A c-kit inhibitor and uses thereof

Abstract

The present application relates to a kind of c-Kit inhibitor and its use.The present application discloses a kind of compound shown in formula (I-b), or its stereoisomer or pharmaceutically acceptable salt and their pharmaceutical compositions, and its use as c-Kit inhibitor in the preparation of drug for treating related diseases, shown in formula (I-b) each group is as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, and particularly relates to a small molecule compound having c-Kit inhibitory activity, its stereoisomer or pharmaceutically acceptable salt, and its use in treating related diseases. Background Technology

[0002] c-Kit is the gene encoding a receptor tyrosine kinase protein, also known as tyrosine protein kinase KIT, CD117 (differentiation cluster 117), or mast / stem cell growth factor receptor (SCFR). The c-Kit gene was cloned and located on human chromosome 4, segment 4q11, and consists of 21 exons. The first exon encodes the translation start codon and signal peptide. The extracellular portion of c-Kit is encoded by exons 2 through 9. The transmembrane region is encoded by exon 10, while the remaining exons encode the intracellular portion of the receptor. c-Kit is a protein composed of 976 amino acids, resulting in a core protein size of approximately 110 kDa. Due to heterogeneous N-linked glycosylation, the mature protein size ranges from 145 to 160 kDa.

[0003] The c-Kit protein consists of three parts: an extracellular region, a transmembrane region, and an intracellular region. The extracellular region comprises five immunoglobulin-like domains, the transmembrane region is a single transmembrane α-helix, and the intracellular region is a receptor catalytic domain, specifically divided into a juxtamembrane domain, a tyrosine kinase 1 domain, a tyrosine kinase insertion domain, and a tyrosine kinase 2 domain. Under normal conditions, c-Kit exists as a monomer when inactivated; once it binds to its ligand, stem cell factor, c-Kit dimers. The dimerized monomers undergo autophosphorylation at Y568, Y570, and / or Y823, thereby activating downstream signaling pathways and inducing cell growth and differentiation.

[0004] c-Kit is primarily expressed on the surface of cells such as hematopoietic stem cells, mast cells, and melanocytes. c-Kit plays a crucial role in normal physiological processes, including the self-renewal of hematopoietic stem cells, the development of melanocytes, the function of mast cells, and the development of the reproductive system. Its normal function is essential for maintaining the body's health. The interaction between c-Kit and its ligand, stem cell factor (SCF), plays a key role in regulating mast cell proliferation, maturation, adhesion, chemotaxis, and survival.

[0005] Functional changes in c-Kit (CD117) under pathological conditions are often associated with a variety of diseases, such as gastrointestinal stromal tumors (GIST), one of the most well-known tumors associated with c-Kit. Approximately 80% of GIST cases have c-Kit gene mutations, which typically lead to persistent receptor activation, resulting in uncontrolled cell proliferation. These mutations may involve exons 9, 11, 13, and 17. Additionally, mast cells are the primary effector cells in certain inflammatory diseases (such as chronic urticaria), driven by abnormal mast cell activation, which is wild-type c-Kit, suggesting that these patients could benefit from wild-type c-Kit-targeted therapy. Summary of the Invention

[0006] The purpose of this invention is to provide a compound, its stereoisomer or pharmaceutically acceptable salt, and its pharmaceutical applications. The compound of this invention has advantages such as good activity, low toxicity, good safety, high selectivity, good pharmacokinetics, and high bioavailability.

[0007] This invention relates to a compound represented by general formula (Ia), formula (I-a'), formula (Ib), formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6), formula (I-7), formula (I-8), (I-9), formula (I-1a), formula (I-2a), formula (I-3a), formula (I-4a), formula (I-5a), formula (I-6a), formula (I-7a), formula (I-1b), formula (I-2b), formula (I-3b), formula (I-4b), formula (I-5b), formula (I-6b), formula (I-7b), and formula (I-8b), its stereoisomers, or pharmaceutically acceptable salts thereof.

[0008]

[0009] L1 is selected from -C(=O)NH-, -C(=S)NH-, -C(=Se)NH-, and -CR. a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The alkylene, alkenylene, or ynylene group is optionally substituted with 1 to 5 groups selected from Rx; in some embodiments, L1 is selected from -C(=O)NH-, -C(=S)NH-, -C(=Se)NH-, -CR a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 1-6 Alkylene, C 2-4 imidene group, C 2-4 The alkylene, alkenylene, or ynylene group is optionally substituted with 1 to 5 groups selected from Rx; in some embodiments, L1 is selected from -C(=O)NH-, -C(=S)NH-, -C(=Se)NH-, -CR a R b NH-; in some embodiments, L1 is selected from -C(=S)NH-; in some embodiments, L1 is selected from -C(=O)NH-; in some embodiments, L1 is selected from -C(=Se)NH-; in some embodiments, L1 is selected from ;

[0010] In some implementations, L 1’ Selected from -C(=S)NH-, -C(=Se)NH-, -CR a R b NH-, -CR a Rb C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 2-4 imidene group, C 2-4 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx;

[0011] Each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy groups; in some embodiments, each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy groups; in some embodiments, each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy groups;

[0012] As an option, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl; in some embodiments, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl; in some embodiments, R a R bTogether with the atoms they are attached to, they form 4-6 membered heterocyclic alkyl groups and 5-10 membered heteroaryl groups; in some embodiments, R a R b The atoms to which R is attached form 4-6 membered heterocyclic alkyl groups; in some embodiments, R a R b The atoms to which R is attached form 4-5 heterocyclic alkyl groups; in some embodiments, R a R b The atoms to which R is attached form a 4-membered heterocyclic alkyl group; in some embodiments, R a R b and the formation of atoms connected to them , , In some implementation schemes, R a R b and the formation of atoms connected to them , ;

[0013] In some implementations, L 1’ Selected from -C(=S)NH-, -C(=Se)NH-, -CR a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 2-4 imidene group, C 2-4 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx;

[0014] R x1 R x2 Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl;

[0015] In some implementation schemes, R x1 R x2 Each is independently selected from hydrogen, deuterium, and C. 1-4 alkyl;

[0016] In some implementation schemes, R x1 R x2 Each is independently selected from hydrogen, deuterium, and C. 1-2 alkyl;

[0017] In some implementation schemes, R x1 Selected from hydrogen, R x2 Selected from methyl;

[0018] In some implementation schemes, R x1 Selected from methyl, R x2 Selected from hydrogen;

[0019] R A R B Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy groups;

[0020] In some implementation schemes, R A R B Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl; in some embodiments, R A Selected from hydrogen, C 1-6 Alkyl; in some embodiments, R B Selected from hydrogen; in some implementations, R A Selected from hydrