), 3.46 (s, 1H), 2.91 (t,J =11.6 Hz, 2H), 2.42 (s, 3H), 1.05 (s, 3H), 0.96 (d,J =6.2 Hz, 3H). 108 542.2 109 530.2 1 H NMR (400 MHz, DMSO-d6)δ9.30 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.50 (s, 1H), 7.47 - 7.35 (m, 2H), 7.30 (dd,J =8.4, 1.9 Hz, 1H), 7.20 (d,J =5.0 Hz, 1H), 6.77 (dd,J =16.6, 10.5 Hz, 1H), 6.11 (d,J =16.5 Hz, 1H), 5.68 (d,J =10.8 Hz, 1H), 4.71 - 4.28 (m, 1H), 4.29 - 3.89 (m, 1H), 3.82 (s, 3H), 3.76 - 3.61 (m, 1H), 3.57 (d, 1H), 3.21 - 2.93 (m, 2H), 2.90 - 2.71 (m, 1H), 2.43 (s, 3H), 1.09 (d,J =6.6 Hz, 3H). 110 530.2 1 H NMR (400 MHz, DMSO-d6)δ9.26 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.49 (s, 1H), 7.45 (d,J =9.5 Hz, 1H), 7.41 (d,J =8.3 Hz, 1H), 7.34 (d,J =8.5 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 6.90 - 6.70 (m, 1H), 6.14 (dd,J =16.8, 8.2 Hz, 1H), 5.74 - 5.65 (m, 1H), 4.37 - 3.88 (m, 3H), 3.82 (s, 3H), 3.57 - 3.41 (m, 1H), 3.23 - 2.78 (m, 3H), 2.43 (s, 3H), 1.01 (d,J =6.3 Hz, 3H). 111 544.3 1 H NMR (400 MHz, DMSO-d6)δ9.18 (s, 1H), 8.48 (dd,J =5.0, 2.4 Hz, 1H), 7.93 (s, 1H), 7.48 (s, 1H), 7.42 - 7.32 (m, 2H), 7.20 (dq,J =5.6, 3.1, 2.1 Hz, 2H), 6.68 (s, 1H), 6.10 (dd,J =16.6, 2.4 Hz, 1H), 5.64 (dd,J =10.3, 2.4 Hz, 1H), 4.37 - 3.92 (m, 3H), 3.81 (s, 3H), 3.55 - 3.39 (m, 1H), 3.08 - 2.76 (m, 2H), 2.42 (s, 3H), 1.05 (s, 3H), 0.96 (d,J =6.2 Hz, 3H). 112 544.3 1H NMR (400 MHz, DMSO-d6)δ9.22 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.50 (s, 1H), 7.41 (t,J =8.4 Hz, 1H), 7.36 (dd,J =11.5, 2.1 Hz, 1H), 7.22 - 7.16 (m, 2H), 6.64 (dd,J =16.7, 10.5 Hz, 1H), 6.00 (dd,J =16.7, 2.4 Hz, 1H), 5.58 (dd,J =10.5, 2.4 Hz, 1H), 3.80 (s, 3H), 3.79 - 3.67 (m, 3H), 3.41 (s, 3H), 2.41 (s, 3H), 1.39 (s, 6H). 113 544.3 1 H NMR (400 MHz, DMSO-d6)δ9.18 (s, 1H), 8.49 (d,J =8.0 Hz, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.53 - 7.40 (m, 4H), 7.20 (d,J =8.0 Hz, 1H), 6.89 - 6.71 (m, 1H), 6.17 - 6.09 (m, 1H), 5.71 - 5.64 (m, 1H), 3.80 (s, 3H), 3.49 - 3.46 (m, 2H), 3.31 - 3.26 (m, 2H), 2.93 - 2.89 (m, 2H), 2.41 (s, 3H), 1.49 (s, 6H). 114 544.3 1H NMR (400 MHz, DMSO-d6)δ9.24 (s, 1H), 8.42 (d,J =5.0 Hz, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.44 (s, 1H), 7.36 (dd,J =10.1, 6.9 Hz, 2H), 7.21 (dd,J =8.3, 2.0 Hz, 1H), 7.13 (d,J =5.0 Hz, 1H), 6.69 (dd,J =16.6, 10.5 Hz, 1H), 6.07 (dd,J =16.5, 2.5 Hz, 1H), 5.61 (dd,J =10.4, 2.5 Hz, 1H), 4.33 (s, 2H), 3.56 (d,J =12.8 Hz, 2H), 2.83 (s, 2H), 2.35 (s, 3H), 1.06 (d,J =6.8 Hz, 6H). 115 544.3 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.48 (d,J= 5.0 Hz, 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.49 (s, 1H), 7.45 – 7.29 (m, 2H), 7.25 – 7.11 (m, 2H), 6.70 (dd,J= 16.5, 10.4 Hz, 1H), 6.19 (dd,J= 16.5, 2.6 Hz, 1H), 5.70 (dd,J= 10.3, 2.6 Hz, 1H), 4.48 – 4.30 (m, 2H), 3.82 (s, 3H), 3.74 – 3.56 (m, 2H), 3.25 – 3.17 (m, 2H), 2.42 (s, 3H), 1.19 (d,J= 6.1 Hz, 6H). 116 542.2 1H NMR (400 MHz, DMSO-d6)δ9.25 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.52 - 7.39 (m, 3H), 7.33 (dd,J =8.6, 2.0 Hz, 1H), 7.20 (d,J =5.0 Hz, 1H), 6.74 (dd,J =16.7, 10.5 Hz, 1H), 6.09 (dd,J =16.7, 2.4 Hz, 1H), 5.65 (dd,J =10.4, 2.4 Hz, 1H), 4.21 (s, 2H), 4.07 (d,J =13.0 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 1H), 3.30 (d,J =2.4 Hz, 1H), 2.94 (d,J =12.9 Hz, 1H), 2.42 (s, 3H), 1.77 (s, 2H), 1.53 (dt,J =18.1, 11.1 Hz, 2H). 117 542.2 118 542.2 1H NMR (400 MHz, DMSO-d6)δ9.19 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.50 (s, 1H), 7.42 - 7.30 (m, 2H), 7.24 - 7.13 (m, 2H), 6.24 (ddd,J =38.4, 16.9, 10.2 Hz, 1H), 6.13 - 6.00 (m, 1H), 5.63 (dd,J =10.1, 2.5 Hz, 1H), 4.54 (d,J =6.7 Hz, 1H), 4.36 - 4.30 (m, 1H), 4.28 (d,J =4.0 Hz, 1H), 3.97 (d,J =16.0 Hz, 4H), 3.80 (s, 3H), 3.77 (s, 1H), 2.41 (s, 3H), 1.34 (dd,J =19.1, 6.5 Hz, 3H). 119 542.2 1 ¹H NMR (400 MHz, deuterated chloroform) δ 8.37 (d, J = 5.0 Hz, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.29 (t, J = 8.3 Hz, 1H), 7.16 – 7.08 (m, 2H), 6.94 (d, J = 5.0 Hz, 2H), 6.34 (t, J = 17.2 Hz, 1H), 6.12 (ddd, J = 26.7, 16.5, 10.1 Hz, 1H), 5.66 (d, J = 10.3 Hz, 1H), 4.43 (q, J = 6.5 Hz, 1H), 4.30 – 4.18 (m, 1H), 4.09 (q,J= 11.1 Hz, 4H), 3.90 (s, 3H), 3.79 (s, 1H), 2.50 (s, 3H), 1.45 (d,J= 6.5 Hz, 3H)

[0486] 117A and 118A in raw material I can be synthesized through the following steps:

[0487] Step 1: 1-(tert-butyl)-3-methyl-3-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)azacyclobutyl-1,3-dicarboxylic acid ester (117D)

[0488] Compounds 117B (4.4 g, 20 mmol) and 117C (1.5 g, 10 mmol) were dissolved in 50 mL of anhydrous tetrahydrofuran, and the resulting solution was cooled to -78°C. A solution of hexamethyldisilamide lithium (1.0 M tetrahydrofuran solution, 20 mL, 20 mmol) was slowly added dropwise with stirring, and the mixture was stirred continuously at -78°C for 3 hours. The reaction solution was quenched with 10 mL of saturated ammonium chloride solution, and then slowly heated to room temperature. 100 mL of ethyl acetate and 50 mL of saturated ammonium chloride solution were added to the resulting mixture. The resulting organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to give compound 117D (2.1 g, yield: 58%).

[0489] MS (ESI+)m / z= 363.2[M+H].

[0490] Step 2: 3-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-3-(hydroxymethyl)azacyclobutyl-1-carboxylic acid tert-butyl ester (117E)

[0491] Compound 117D (2.1 g, 5.8 mmol) was dissolved in 40 mL of anhydrous tetrahydrofuran, and the resulting solution was cooled to 0°C. Lithium aluminum hydride (0.38 g, 10 mmol) was slowly added to the reaction solution, and the mixture was stirred at 0°C for 2 hours. 10 g of sodium sulfate decahydrate was added to the resulting reaction solution, and the mixture was stirred at 0°C for 1 hour, then slowly raised to room temperature and stirred for another 16 hours. The resulting mixture was filtered under reduced pressure, and the filter cake was washed with 50 mL of ethyl acetate. The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (elution phase: dichloromethane containing 3% methanol) to give the main product 117E (1.2 g, yield 62%).

[0492] MS (ESI+) m / z = 335.2[M+H].

[0493] Step 3 (S)-6-((R)-tert-butylsulfinyl)-5-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (117F)

[0494] Crude compound 117E (1.2 g, 3.6 mmol) and p-toluenesulfonyl chloride (1.03 g, 5.4 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran. Sodium hydride (0.7 g, 60%, 17.4 mmol) was slowly added at 0°C. The resulting mixture was stirred at 0°C for 2 hours, and then quenched with 20 mL of water. The resulting reaction solution was extracted three times with 30 mL of ethyl acetate. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to give compound 117F (1.0 g, yield: 88%).

[0495] MS (ESI+)m / z= 317.2 [M+H].

[0496] Step 4: (R)-5-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (117A) and (R)-2-((S)-tert-butylsulfinyl)-1-methyl-2,6-diazaspiro[3.3]heptane (118A)

[0497] Compound 117F (0.63 g, 2.0 mmol) was dissolved in 5 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added at 0°C. The resulting reaction solution was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure at 0°C, and the crude product was purified by C18 reverse-phase column (mobile phase: 0-60% acetonitrile aqueous solution) to give compounds 117A (63 mg, yield: 15%) and 118A (122 mg, yield: 28%).

[0498] Compound 117A MS (ESI+) m / z = 213.2 [M+H].

[0499] Compound 118A MS (ESI+) m / z = 217.2 [M+H].

[0500] 119A was synthesized by using a similar synthetic method and steps to that of compound 118A, but with 119C replacing 117C.

[0501] MS (ESI+) m / z = 217.2[M+H].

[0502] Example 43

[0503] By using the same methods and steps as in steps one to four of Example 39, replacing compound 81B in step one with raw material I in the table below, and using the same methods and steps as in Example 41 in step five, compounds 120-125 corresponding to the table can be synthesized. serial number Raw material I Compound Structure m / z [M+H] 1 HNMR 120 546.2 1 H NMR (400 MHz, DMSO-d6)δ9.17 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.36 (s, 1H), 7.31 (dd,J =11.5, 1.8 Hz, 1H), 7.20 (d,J =5.0 Hz, 1H), 7.17 (dd,J =8.2, 1.8 Hz, 1H), 5.47 (d,J =3.6 Hz, 0.5H), 5.36 (s, 0.5H), 5.28 (s, 0.5H), 5.24 (s, 0.5H), 4.48 (s, 2H), 4.09 (s, 2H), 4.03 - 3.93 (m, 4H), 3.80 (s, 3H), 2.43 (s, 3H). 121 534.2 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.70 (d,J= 6.6 Hz, 1H), 8.48 (d,J= 5.0 Hz, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.40 – 7.27 (m, 2H), 7.23 – 7.11 (m, 2H), 5.59 (d,J= 3.4 Hz, 0.5H), 5.47 (d,J= 3.4 Hz, 0.5H), 5.25 (dd,J= 15.6, 3.4 Hz, 1H), 4.34 – 4.30 (m, 1H), 3.79 (s, 3H), 3.50 – 3.38 (m, 2H), 3.29 – 3.14 (m, 2H), 2.42 (s, 3H), 2.09 – 2.00 (m, 1H), 1.93 – 1.85 (m, 1H). 122 534.2 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.70 (d,J= 6.7 Hz, 1H), 8.48 (d,J= 5.0 Hz, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.41 – 7.27 (m, 2H), 7.24 – 7.12 (m, 2H), 5.59 (d,J= 3.4 Hz, 0.5H), 5.47 (d,J= 3.4 Hz, 0.5H), 5.25 (dd,J= 15.7, 3.4 Hz, 1H), 4.36 – 4.29 (m, 1H), 3.79 (s, 3H), 3.49 – 3.38 (m, 2H), 3.30 – 3.15 (m, 2H), 2.42 (s, 3H), 2.08 – 2.00 (m, 1H), 1.95 – 1.85 (m, 1H). 123 530.2 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.49 (d,J= 5.0 Hz, 1H), 8.44 (d,J= 8.1 Hz, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.51 (s, 1H), 7.47 – 7.37 (m, 2H), 7.31 (dd,J= 8.3, 2.0 Hz, 1H), 7.20 (d,J= 5.0 Hz, 1H), 5.57 (d,J= 3.4 Hz, 0.5H), 5.45 (d,J= 3.4 Hz, 0.5H), 5.23 (dd,J= 15.7, 3.4 Hz, 1H), 3.93 – 3.86 (m, 1H), 3.80 – 3.74 (m, 5H), 2.91 – 2.79 (m, 2H), 2.42 (s, 3H), 1.70 – 1.67 (m, 2H), 1.59 – 1.50 (m, 2H). 124 516.2 1 H NMR (400 MHz, DMSO-d6)δ9.24 (s, 1H), 8.42 (d,J =5.0 Hz, 1H), 7.99 (s, 1H), 7.75 (s, 1H), 7.48 - 7.39 (m, 2H), 7.39 - 7.26 (m, 2H), 7.13 (d,J =5.0 Hz, 1H), 5.24 (d,J =4.0 Hz, 1H), 5.22 - 5.17 (m, 1H), 5.07 (d,J =4.0 Hz, 1H), 3.75 (s, 3H), 3.50 (s, 4H), 3.24 (s, 4H), 2.36 (s, 3H). 125 530.2 1H NMR (400 MHz, DMSO-d6)δ9.32 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.49 (s, 1H), 7.47 - 7.38 (m, 2H), 7.30 (dd,J =8.3, 1.9 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 5.34 - 5.06 (m, 2H), 4.48 - 4.18 (m, 1H), 3.97 - 3.74 (m, 4H), 3.69 (d,J =13.0 Hz, 1H), 3.58 (d,J =13.0 Hz, 1H), 3.30 - 2.98 (m, 2H), 2.93 - 2.75 (m, 1H), 2.42 (s, 3H), 1.14 (d,J =6.7 Hz, 3H).

[0504] Example 44

[0505] Using a similar method and steps as in Example 39, by replacing compound 81B in the first step with raw material I in the table below, and replacing 60E in the third step with raw material J in the table below, compounds 126-154 corresponding to those in the table below can be synthesized. serial number Raw material I Raw material J Compound Structure m / z [M+H] 1 HNMR 126 422.2 1H NMR (400 MHz, DMSO-d6)δ8.70 (d,J =6.7 Hz, 1H), 8.47 (d,J =5.0 Hz, 1H), 7.77 (s, 1H), 7.36 (t,J =8.4 Hz, 1H), 7.26 (dd,J =11.5, 2.0 Hz, 1H), 7.18 (d,J =5.0 Hz, 1H), 7.13 (dd,J =8.5, 1.9 Hz, 1H), 6.35 (s, 2H), 6.19 - 6.02 (m, 2H), 5.60 (dd,J =9.6, 2.6 Hz, 1H), 4.45 (d,J =7.0 Hz, 1H), 3.97 (s, 2H), 3.56 (s, 2H), 2.41 (s, 3H). 127 521.3 1 H NMR (400 MHz, DMSO-d6)δ8.67 (d,J =6.7 Hz, 1H), 8.47 (d,J =5.0 Hz, 1H), 7.81 (s, 1H), 7.36 (t,J =8.5 Hz, 1H), 7.26 (d,J =11.9 Hz, 1H), 7.19 (d,J =5.1 Hz, 1H), 7.13 (d,J =8.2 Hz, 1H), 6.92 (s, 1H), 6.17 - 6.03 (m, 2H), 5.60 (dd,J =9.7, 2.6 Hz, 1H), 4.44 (s, 1H), 3.98 (s, 2H), 3.58 (s, 2H), 3.29 - 3.22 (m, 2H), 2.41 (s, 3H), 2.27 (s, 2H), 1.51 (s, 4H), 1.23 (s, 6H). 128 528.2 1H NMR (400 MHz, DMSO-d6)δ8.72 (d,J =6.6 Hz, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.40 - 8.36 (m, 1H), 7.97 (s, 1H), 7.70 (s, 1H), 7.41 (t,J =8.4 Hz, 1H), 7.35 (dd,J =11.4, 2.0 Hz, 1H), 7.22 - 7.17 (m, 2H), 7.06 - 7.00 (m, 1H), 6.95 (td,J =8.4, 7.3, 4.4 Hz, 2H), 6.16 - 6.04 (m, 2H), 5.61 (dd,J =9.6, 2.7 Hz, 1H), 4.49 (q,J =6.7 Hz, 1H), 4.08 (s, 2H), 3.88 (s, 3H), 3.67 (s, 2H), 2.41 (s, 3H). 129 516.2 130 499.2 1 H NMR (400 MHz, DMSO-d6)δ9.57 (s, 1H), 8.93 (dd,J =2.7, 0.7 Hz, 1H), 8.72 (d,J =6.6 Hz, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.27 (ddd,J =8.4, 2.7, 1.5 Hz, 1H), 8.12 (dd,J =4.6, 1.5 Hz, 1H), 8.00 (s, 1H), 7.41 (t,J =8.4 Hz, 1H), 7.36 (dd,J =11.3, 2.1 Hz, 1H), 7.30 (dd,J =8.4, 4.6 Hz, 1H), 7.22 - 7.18 (m, 2H), 6.19 - 6.03 (m, 2H), 5.61 (dd,J =9.6, 2.7 Hz, 1H), 4.50 (h,J =6.6 Hz, 1H), 4.09 (s, 2H), 3.68 (s, 2H), 2.41 (s, 3H). 131 516.2 1 H NMR (400 MHz, DMSO-d6)δ8.70 (t,J =3.3 Hz, 2H), 8.48 (d,J =5.0 Hz, 1H), 7.93 (s, 1H), 7.90 (dd,J =8.3, 1.7 Hz, 1H), 7.40 (t,J =8.3 Hz, 1H), 7.34 (dd,J =11.4, 2.0 Hz, 1H), 7.25 - 7.12 (m, 4H), 7.07 (tdd,J =7.6, 4.8, 1.8 Hz, 1H), 6.19 - 6.02 (m, 2H), 5.61 (dd,J =9.6, 2.6 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.03 (s, 2H), 3.62 (s, 2H), 2.41 (s, 3H). 132 498.2 1 H NMR (400 MHz, DMSO-d6)δ9.36 (s, 1H), 8.72 (d,J =6.6 Hz, 1H), 8.49 (d,J =5.0 Hz, 1H), 7.98 (s, 1H), 7.84 - 7.77 (m, 2H), 7.43 - 7.32 (m, 2H), 7.30 - 7.23 (m, 2H), 7.23 - 7.17 (m, 2H), 6.90 (tt,J =7.3, 1.1 Hz, 1H), 6.19 - 6.03 (m, 2H), 5.61 (dd,J =9.6, 2.6 Hz, 1H), 4.50 (p,J =6.6 Hz, 1H), 4.09 (s, 2H), 3.68 (s, 2H), 2.42 (s, 3H). 133 501.2 134 528.2 1 H NMR (400 MHz, DMSO-d6)δ9.37 (s, 1H), 8.72 (d,J =6.6 Hz, 1H), 8.49 (d,J =5.0 Hz, 1H), 7.99 (s, 1H), 7.65 (t,J =2.2 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.32 - 7.26 (m, 1H), 7.22 - 7.18 (m, 2H), 7.14 (t,J =8.1 Hz, 1H), 6.51 - 6.47 (m, 1H), 6.20 - 6.03 (m, 2H), 5.61 (dd,J =9.6, 2.6 Hz, 1H), 4.50 (q,J =6.6 Hz, 1H), 4.09 (s, 2H), 3.73 (s, 3H), 3.69 (s, 2H), 2.42 (s, 3H). 135 488.2 136 525.2 1 H NMR (400 MHz, DMSO-d6)δ9.56 (s, 1H), 8.93 (d,J =2.6 Hz, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.31 – 8.26 (m, 1H), 8.12 (dd,J =4.6, 1.5 Hz, 1H), 7.99 (s, 1H), 7.41 (d,J =8.4 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.31 – 7.27 (m, 1H), 7.22 – 7.18 (m, 2H), 6.22 (dd,J =17.0, 10.3 Hz, 1H), 6.05 (dd,J =17.0, 2.4 Hz, 1H), 5.64 (dd,J =10.2, 2.4 Hz, 1H), 4.33 (s, 2H), 4.03 (s, 2H), 3.99 (s, 4H), 2.42 (s, 3H). 137 525.2 138 514.2 1 H NMR (400 MHz, DMSO-d6)δ12.42 (s, 1H), 9.18 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 7.90 (s, 1H), 7.87 – 7.55 (m, 2H), 7.38 (t,J =8.4 Hz, 1H), 7.32 (dd,J =11.4, 2.1 Hz, 1H), 7.25 – 7.12 (m, 2H), 6.23 (dd,J =16.9, 10.2 Hz, 1H), 6.05 (dd,J =17.0, 2.4 Hz, 1H), 5.64 (dd,J =10.2, 2.4 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 2H), 3.98 (s, 4H), 2.42 (s, 3H). 139 636.3 1H NMR (400 MHz, DMSO-d6)δ9.09 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 7.92 (s, 1H), 7.68 – 7.60 (m, 2H), 7.43 – 7.29 (m, 2H), 7.23 – 7.14 (m, 2H), 6.90 – 6.83 (m, 2H), 6.23 (dd,J =17.0, 10.3 Hz, 1H), 6.06 (dd,J =16.9, 2.4 Hz, 1H), 5.64 (dd,J =10.2, 2.4 Hz, 1H), 4.33 (s, 2H), 4.03 (s, 2H), 3.99 – 3.94 (m, 4H), 3.09 – 3.01 (m, 4H), 2.55 – 2.51 (m, 4H), 2.43 (s, 3H), 2.40 – 2.31 (m, 2H), 1.03 (t,J =7.2 Hz, 3H). 140 558.2 1 H NMR (400 MHz, DMSO-d6)δ9.19 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.52 (s, 1H), 7.38 (t,J =8.4 Hz, 1H), 7.32 (dd,J =11.4, 2.0 Hz, 1H), 7.20 (d,J =5.0 Hz, 1H), 7.17 (dd,J =8.3, 2.0 Hz, 1H), 6.23 (dd,J =17.0, 10.2 Hz, 1H), 6.06 (dd,J =17.0, 2.4 Hz, 1H), 5.64 (dd,J =10.2, 2.4 Hz, 1H), 4.90 (q,J =5.1 Hz, 1H), 4.33 (s, 2H), 4.09 (t,J =5.6 Hz, 2H), 4.03 (s, 2H), 3.98 (s, 4H), 3.71 (q,J =5.5 Hz, 2H), 2.42 (s, 3H). 141 568.3 1 H NMR (400 MHz, DMSO-d6)δ9.09 (s, 1H), 8.41 (d,J =5.0 Hz, 1H), 7.83 - 7.79 (m, 2H), 7.45 (s, 1H), 7.34 - 7.23 (m, 2H), 7.13 - 7.08 (m, 2H), 6.50 - 6.41 (m, 1H),6.07- 6.01 (m, 1H), 5.60 - 5.56 (m, 1H), 3.72 - 3.59 (s, 6H), 3.49 - 3.47 (m, 2H), 2.35 (s, 3H), 2.06 - 2.02 (s, 1H), 1.97 -1.90 (s, 2H), 0.91 - 0.84 (m, 4H). 142 570.3 1 H NMR (400 MHz, DMSO-d6)δ9.17 (s, 1H), 8.48 - 8.47 (m, 1H), 7.90 - 7.85 (m, 2H), 7.55 - 7.54 (m, 1H), 7.39 - 7.32 (m, 2H), 7.20 - 7.17 (m, 2H), 6.57 - 6.48 (m, 1H), 6.14 - 6.08 (m, 1H), 5.67 - 5.62 (m, 1H), 3.80 - 3.72 (m, 6H), 3.50 - 3.54 (m, 2H), 2.40 (s, 3H), 2.13 - 2.09 (m, 1H), 2.03 - 1.97 (m, 2H), 1.39 (d,J =8.0 Hz, 6H). 143 556.3 1H NMR (400 MHz, DMSO-d6)δ9.18 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 7.90 (d,J =2.1 Hz, 1H), 7.84 (s, 1H), 7.53 (s, 1H), 7.38 (t,J =8.4 Hz, 1H), 7.35 – 7.29 (m, 1H), 7.23 – 7.13 (m, 2H), 6.52 (dt,J =16.8, 9.9 Hz, 1H), 6.11 (ddd,J =16.8, 3.7, 2.4 Hz, 1H), 5.65 (ddd,J =10.3, 4.5, 2.5 Hz, 1H), 4.08 (q,J =7.3 Hz, 2H), 3.87 – 3.67 (m, 4H), 3.59 – 3.49 (m, 2H), 3.42 – 3.35 (m, 2H), 2.40 (s, 3H), 2.06 (dt,J =37.4, 6.9 Hz, 2H), 1.34 (q,J =8.2, 7.7 Hz, 3H). 144 578.2 1H NMR (400 MHz, DMSO-d6)δ9.47 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 8.26 (s, 1H), 7.98 - 7.92 (m, 1H), 7.87 (d,J =2.9 Hz, 1H), 7.78 (s, 0.6H), 7.63 (s, 0.4H), 7.45 - 7.32 (m, 2H), 7.26 - 7.16 (m, 2H), 6.57 - 6.47 (m, 1H), 6.11 (ddd,J =16.8, 3.9, 2.4 Hz, 1H), 5.65 (ddd,J =10.3, 4.2, 2.4 Hz, 1H), 3.80 - 3.72 (m, 5H), 3.56 - 3.53 (m, 2H), 3.38 - 3.36 (m, 1H), 2.40 (d,J =1.7 Hz, 3H), 2.11 (t,J =6.8 Hz, 1H), 2.02 (t,J =7.0 Hz, 1H). 145 587.3 1 H NMR (400 MHz, DMSO-d6)δ9.31 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.49 (s, 1H), 7.48 – 7.38 (m, 2H), 7.30 (dd,J =8.2, 2.0 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 6.75 (dd,J =16.6, 10.5 Hz, 1H), 6.11 (d,J =16.1 Hz, 1H), 5.67 (d,J =10.3 Hz, 1H), 4.69 – 4.27 (m, 1H), 4.17 (t,J =6.1 Hz, 2H), 3.84 – 3.48 (m, 3H), 3.17 – 2.73 (m, 3H), 2.67 (s, 3H), 2.61 (t,J =6.4 Hz, 2H), 2.43 (s, 3H), 2.17 (s, 6H), 1.09 (d,J =6.7 Hz, 3H). 146 599.3 1H NMR (400 MHz, DMSO-d6)δ9.37 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.03 (s, 2H), 7.54 – 7.39 (m, 3H), 7.30 (dd,J =8.2, 2.0 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 6.80 – 6.69 (m, 1H), 6.11 (d,J =16.5 Hz, 1H), 5.67 (d,J =10.4 Hz, 1H), 4.92 – 4.80 (m, 1H), 4.71 – 4.20 (m, 2H), 4.20 – 3.78 (m, 2H), 3.72 – 3.47 (m, 2H), 3.14 – 2.99 (m, 1H), 2.89 – 2.58 (m, 4H), 2.47 – 2.33 (m, 4H), 2.30 (s, 3H), 2.07 – 1.90 (m, 1H), 1.09 (d,J =6.6 Hz, 3H). 147 613.3 1 H NMR (400 MHz, DMSO-d6)δ9.30 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.55 (s, 1H), 7.50 – 7.38 (m, 2H), 7.29 (dd,J =8.2, 2.0 Hz, 1H), 7.20 (d,J =5.0 Hz, 1H), 6.76 (dd,J =16.6, 10.5 Hz, 1H), 6.11 (d,J =16.6 Hz, 1H), 5.67 (d,J =10.7 Hz, 1H), 4.68 – 4.23 (m, 1H), 4.19 – 4.02 (m, 0H), 3.76 – 3.52 (m, 2H), 3.19 – 2.97 (m, 2H), 2.95 – 2.74 (m, 3H), 2.43 (s, 3H), 2.22 (s, 3H), 2.16 – 2.02 (m, 2H), 2.01 – 1.86 (m, 4H), 1.09 (d,J =6.7 Hz, 3H). 148 638.3 1 H NMR (400 MHz, DMSO-d6)δ9.21 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.04 (s, 1H), 7.61 (s, 1H), 7.59 (d,J =2.3 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.30 (dd,J =8.3, 1.9 Hz, 1H), 7.20 (d,J =5.0 Hz, 1H), 6.94 – 6.87 (m, 2H), 6.76 (dd,J =16.6, 10.5 Hz, 1H), 6.17 – 6.05 (m, 1H), 5.75 – 5.61 (m, 1H), 4.63 – 4.29 (m, 1H), 4.18 – 3.84 (m, 1H), 3.76 – 3.51 (m, 2H), 3.19 – 2.92 (m, 6H), 2.84 – 2.71 (m, 1H), 2.59 – 2.51 (m, 4H), 2.43 (s, 3H), 2.41 – 2.31 (m, 2H), 1.14 – 0.95 (m, 6H). 149 627.3 1H NMR (400 MHz, DMSO-d6)δ9.27 (s, 1H), 8.50 (d,J =4.0 Hz, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 7.55 (s, 1H), 7.46 - 7.42 (m, 2H), 7.33 - 7.29 (m, 1H), 7.21 (d,J =4.0 Hz, 1H), 6.82 - 6.72 (m, 1H), 6.15 - 6.10 (m, 1H), 5.70 - 5.65 (m, 1H), 4.67 - 4.61 (m, 1H), 4.29 - 4.00 (m, 3H), 3.97 - 3.67 (m, 3H), 2.90 - 2.85 (m, 2H), 2.43 (s, 3H), 2.23 (s, 3H), 2.14 - 2.05 (m, 2H), 2.01 - 1.91 (m, 4H), 1.10 - 1.08 (m, 3H), 1.04 - 1.00 (m, 3H). 150 613.3 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.49 (d,J= 5.0 Hz, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.47 – 7.42 (s, 3H), 7.31 (t,J= 7.7 Hz, 1H), 7.20 (d,J= 5.0 Hz, 1H), 6.82 – 6.70 (m, 1H), 6.15 – 6.10 (m, 1H), 5.74 – 5.63 (m, 1H), 4.87 -4.66 (m, 2H), 4.28 – 3.98 (m, 3H), 2.88 – 2.65 (m, 3H), 2.43 (s, 3H), 2.40 – 2.36 (m, 1H), 2.33 – 2.30 (m, 3H), 2.03 – 1.95 (m, 1H), 1.10 – 1.01 (m, 5H). 151 652.3 1 H NMR (400 MHz, DMSO-d6)δ9.19 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.02 (s, 1H), 7.60 (d,J =2.2 Hz, 1H), 7.58 (d,J =2.2 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.31 (d,J =8.5 Hz, 1H), 7.21 (d,J =5.0 Hz, 1H), 6.90 (d,J =2.2 Hz, 1H), 6.89 (d,J =2.2 Hz, 1H), 6.77 (td,J =17.9, 10.5 Hz, 1H), 6.13 (dd,J =16.6, 2.4 Hz, 1H), 5.72 – 5.62 (m, 1H), 4.70 – 4.54 (m, 1H), 4.36 – 4.19 (m, 1H), 4.19 – 4.06 (m, 1H), 3.97 (d,J =13.2 Hz, 1H), 3.71 (d,J =13.8 Hz, 1H), 3.53 – 3.41 (m, 1H), 3.26 – 3.12 (m, 2H), 3.06 (t,J =5.0 Hz, 4H), 2.43 (s, 3H), 2.37 (q,J =7.2 Hz, 2H), 1.18 – 0.91 (m, 9H). 152 601.3 1H NMR (400 MHz, DMSO-d6)δ9.27 (s, 1H), 8.50 (d,J =4.0 Hz, 1H), 8.02 (s, 1H), 7.88 (s, 1H), 7.49 - 7.42 (m, 3H), 7.34 - 7.29 (m, 1H), 7.21 (d,J =4.0 Hz, 1H), 6.82 - 6.70 (m, 1H), 6.15 - 6.10 (m, 1H), 5.71 - 5.65 (m, 1H), 4.69 - 4.61 (m, 1H), 4.31 - 4.24 (m, 1H), 4.18 - 4.14 (m, 2H), 2.62 - 2.59 (m, 2H), 2.43 (s, 3H), 2.17 (s, 6H), 1.11 - 1.07 (m, 3H), 1.04 - 1.00 (m, 3H). 153 638.3 1 H NMR (400 MHz, DMSO-d6)δ9.19 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.04 (s, 1H), 7.66 – 7.55 (m, 2H), 7.48 (d,J =11.7 Hz, 1H), 7.42 (t,J =8.3 Hz, 1H), 7.34 (d,J =8.6 Hz, 1H), 7.20 (d,J =5.1 Hz, 1H), 6.89 (d,J =8.8 Hz, 2H), 6.86 – 6.68 (m, 1H), 6.13 (dd,J =16.7, 8.6 Hz, 1H), 5.68 (dd,J =10.3, 2.4 Hz, 1H), 4.44 – 3.80 (m, 3H), 3.60 – 3.26 (m, 4H), 3.21 – 2.73 (m, 6H), 2.55 – 2.51 (m, 4H), 2.43 (s, 3H), 2.37 (q,J =7.2 Hz, 2H), 1.11 – 0.95 (m, 5H). 154 580.2 1 H NMR (400 MHz, DMSO-d6)δ9.56 (s, 1H), 8.48 (d,J= 5.0 Hz, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.95 (s, 0.25H), 7.87 (s, 1H), 7.80 (s, 0.25H), 7.48 – 7.35 (m, 2H), 7.21 – 7.18 (m, 2H), 6.70 (dd,J= 16.5, 10.4 Hz, 1H), 6.19 (dd,J= 16.5, 2.5 Hz, 1H), 5.70 (dd,J= 10.3, 2.6 Hz, 1H), 4.46 - 4.29 (m, 2H), 3.74 – 3.60 (m, 2H), 3.25 – 3.16 (m, 2H), 2.43 (s, 3H), 1.19 (d,J= 6.6 Hz, 6H).

[0506] Example 45

[0507] Using a similar method and steps as in Example 39, replace compound 81B in the first step with raw material I in the table below, and replace 1G in the second step with raw material K in the table below, to synthesize compounds 156-159 corresponding to those in the table below. serial number Raw material I Raw material K Compound Structure m / z [M+H] 1 HNMR 156 510.2 1H NMR (400 MHz, DMSO-d6)δ9.13 (s, 1H), 8.48 (d,J =4.0 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.49 (s, 1H), 7.35 - 7.33 (m, 2H), 7.22 - 7.20 (m, 2H), 7.17-7.16 (m, 1H), 6.26 - 6.19 (m, 1H), 6.08 - 6.03 (m, 1H), 5.65 - 5.62 (m, 1H), 4.40 - 4.28 (m, 2H), 4.08 - 3.88 (m, 6H), 3.80 (s, 3H), 2.41 (s, 3H). 157 499.2 1 H NMR (400 MHz, DMSO-d6)δ9.18 (s, 1H), 7.85 (d,J =4.0 Hz, 2H), 7.55 (d,J =8.0 Hz, 2H), 7.49 (s, 1H), 7.35 (d,J =8.0 Hz, 2H), 6.25 - 6.18 (m, 1H), 6.07 - 6.02 (m, 1H), 5.64 - 5.61 (m, 1H), 4.37 - 4.28 (m, 2H), 4.08 - 3.85 (m, 6H), 3.80 (s, 3H), 3.50 - 3.34 (m, 4H), 1.91 - 1.81 (m, 4H). 158 158A 539. 1H NMR (400 MHz, DMSO-d6)δ9.13 (s, 1H), 7.87 (d,J =24.0 Hz, 2H), 7.69 (s, 1H), 7.49 (s, 1H), 7.11 (d,J =8.0 Hz, 1H), 7.05 (s, 1H), 6.91 (dd,J =16.9, 7.7 Hz, 2H), 6.66 (d,J =8.2 Hz, 1H), 6.23 (dd,J =16.9, 10.4 Hz, 1H), 6.13 - 6.01 (m, 1H), 5.69 - 5.59 (m, 1H), 4.33 (s, 2H), 4.03 - 3.98 (m, 6H), 3.80 (s, 3H), 3.74 (s, 3H), 2.27 (s, 3H). 159 159A 514. 1 H NMR (400 MHz, DMSO-d6)δ9.12 (s, 1H), 8.63 - 8.62 (m, 2H), 7.83 - 7.77 (m, 2H), 7.42 (s, 1H), 7.37 - 7.32 (m, 1H), 7.28 - 7.25 (m, 2H), 7.15 - 7.10 (m, 1H), 6.20 - 6.13 (m, 1H), 6.02 - 5.97 (m, 1H), 5.59 - 5.56 (m, 1H), 4.27 (s, 2H), 3.97 - 3.92 (m, 6H), 3.73 (s, 3H).

[0508] The synthetic route of compound 158A is as follows:

[0509] Using a similar synthetic procedure to compound 1G in Example 1, in step one, compound 1C is replaced by compound 158B, and compound 1D is replaced by compound 158C. The reaction solvent is replaced by N,N-dimethylformamide, and the reaction temperature is increased to 130 degrees Celsius for 12 hours. Compound 158A can then be synthesized by proceeding with a similar step two. MS (ESI+) m / z = 342.0 [M+H].

[0510] 1H NMR (400 MHz, DMSO-d6) δ = 7.66 (t,J= 7.6 Hz, 1H), 7.36 - 7.24 (m, 2H), 7.09 (d,J= 8.0 Hz, 1H), 6.92 (d,J= 7.2 Hz, 1H), 6.69 (d,J= 8.0 Hz, 1H), 3.70 (s, 3H), 2.26 (s, 3H), 1.31 (s, 12H).

[0511] The synthetic route of compound 159A is as follows:

[0512] Compound 159A can be synthesized by using a similar synthetic procedure to compound 1G in Example 1, but replacing compound 1D with compound 159B in step one. MS (ESI+) m / z = 234.9 [M+H].

[0513] 1H NMR (400 MHz, DMSO-d6) δ = 8.66 (d,J= 4.8 Hz, 2H), 7.55 (d,J= 8.0 Hz, 1H), 7.51 (d,J= 11.2 Hz, 1H), 7.41 (t,J= 7.2 Hz, 1H), 7.32 (t,J= 4.8 Hz, 1H), 1.31 (s, 12H).

[0514] Example 46

[0515] (2S)-1-(4-(4-((2S,5R)-4-propenyl-2,5-dimethylpiperazin-1-yl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)cyclohex-3-ene-1-carbonyl)pyrrolidine-2-carboxynitrile (162)

[0516] Referring to the synthetic route and method of Example 39, 81B was replaced with 162A and 1G was replaced with 55A to synthesize compound 162F.

[0517] Then, 55G in Example 17 was replaced by compound 162F, and compound 162 was synthesized by the synthesis steps and methods in steps 5 and 6 of Example 17.

[0518] MS (ESI+)m / z= 544.3 [M+H].

[0519] 1H NMR (400 MHz, DMSO-d6)δ9.01 (s, 1H), 7.74 - 7.72 (m, 2H), 7.44 - 7.43 (m, 1H), 6.89 - 6.76 (m, 1H), 6.18 - 6.13 (m, 1H), 5.76 - 5.68 (m, 2H), 4.77 - 4.72 (m, 1H), 4.60 - 4.41 (m, 3H), 4.16 - 4.12 (m, 1H), 3.91 - 3.87 (m, 1H), 3.79 (s, 3H), 3.74 - 3.70 (m, 2H), 3.62 - 3.55 (m, 2H), 2.77 - 2.58 (m, 2H), 2.32 - 2.26 (m, 3H), 2.21 - 2.15 (m, 2H), 2.05 - 1.91 (m, 5H), 1.16 - 1.09 (m, 3H), 1.04 - 0.96 (m, 3H).

[0520] Example 47

[0521] (R)-4-propenylated-1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-5-methylpiperazin-2-one (163)

[0522] Step 1 (R)-4-(5-bromo-2-chloropyrimidin-4-yl)-2-methyl-5-carbonylpiperazine-1-carboxylic acid tert-butyl ester (163B)

[0523] Compound 163A (84 mg, 0.4 mmol) was dissolved in 3 mL of dioxane, and sodium hydride (32 mg, 60%, 0.8 mmol) was added with stirring at 0°C. The resulting mixture was stirred at 0°C for 30 minutes, and then 2,4-dichloro-5-bromopyrimidine 81A (123 mg, 0.5 mmol) was added. Stirring was continued at 0°C for 1 hour. The reaction mixture was quenched with 1 mL of saturated ammonium chloride solution, followed by the addition of 20 mL of saturated sodium chloride solution, and extracted three times with 20 mL of ethyl acetate. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 2) to obtain compound 163B (89 mg, yield: 55%).

[0524] MS (ESI+)m / z= 405.0, 407.0 [M+H].

[0525] Compound 163 was synthesized by replacing 81C with compound 163B and using experimental methods and steps similar to those in steps two to five of Example 39.

[0526] MS (ESI+)m / z= 544.2 [M+H].

[0527] 1H NMR (400 MHz, DMSO-d6) δ9.83 (s, 1H), 8.54 – 8.45 (m, 2H), 7.87 (s, 1H), 7.54 (s, 1H), 7.35 (d,J =11.6 Hz, 1H), 7.28 (s, 1H), 7.19 (d,J =5.0 Hz, 2H), 6.72 (d,J =64.7 Hz, 1H), 5.65 (s, 1H), 4.73 (d,J =57.0 Hz, 1H), 4.20 (d,J =84.4 Hz, 3H), 3.86 – 3.78 (m, 3H), 3.70 (t,J =20.6 Hz, 1H), 2.42 (s, 3H), 1.22 (s, 4H).

[0528] Example 48

[0529] 1-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (164)

[0530] Step 1: 4-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (164B)

[0531] Compound 60B (0.35 g, 1.0 mmol), compound 164A (0.40 g, 1.3 mmol), potassium carbonate (0.34 g, 2.4 mmol), and (diphenylphosphine ferrocene)palladium dichloride (70 mg, 0.10 mmol) were added to a mixed solvent of dioxane (5 mL) and water (0.5 mL). After purging with nitrogen three times, the mixture was stirred at 100 °C for 2 hours. The reaction solution was quenched with 10 mL of ammonium chloride and then extracted with 20 mL of ethyl acetate. The resulting organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1-1 / 1) to obtain compound 164B (270 mg, yield: 54%).

[0532] MS (ESI+)m / z=498.2[M+H].

[0533] Compound 164 can be synthesized by replacing 81D with compound 164B and using experimental methods and steps similar to those in steps three to five of Example 39.

[0534] MS (ESI+)m / z= 513.2 [M+H].

[0535] 1H NMR (400 MHz, DMSO-d6) δ9.65 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.39 (t,J =8.3 Hz, 2H), 7.30 – 7.14 (m, 2H), 6.86 (dd,J =16.6, 10.4 Hz, 1H), 6.12 (dd,J =16.6, 2.4 Hz, 1H), 5.86 (s, 1H), 5.68 (d,J =10.4 Hz, 1H), 4.16 – 3.97 (m, 2H), 3.82 (s, 3H), 3.66 (s, 2H), 2.48 – 2.29 (m, 5H).

[0536] Example 49

[0537] Using a similar method and steps as in the synthesis of compound 164, replacing 164A in the first step with raw material L in the table below, compounds 165-166 corresponding to those in the table below were synthesized. serial number Raw material L Compound Structure m / z [M+H] 1 HNMR 165 499.2 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.50 (dd, J = 5.0, 2.0 Hz, 1H), 8.36 (s, 1H), 7.94 – 7.78 (m, 1H), 7.61 – 7.49 (m, 1H), 7.50 – 7.39 (m, 2H), 7.30 – 7.24 (m, 1H), 7.21 (d, J = 5.0 Hz, 1H), 6.65 – 6.47 (m, 1H), 6.26 – 6.12 (m, 1H), 5.84 – 5.64 (m, 2H), 4.79 (s, 1H), 4.59 – 4.41 (m, 2H), 4.25 (s, 1H), 3.83 (s, 3H), 2.43 (s, 3H). 166 534.2 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (d, J = 12.9 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.43 (s, 1H), 8.06 – 7.85 (m, 1H), 7.51 (s, 1H), 7.44 – 7.32 (m, 2H), 7.24 (dd, J = 8.3, 2.0 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 6.93 – 6.74 (m, 1H), 6.21 – 6.06 (m, 1H), 5.85 – 5.65 (m, 2H), 4.65 – 4.33 (m, 2H), 3.83 (d, J = 5.5 Hz, 3H), 3.73 – 3.53 (m, 2H), 2.42 (s, 3H), 2.15 – 1.98 (m, 2H).

[0538] Example 50

[0539] N-(3-(2-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)propenylated amide (167)

[0540] Step 1: 3-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)aniline (167B)

[0541] Compound 60B (3.0 g, 8.5 mmol), compound 167A (1.9 g, 8.5 mmol), and (diphenylphosphine ferrocene)palladium dichloride (0.38 g, 0.51 mmol), potassium carbonate (2.4 g, 17 mmol) were dissolved in dioxane (35 mL) and water (3.5 mL). The resulting mixture was reacted at 100 °C under nitrogen atmosphere for 2 hours, and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-2 / 1) to give compound 167B (0.40 g, 0.98 mmol, yield: 11%).

[0542] MS (ESI+)m / z= 407.9[M+H].

[0543] Step 2: 4-(3-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-2-amine (167C)

[0544] Compound 167B (0.4 g, 0.98 mmol) was placed in a pressure-resistant reaction tube, and a methanol solution of ammonia (7 mol / L, 6 mL) was added. The resulting solution was reacted under sealed stirring at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1-1 / 2) to give compound 167C (0.11 g, 0.28 mmol, yield: 29%).

[0545] MS (ESI+)m / z= 389.2[M+ H].

[0546] Step 3: N-(3-(2-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)propenylated amide (167)

[0547] Compound 167C (0.10 g, 0.26 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (78 mg, 0.77 mmol) was added. Acrylamide chloride (19 mg, 0.21 mmol) was added at 0 °C. The reaction was stirred at 0 °C for 1 hour. The reaction solution was concentrated, and the crude product was purified by preparative high performance liquid chromatography (mobile phase: 25%-55% aqueous acetonitrile solution (containing 0.1% formic acid)) to give solid compound 167 (17 mg, yield: 15%).

[0548] MS (ESI+)m / z= 443.0[M+H].

[0549] 1H NMR (400 MHz, DMSO-d6) δ10.20 (s, 1H), 8.45 (d,J= 5.2 Hz, 1H), 8.36 (s, 1H), 7.83 (s, 1H), 7.72 - 7.66 (m, 1H), 7.23 (dt,J= 8.2, 6.4 Hz, 2H), 7.19 - 7.11 (m, 2H), 6.98 - 6.85 (m, 4H), 6.47 - 6.38 (m, 1H), 6.29 - 6.20 (m, 1H), 5.78 - 5.72 (m, 1H), 2.40 (s, 3H).

[0550] Example 51

[0551] N-(3-(2-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2-methylphenyl)propenylated amide (168)

[0552] Using a similar synthesis method and steps as in Example 50, compound 168 was synthesized by replacing compound 167A with compound 168A.

[0553] MS (ESI+)m / z= 457.0[M+H].

[0554] 1H NMR (400 MHz, DMSO-d6) δ9.49 (s, 1H), 8.46 (d,J= 5.2 Hz, 1H), 8.33 (s, 1H), 7.72 (s, 1H), 7.26 (t,J= 8.4 Hz, 1H), 7.21 - 7.09 (m, 3H), 6.96 (d,J= 8.2 Hz, 1H), 6.92 (d,J= 8.0 Hz, 1H), 6.87 (s, 2H), 6.52 (dd,J= 17.6, 10.4 Hz, 1H), 6.23 (dd,J= 16.8,1.6 Hz, 1H), 5.74 (d,J= 9.6 Hz, 1H), 2.41 (s, 3H), 2.20 (s, 3H).

[0555] Example 52

[0556] N-(3-(2-hydroxy-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)propenylated amide (169)

[0557] Compound 169 was synthesized by using a synthesis method and steps similar to those in steps two and three of Example 50, except that the 7 mol / L methanol solution of ammonia was replaced with a 1.0 mol / L sodium hydroxide solution of dioxane / water (1 / 1, v / v).

[0558] MS (ESI+)m / z= 444.1[M+H].

[0559] Example 53

[0560] Using a method and steps similar to the first to fourth steps in Example 39, replace compound 81B in the first step with raw material I in the table below, and then use a method and steps similar to those in Example 41 in the fifth step, replace compound 63A with raw material M in the table below, to synthesize the corresponding compounds 170-174 in the table. serial number Raw material I Raw material M Compound Structure m / z [M+H] 1 HNMR 170 585.3 1 H NMR (400 MHz, DMSO-d6)δ9.19 (s, 1H), 8.48 (d,J =5.0 Hz, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 7.48 (s, 1H), 7.38 (t,J =8.4 Hz, 1H), 7.31 (dd,J =11.5, 2.1 Hz, 1H), 7.23 – 7.12 (m, 2H), 6.53 (dt,J =15.5, 6.1 Hz, 1H), 6.05 – 5.97 (m, 1H), 4.30 (s, 2H), 3.99 (d,J =16.2 Hz, 6H), 3.80 (s, 3H), 2.98 (dd,J =6.1, 1.6 Hz, 2H), 2.42 (s, 3H), 2.11 (s, 6H). 171 560.2 1 H NMR (400 MHz, DMSO-d6)δ9.19 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.38 (t,J =8.4 Hz, 1H), 7.32 (dd,J =11.4, 2.1 Hz, 1H), 7.18 (dd,J =12.4, 6.6 Hz, 2H), 6.75 – 6.62 (m, 1H), 6.11 (dd,J =15.5, 2.2 Hz, 1H), 5.16 (s, 1H), 5.04 (d,J =3.5 Hz, 1H), 4.33 (s, 2H), 4.04 (s, 2H), 3.97 (s, 4H), 3.80 (s, 3H), 2.42 (s, 3H). 172 573.3 1H NMR (400 MHz, DMSO-d6)δ9.30 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 7.49 (d,J =11.8 Hz, 2H), 7.45 - 7.30 (m, 2H), 7.21 (d,J =5.0 Hz, 1H), 6.65 - 6.56 (m, 2H), 3.82 (s, 3H), 3.51 - 3.64 (m, 4H), 3.30 - 3.21 (m, 4H), 3.01 (d,J =3.2 Hz, 2H), 2.43 (s, 3H), 2.13 (s, 6H). 173 587.3 1 H NMR (400 MHz, DMSO-d6)δ9.30 (s, 1H), 8.49 (d,J =5.0 Hz, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.50 (s, 1H), 7.48 – 7.38 (m, 2H), 7.36 – 7.26 (m, 1H), 7.21 (d,J =5.0 Hz, 1H), 6.67 – 6.48 (m, 2H), 4.62 – 4.35 (m, 1H), 4.19 – 3.87 (m, 1H), 3.82 (s, 3H), 3.70 – 3.52 (m, 2H), 3.13 – 2.98 (m, 3H), 2.85 – 2.72 (m, 1H), 2.43 (s, 3H), 2.15 (s, 6H), 1.09 (d,J =6.7 Hz, 3H). 174 542.2 1H NMR (400 MHz, DMSO-d6)δ9.32 (s, 1H), 8.50 (d,J =5.0 Hz, 1H), 8.03 (d,J =3.1 Hz, 1H), 7.81 (s, 1H), 7.50 (s, 1H), 7.47 – 7.36 (m, 2H), 7.31 (s, 1H), 7.20 (d,J =5.1 Hz, 1H), 4.56 – 4.43 (m, 1H), 4.06 (t,J =15.6 Hz, 1H), 3.82 (s, 3H), 3.67 – 3.54 (m, 2H), 3.09 – 2.89 (m, 2H), 2.83 – 2.68 (m, 1H), 2.42 (s, 3H), 2.00 (s, 3H), 1.10 (dd,J =30.4, 6.7 Hz, 3H).

[0561] Example 54

[0562] 2-Fluoro-N-(5-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)propenylamide (181)

[0563] Step 1: 5-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)pyridine-3-amine (181B)

[0564] Compound 60B (1.5 g, 4.3 mmol), compound 181A (0.94 g, 4.3 mmol), potassium carbonate (2.2 g, 17 mmol), and (diphenylphosphine ferrocene)palladium dichloride (0.62 g, 0.85 mmol) were mixed in 1,4-dioxane (20 mL) and water (2 mL). The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to preparative high performance liquid chromatography (Waters Xbridge C18, 20-60% acetonitrile aqueous solution (containing 0.01% ammonia)) to obtain compound 181B (0.67 g, yield: 38%).

[0565] MS (ESI+)m / z= 409.1[M+H]

[0566] Step 2: 4-(5-aminopyridin-3-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (181C)

[0567] Compound 118B (0.52 g, 1.3 mmol), compound 60E (0.24 g, 2.5 mmol), and p-toluenesulfonic acid (0.22 g, 1.3 mmol) were dissolved in N-methylpyrrolidone (4 mL). The resulting mixture was stirred in a microwave at 140°C for 1 hour. After cooling to room temperature, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to preparative high-performance liquid chromatography (Waters Xbridge C18, 20-60% acetonitrile aqueous solution (containing 0.01% ammonia)) to obtain compound 181C (67 mg, yield 11%).

[0568] MS (ESI+)m / z= 470.3[M+1].

[0569] Step 3: 2-Fluoro-N-(5-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)propenylamide (181)

[0570] Compound 181C (10 mg, 0.021 mmol) was dissolved in dichloromethane (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (16 mg, 0.042 mmol), compound 63A (1.9 mg, 0.021 mmol), and N,N-diisopropylethylamine (8.1 mg, 0.063 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed by vacuum distillation, and the crude product was purified by preparative high-performance liquid chromatography (Waters Xbridge C18, 20-60% acetonitrile aqueous solution (containing 0.01% ammonia)) to give compound 181 (2.4 mg, yield: 21%).

[0571] MS (ESI+)m / z= 542.2[M+H].

[0572] 1H NMR (400 MHz, DMSO-d6) δ10.70 (s, 1H), 9.86 (s, 1H), 8.82 (s, 1H), 8.80 - 8.61 (m, 1H), 8.58 (s, 1H), 8.46 (d,J= 5.2 Hz, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.54 (s, 1H), 7.38 - 7.26 (m, 2H), 7.19 (d,J= 5.2 Hz, 1H), 7.06 (d,J= 6.4 Hz, 1H), 5.85 - 5.68 (m, 1H), 5.51 (dd,J= 15.2, 3.6 Hz, 1H), 3.84 (s, 3H), 2.42 (s, 3H).

[0573] Biological Evaluation

[0574] The following description and explanation of this application are combined with test examples, but these embodiments are not intended to limit the scope of this application.

[0575] Test Example 1: FGFR enzyme inhibition experiment of the compound of the present invention

[0576] The control positive compound BGJ398 used in the experiment was purchased from Selleck, catalog number S2183. The test compound sample was dissolved in DMSO to prepare a 10 mM stock solution and stored at -30°C.

[0577] Enzyme reactions were performed using enzyme reaction kits manufactured by Promega (FGFR1 Kit, catalog number V2991; FGFR2 kit, catalog number V4060; FGFR3 kit, catalog number VA7459; substrate: Poly E4Y1), according to the manufacturer's recommended methods. The reaction products were detected using an ADP assay kit manufactured by Promega (ADP-Glo™ Kinase Assay, catalog number V9101).

[0578] The 5 μL reaction system contains 0.4 ng / μL FGFR1 kinase (or 1.4 ng / μL FGFR2 (WT (wild-type) or V564F mutant) kinase, or 1 ng / μL FGFR3 kinase), 0.2 ng / μL Poly E4Y1, 5 μM ATP, and serially diluted test compounds. The final concentration of DMSO in the reaction system is 1%. The reaction is performed in 384-well plates (Perkinelmer, Cat. 6007290), and all assays are performed in duplicate. In the above system, ATP is added last to start the reaction. The 384-well reaction plate is incubated at 25°C for 60 minutes, then 5 μL ADP-Glo ​​is added, and the reaction is carried out at 25°C for 40 minutes. Then 10 μL of detection buffer is added, and the reaction is carried out at 25°C for 30 minutes. After the reaction, the Luminescence value is measured using Perkinelmer Envision. Luminescence value represents the amount of ADP produced. The inhibition rate of kinase activity is calculated using high signal (Luminescence value with enzyme but no inhibitor), low signal (Luminescence value without enzyme), and sample signal (Luminescence value with enzyme and inhibitor). The half-maximal inhibitory concentration (IC50) is calculated using XLfit2.0 software (ID Business Solutions Ltd).

[0579] Inhibition rate % = (high signal -sample signal) / (high signal -low signal)×100%.

[0580] The in vitro activity of the compounds in the embodiments of the present invention against wild-type FGFR2 enzyme was determined by the above experiments, and the measured IC50 values ​​are shown in Table 1. Table 1 Compound numbering IC 50 (nM) Compound numbering IC 50 (nM) Compound numbering IC 50 (nM) 1 62.6 79 63.9 134 32.3 8 69.3 80 5.1 135 8.3 12 85.5 81 9.5 136 59.6 18 92.6 82 124.0 137 130.6 20 124.7 83 164.1 138 27.4 45 175.4 84 8.1 139 80.1 47 94.8 89 80.2 140 44.4 50 179.5 90 40.4 141 154.8 57 194.8 93 88.7 142 63.3 60 27.5 96 135.9 143 47.3 64 9.9 97 137.2 145 17.7 65 13.2 98 26.1 146 12.6 66 30.2 99 152.0 147 8.6 67 16.6 105 123.5 148 42.7 68 18.0 109 8.7 149 48.9 69 23.2 114 69.8 150 179.7 70 175.2 115 104.1 156 72.9 71 37.8 118 140.4 159 52.5 72 25.8 119 94.6 164 8.7 74 43.1 120 127.1 167 178.3 75 189.6 130 17.2 170 120.7 76 11.5 132 34.4 174 56.6 77 11.5 133 151.8 181 149.0

[0581] The in vitro activity of the compounds in the embodiments of the present invention against the V564F mutant FGFR2 enzyme was determined by the above experiments, and the measured IC50 values ​​are shown in Table 2. Table 2 Compound numbering IC 50 (nM) Compound numbering IC 50 (nM) Compound numbering IC 50 (nM) 1 104.2 8 105.2 43 200.4 50 125.9 60 11.6 65 13.4 67 15.6 69 twenty two 71 55.7 72 12.5 76 14.6 77 14.8 78 twenty two 79 105.2 80 11.9 81 19.8 84 43.8 89 151.6 90 19.6 93 61.3 96 131.6 98 23 99 35.2 105 21.1 109 11.1 114 41.4 115 43.6 118 142.1 119 62.2 130 15.8 132 25 133 82.4 134 22.8 135 9.1 136 35.9 138 16.6 139 75.4 140 37.4 141 161.5 142 146.2 143 101 144 136.4 145 11.9 146 16.7 147 16.3 148 24 149 28.1 154 29.4 156 47.5 159 34 162 181.2 163 201.2 163 56.1 164 16.6 170 125 174 20.4 BGJ398 >1000

[0582] Test Example 2: Cell proliferation experiment of the compound of the present invention

[0583] The test compound sample was dissolved in DMSO to prepare a 10 mM stock solution and stored at -30°C. For assay, the compound was diluted 10 times to the assay concentration in serum-free medium containing 5% DMSO.

[0584] In the experiment, SNU-16 cells were purchased from ATCC (American Type Culture Collection, USA, catalog number ATCC® CRL-5974), RT-112 cells were purchased from Cobioer (Nanjing Kebai Biotechnology Co., Ltd., catalog number CBP60316), KG-1 cells were purchased from ATCC (catalog number CCL-246), and JMSU-1 cells were purchased from DSMZ (catalog number ACC505). IMDM culture medium was purchased from Gibco (catalog number 12440-061), 1640 culture medium was purchased from Gibco (catalog number 12634-010), and serum was purchased from Gibco (catalog number 10099-141C). Cell-counting kit-8 (CK04) was purchased from Tongren Chemical Co., Ltd. CellTiter-Glo® Luminescent Cell Viability Assay was purchased from Promega (catalog number G7570).

[0585] Logarithmic growth phase cells were seeded in 96-well cell culture plates at a volume of 100 µL. The cells were incubated overnight at 37°C with 5% CO2. The next day, 10 µL / well of serially diluted test compound was added. For the control group, 10 µL / well of serum-free medium containing 5% DMSO was added instead of the drug dilution. The final concentration of DMSO was 0.5%. The cells were incubated for 72 hours. 10 µL / well of Cell-counting kit-8 reagent (or 50 µL / well of CTG) was added. The cells were incubated at 37°C for 40 minutes in a CO2 incubator, and the absorbance at 450 nm was read on a Perkinelmer Envision (for CTG, Luminescence was read). The inhibitory rate of the compound on cell growth was calculated using the following formula, with the half-maximal inhibitory concentration (GI50) calculated using XLFit 2.0 software.

[0586] Inhibition rate (%) = [1 - ([OD450]compound - [OD450]background) / ([OD450]cell - [OD450]background)] × 100%

[0587] Among them:

[0588] [OD450] The compound represents the optical density value of the pore treated with the compound;

[0589] [OD450] Cells represent the optical density values ​​of cell pores on day 3 when DMSO is used instead of the compound;

[0590] [OD450] The background represents the optical density value of the cell pore on day 0 when DMSO was used instead of the compound;

[0591] The compounds of the present invention were tested in cell proliferation experiments using the methods described above, and the measured GI50 values ​​are shown in Table 3. Table 3 Compound numbering SNU-16 GI 50 (nM) JMSU-1 GI 50 (nM) Compound numbering SNU-16 GI 50 (nM) JMSU-1 GI 50 (nM) 1 4.4 196.5 4 107.7 - 8 2.5 106 10 17.9 - 18 4.8 50.8 19 12.7 75.5 20 13.3 71 21 19.2 875.1 22 11.2 63.2 23 13.3 188.8 34 25.9 1649.2 43 6.1 164.2 49 15 308.4 50 24.2 1517.9 54 38.3 - 55 39.2 884.2 60 4.7 81.4 64 11 - 65 2.1 - 66 14.1 57.9 67 22 62.9 68 9.7 58.6 69 5.1 48.1 70 16.1 774.0 71 10 237.6 72 3.3 - 73 27.3 197.4 75 37.6 487.6 76 2.6 - 77 7.4 - 78 3.5 67.5 79 13.3 328.2 80 3.8 - 81 2.9 21.9 82 12.7 119.7 83 29.5 182.2 84 4.4 88.9 87 39 - 88 30.4 348.6 89 9.8 207 90 3.4 39.1 93 5.9 88.5 96 41 228.8 97 14.9 - 98 2.6 24.3 99 5.4 138.1 105 4.8 53 109 2.1 32.3 114 5.1 92.2 115 6 24 117 16.6 182 118 8 44.3 119 6.7 117.8 130 4.3 43.5 132 4.4 91.3 134 4.5 83.1 135 6.2 348.2 136 7 81.9 137 11.4 - 138 28 478.2 139 9.4 40.3 141 7.5 171.3 142 4 45.6 143 8.1 126 144 12.7 91 145 1.1 - 146 2.1 - 147 2.2 - 148 6.6 - 149 4.1 - 150 5.6 191.8 151 13.3 367.6 154 9 - 156 13.3 185 159 12.4 - 162 36.7 769.1 164 1.6 - 167 26.1 487.2 174 5.8 48.2 181 29.4 - "-" indicates that it has not been tested.

[0592] Test Example 3: Blood Stability Test of the Compounds of the Invention

[0593] The stability of the compound of the invention in whole blood was evaluated by determining the percentage of the test compound remaining in the blood (containing EDTA-K2 anticoagulant) of SD rats or humans at different time points by liquid chromatography-tandem mass spectrometry (LC / MS / MS).

[0594] Add 398 μL of blood to the wells of a culture plate and pretreat at 37°C for 15 minutes. Add 2 μL of the test compound (1 mmol / L DMSO solution) or positive compound (1 mmol / L DMSO solution) to the pretreated 398 μL of blood and mix to achieve a final concentration of 5 µM for the test compound (or positive compound) and a final concentration of 0.5% for the organic solvent. Each test compound or positive compound is tested twice. The resulting mixture is incubated at 37°C. At 0, 15, 30, 60, 120, and 240 minutes of the reaction, 50 μL of sample is taken each time, and 50 µL of ultrapure water and 400 µL of cold acetonitrile containing the internal standard compound (0.5 μM tolbutamide) are added to terminate the reaction. All samples are vortexed for 10 minutes and centrifuged at 3220 g for 30 minutes to precipitate the protein. 200 μL of the supernatant is taken for LC-MS / MS analysis.

[0595] All calculations were performed using Microsoft Excel. Peak area ratios were determined from the extracted ion chromatograms. The percentage of remaining compounds at each time point was calculated using the following formula:

[0596] Remaining percentage tmin (%) = Peak area ratio tmin / Peak area ratio 0min x 100%

[0597] wherein the peak area ratio tmin is the peak area ratio of the tested compound (or positive compound) and the internal standard compound at time point t minutes;

[0598] Peak area ratio 0 min is the peak area ratio of the tested compound (or positive compound) and the internal standard compound at the 0-minute time point.

[0599] The slope value k was determined by linear regression of the natural logarithm of the curve of the remaining percentage of the tested compound versus the incubation time.

[0600] The in vitro half-life (in vitro t1 / 2) is determined by the slope value k:

[0601] The half-lives of the compounds of the present invention in SD rat or human blood are shown in Table 4. Table 4. Stability of the compounds of the present invention in SD rat and human blood. compound Whole blood half-life of SD rats Human whole blood half-life compound Whole blood half-life of SD rats Human whole blood half-life serial number t1 / 2 (min) t 1 / 2 (min) serial number t 1 / 2 (min) t 1 / 2 (min) 1 95 - 8 161 - 13 466 - 18 122 - twenty two 111 - 34 115 - 59 83 - 76 354 - 78 >600 - 80 192 - 81 160 - 83 >600 >600 84 110 - 89 305 416 90 141 - 93 329 - 105 300 >600 109 291 336 114 379 - 115 >600 >600 118 152 - 119 217 335 135 413 - 142 351 - 144 437 - 147 224 172 154 >600 - 163 30 - 164 307 - "-" indicates that it has not been tested.

[0602] Test Example 4: CYP enzyme inhibition test of the compound of the present invention

[0603] Representative substrate metabolism of the five major human CYP subtypes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was evaluated using a mixture of 150 donor human liver microsomes (purchased from Corning, catalog number 452117). The effects of different concentrations of the analytes on the metabolism of phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-metphenytoin (CYP2C19), butifrolol hydrochloride (CYP2D6), and midazolam (CYP3A4) were determined by liquid chromatography-tandem mass spectrometry (LC / MS / MS).

[0604] Incubate 200 μL of a reaction system (100 mmol / L phosphate buffer, pH 7.4, containing 0.3% DMSO, 0.6% acetonitrile, and 0.1% methanol by volume) with 30 μM phenacetin, 10 μM diclofenac sodium, 35 μM S-mphenanthridine, 5 μM buturolol hydrochloride, 3 μM midazolam, 1 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH), the test compound (concentrations of 0.1, 0.3, 1, 3, 10, and 30 μmol / L, respectively), or the positive compound or blank control, and mixed human liver microsomes (0.2 mg / mL) at 37 °C for 5 min. Then add 200 μL of acetonitrile solution containing 3% formic acid and 40 nM internal standard verapamil, and centrifuge at 4000 rpm for 50 min. The sample was cooled on ice for 20 minutes, then centrifuged at 4000 rpm for 20 minutes to precipitate the protein. 200 μL of the supernatant was analyzed by LC-MS / MS.

[0605] Peak area is calculated based on the chromatogram. Residual activity percentage (%) is calculated using the following formula:

[0606] Peak area ratio = Metabolite peak area / Internal standard peak area

[0607] Residual activity ratio (%) = Peak area ratio of the test compound group / Peak area ratio of the blank group

[0608] The CYP half-maximal inhibitory concentration (IC50) was calculated using Excel XLfit 5.3.1.3.

[0609] The CYP half-maximal inhibitory concentrations (IC50) of the compounds of the present invention are shown in Table 5. Table 5. Half-maximal inhibitory concentrations (IC50) of the compounds of the present invention against CYP compound serial number CYP 1A2 IC 50 (μM) CYP 2C9 IC 50 (μM) CYP 2C19 IC 50 (μM) CYP 2D6 IC 50 (μM) CYP 3A4 IC 50 (μM) 83 >30 10.69 >30 12.97 2.38 89 >30 16.15 >30 26.60 13.08 115 >30 3.33 18.75 4.34 0.69 119 >30 11.89 28.67 >30 >30

[0610] Test Example 5, Caco-2 Permeability Test

[0611] The apparent permeability coefficient (Papp) of the drug was determined and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS) in a Caco-2 cell model.

[0612] In this test case, Caco-2 cells were purchased from the American Type Culture Collection (ATCC), HEPES were purchased from Beijing Solarbio Science & Technology Co., Ltd., Hank Balanced Salt Solution (HBSS) and Non-essential Amino Acids (NEAA) were purchased from Thermo Fisher Scientific, penicillin, streptomycin and trypsin / EDTA were purchased from Solarbio, fetal bovine serum (FBS) and DMEM medium were purchased from Corning, HTS-96-well Transwell plates and other sterile consumables were purchased from Corning, Millicell resistance measurement system was purchased from Millipore, Cellometer® K2 was purchased from Nexcelom Bioscience, Infinite 200 PRO microplate reader was purchased from Tecan, and MTS2 / 4 orbital shaker was purchased from IKA Labortechnik.

[0613] Step 1: Cell Culture and Seeding

[0614] Culture Caco-2 cells in cell culture flasks. Set the incubator to 37°C, 5% CO2, and maintain a relative humidity of 95%. Cells can be seeded into Transwell culture plates when confluence reaches 70-90%. Before seeding, add 50 μL of cell culture medium to each well in the upper chamber of the Transwell and 25 mL of cell culture medium to the lower chamber. Incubate the culture plate at 37°C, 5% CO2 for 1 hour before seeding. After cell digestion, transfer the cell suspension to a round-bottom centrifuge tube and centrifuge at 120 g for 5 minutes. Resuspend the cells in culture medium to a final concentration of 6.86 × 10⁵ cells / mL. Add 50 μL of the cell suspension to each well in the lower chamber of a 96-well Transwell culture plate, resulting in a final seeding density of 2.4 × 10⁵ cells / cm². Change the medium 24 hours after seeding and culture for 14-18 days, changing the medium every other day. The process of changing the culture medium is as follows: separate the Transwell chamber from the receiving plate, discard the culture medium in the receiving plate first, then discard the culture medium in the Transwell chamber, and finally add 75 μL of fresh culture medium to each chamber and 25 mL of fresh culture medium to the receiving plate.

[0615] Step 2: Evaluation of Cell Monolayer Integrity

[0616] After approximately 14 days of culture, Caco-2 cells reach convergence and complete differentiation. At this point, they can be used for breakthrough experiments. The monolayer membrane resistance is measured using a resistance meter (Millipore, USA), and the resistance of each well is recorded. After the measurement, the Transwell plate is returned to the incubator. The resistance value is calculated as follows: Measured resistance value (ohms) × Membrane area (cm²) = TEER value (ohms∙cm²). If the TEER value < 230 ohms∙cm², the well cannot be used for breakthrough experiments.

[0617] Step 3: Solution Preparation

[0618] Weigh 2.38 g HEPES and 0.35 g sodium bicarbonate respectively, add 900 mL of pure water to dissolve them, then add 100 mL of 10×HBSS and stir well. Adjust the pH to 7.4, and finally filter to obtain 1 L of transfer buffer (HBSS, 10 mM HEPES, pH 7.4).

[0619] A 1 mM stock solution of the test compound in DMSO was diluted with transfer buffer to obtain a 5 μM test solution. The control compound digoxin or minoxidil was diluted to 2 mM with DMSO and then to 10 μM with the same transfer buffer to obtain a control compound test solution. Additionally, DMSO was also diluted with the same transfer buffer to a receiving end solution containing 0.5% DMSO.

[0620] Step 4 Drug Penetration Test

[0621] Remove the Transwell culture plate from the incubator. Rinse the cell monolayer twice with transport buffer (10 mM HEPES, pH 7.4) and incubate at 37°C for 30 minutes.

[0622] Determine the transport rate of the compound from the top to the base. Add 125 μL of test solution to each well in the upper chamber (top), and immediately transfer 50 μL of the solution from the top to 200 μL of acetonitrile (0.1 μM tolbutamide) containing the internal standard as the initial sample from the top to the base. Add 235 μL of receiving end solution to each well in the lower chamber (base).

[0623] Determine the transport rate of the compound from the base to the top. Add 285 μL of the receiving end solution to each well in the upper chamber (top), and immediately transfer 50 μL of the solution from the top to 200 μL of acetonitrile (0.1 μM tolbutamide) containing the internal standard as the initial sample from the base to the top. Add 75 μL of the test solution to each well in the lower chamber (base).

[0624] After merging the upper and lower transfer devices, incubate at 37 °C for 2 hours.

[0625] After incubation, 50 μL of sample was taken from each well of the upper and lower chambers of the Transwell culture plate and added to a new sample tube. 200 μL of acetonitrile (0.1 μM tolbutamide) containing the internal standard was added to the sample tube, vortexed for 10 minutes, and then centrifuged at 3220 g for 40 minutes. 150 μL of the supernatant was collected, diluted with 150 μL of water, and analyzed by LC-MS / MS. All samples were prepared in triplicate.

[0626] The integrity of the cell monolayer was evaluated by the leakage of Fluorescein after 2 hours of incubation. The Fluorescein stock solution was diluted to a final concentration of 100 μM using transport buffer (10 mM HEPES, pH 7.4). 100 μL of Fluorescein solution was added to each well of the upper Transwell plate, and 300 μL of transport buffer (10 mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 μL of solution was aspirated from both the upper and lower layers of each well into a new 96-well plate. Fluorescence was measured using a microplate reader at an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

[0627] Step 5: Data Analysis. All calculations were performed using Microsoft Excel. Peak areas were determined using the extracted ion chromatograms.

[0628] The apparent permeability coefficient (Papp, unit: cm / s*10-6) is calculated using the following formula:

[0629] In the formula: VA is the volume of the receiving solution (Ap→Bl is 0.3 mL, Bl→Ap is 0.1 mL), Area (membrane area) is the membrane area of ​​the Transwell-96 well plate (0.143 cm2); time (time) is the incubation time (unit: s); [drug]receiver ([drug]receiver) is the drug concentration at the receiving end; [drug]initial,donor ([drug]initial,donor) is the initial drug concentration at the dosing end.

[0630] The efflux ratio is calculated using the following formula:

[0631] In the formula: Papp (BA) is the apparent permeability coefficient from the basal end to the apex;

[0632] Papp (AB) is the apparent permeability coefficient from the top to the base.

[0633] The recovery rate ("Percentage recovery" (%)) is calculated using the following formula: %

[0634] In the formula: VA is the solution volume at the receiving end (unit: mL); VD is the solution volume at the giving end (unit: mL); and [drug]donor is the drug concentration at the administration end.

[0635] The leakage rate (Percentage leakage (%) or LY (%)) is calculated using the following formula: %

[0636] In the formula: Ireceiver (I receiving end) refers to the fluorescence density of the receiving well (0.3 mL), and Idonor (I donor) refers to the fluorescence density of the drug delivery well (0.1 mL). LY < 1.5% indicates an intact monolayer cell membrane. For individual cases where LY > 1.5%, if the Papp value is close to other parallel values, the final data can be adopted based on scientific judgment.

[0637] The Caco2 permeability data of the compounds of the present invention obtained by testing are shown in Table 6 below. Table 6. Caco2 permeability data of the compounds of the present invention Compound numbering Papp (A-B) (10 -6 (cm / s) Papp (B-A) (10 -6 (cm / s) Efflux Ratio 8 0.90 15.4 17.2 34 0.50 27.1 54.7 78 0.71 5.0 7.0 83 1.45 19.5 13.5 84 0.59 32.0 54.4 89 0.53 30.6 58.3 90 0.85 14.6 17.3 93 1.20 20.2 16.9 98 3.10 12.4 4.0 99 3.75 19.9 5.4 105 1.47 23.7 16.1 109 0.89 17.8 20.2 114 1.27 6.5 5.1 115 1.76 21.2 12.1 118 0.55 24.1 44.2 119 1.62 23.9 14.9 120 1.75 18.8 10.8 142 0.39 23.6 60.2 143 0.40 28.7 71.2 144 0.70 13.0 18.8 154 2.08 6.2 3.0 164 1.99 18.0 9.2

[0638] Test Example 6: Pharmacokinetic Test of Compounds of the Invention in Rats

[0639] Using SD rats as test animals, the plasma drug concentrations at different time points after intravenous injection and gavage administration of the compound of the present invention were determined by LC / MS / MS. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

[0640] Three healthy male SD rats aged 6-8 weeks were included in each group.

[0641] Intravenous administration: Weigh a certain amount of the drug, add 10% volume of N,N-dimethylacetamide, 33% volume of triethylene glycol and 57% volume of physiological saline to prepare a colorless, clear and transparent liquid of 1 mg / mL.

[0642] Administer by gavage: Weigh a certain amount of the drug, add 0.5% high-quality hydroxypropyl methylcellulose, 0.1% volume of Tween 80 and 99.6% volume of physiological saline to prepare a white suspension of 1 mg / mL.

[0643] After fasting overnight, SD rats were administered the drug via intravenous injection or gavage.

[0644] The compound of the present invention was administered to rats via intravenous injection. 0.2 mL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration. The blood was placed in a test tube containing EDTA-K2, centrifuged at 4000 rpm for 5 minutes at 4°C to separate the plasma, and stored at -75°C.

[0645] Or administer the compound of the present invention to rats by gavage. 0.2 mL of blood is collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration. The blood is placed in a test tube containing EDTA-K2, centrifuged at 3500 rpm for 10 minutes at 4°C to separate the plasma, and stored at -75°C.

[0646] Determination of the content of the target compound in rat plasma after intravenous injection or gavage administration of different concentrations of the drug: Take 30 μL of rat plasma at each time point after administration, add 200 μL (50 ng / mL) of acetonitrile solution of internal standard dexamethasone, vortex mix for 30 seconds, centrifuge at 4700 rpm for 15 minutes at 4℃, take the supernatant of the plasma sample, dilute it three times with water, and take 2.0 μL for LC-MS / MS analysis.

[0647] The pharmacokinetic parameters of the compounds of the present invention in rats are shown in Table 7 below: Table 7. Pharmacokinetic Results of the Compounds of the Present Invention in SD Rats Compound number and administration method / dosage Pharmacokinetic Experiment Maximum blood drug concentration Area under unit dose curve half life Clearance Apparent volume distribution Bioavailability Cmax AUC last / D T 1 / 2 (h) CL_obs V ss _obs F (ng / mL) (h*mg / mL) (ml / min / kg) (L / kg) (%) 1 IV - 133 0.23 126 1.4 7.8 1 mg / kg PO 92.2 9.6 - - - 10 mg / kg 81 IV - 207 0.83 80.6 2.3 0.95 1 mg / kg PO 3.8 1.8 - - - 5 mg / kg 83 IV - 594 4.3 126 4.4 60.4 1 mg / kg PO 3016 359 - - - 10 mg / kg 84 IV - 251 0.29 66.4 1.2 - 1 mg / kg 89 IV - 706 0.70 23.6 0.8 13.6 1 mg / kg PO 648 94.3 - - - 10 mg / kg 93 IV - 482 0.48 35.0 0.76 - 1 mg / kg 105 IV - 406 0.54 41.1 1.1 17.6 1 mg / kg PO 472 70.8 - - - 10 mg / kg 109 IV - 325 0.52 51.8 1.2 13.6 1 mg / kg PO 242 41 - - - 10 mg / kg 115 IV - 664 1.02 26.0 1.2 60.7 5 mg / kg PO 2388 402 - - - 10 mg / kg 119 IV - 536 1.02 31.3 1.3 49.0 5 mg / kg PO 933 238 - - - 10 mg / kg IV indicates intravenous injection; PO indicates gavage.

Claims

1. A compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein (I) X is selected from CH or N; Z is selected from CR9; W is selected from O or C (=O); Y is selected from N (CH3) or bond; ring A is selected from 5-6-membered heteroaryl or 5-6-membered heterocyclic group; ring B is selected from phenyl or cyclohexenyl; E is selected from C6-C10 aryl, 3-10-membered heterocyclic group or 5-6-membered heteroaryl, wherein the C6-C10 aryl, 3-10-membered heterocyclic group or 5-6-membered heteroaryl group is optionally substituted by one or more R1a groups; R1a is independently selected from halogen, -NR8aR8b, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl is optionally substituted by one or more groups independently selected from halogen, OH, CN or C1-C3 alkoxy groups; R1 is selected from -C≡CR5, -C(=O)C≡CR5, -C(=O)CR6=C(R5)2, -R7C(=O)CH=C(R5)2, -NHC(=O)CR6=C(R5)2, -R7NHC(=O)CH=C(R5)2, -NHC(=O)C≡CR5, -NHS(=O)2CR6=C(R5)2, -NR6C(=O)CR6=C(R5)2, or NHC(=O)R5; R5 is independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cyclic hydrocarbon group, wherein the C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cyclic hydrocarbon group is optionally substituted by one or more R5a; R5a is independently selected from halogen, CN, or N(R5b)2; R5b is CH3; R6 is selected from H, CN, halogen, or C1-C6 alkyl; R7 is selected from -CH2-, or; R2 is selected from H, NH2, C1-C6 alkyl, OH, or halogen; R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; R4 is independently selected from halogen, CN, C1-C6 alkyl, or C1-C6 alkoxy; R8a and R8b are each independently selected from H or C1-C6 alkyl; R9 is selected from H, OH, NH2, -NHR10, or -NH-C1-C6 alkyl, wherein the -NH-C1-C6 alkyl is optionally substituted by one or more R10; R10 is independently selected from NH2, C6-C10 aryl, or 5-6 heteroaryl, wherein the NH2, C6-C10 aryl, or 5-6 heteroaryl is optionally substituted by one or more R11; R11 is independently selected from the following groups that are optionally substituted with methyl, ethyl, OH, -N(CH3)2 or F: methyl, ethyl, tetrahydropyrrolyl, piperidyl, piperazinyl, cyclopropyl or isopropyl; n and m are each independently selected from 0 or 1.

2. The compound represented by formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: X is N.

3. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: ring A is selected from pyrimidinyl, pyridinyl or tetrahydropyrroleyl.

4. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: ring B is selected from phenyl.

5. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: R5 is independently selected from H, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3-C6 cycloalkyl is optionally substituted by one or more R5a.

6. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from the following groups: , ...

7. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: R6 is selected from H, halogens or C1-C6 alkyl groups.

8. The compound represented by formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from H, NH2, CH3, OH or halogen.

9. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from H, NH2 or halogen.

10. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: R3 is independently selected from halogens or C1-C6 alkoxy groups.

11. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: R4 is independently selected from CN or C1-C6 alkyl groups.

12. The compound represented by formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: the compound represented by formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound represented by formula (II), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (II).

13. The compound represented by formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: the compound represented by formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound represented by formula (III), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (III).

14. The compound of formula (I) according to claim 12 or 13, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: the compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (IV), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (IV).

15. The compound represented by formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: the compound represented by formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the compound represented by formula (V), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (V).

16. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: the compound of formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or stereoisomers thereof or pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. Use of a compound of formula (I) as described in any one of claims 1-16, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of diseases associated with FGFR.

19. The use according to claim 18, characterized in that: the disease associated with FGFR is selected from cancer.

20. Use of the pharmaceutical composition as claimed in claim 17 in the preparation of a medicament for the prevention or treatment of diseases associated with FGFR.

21. The use according to claim 20, characterized in that: the disease associated with FGFR is selected from cancer.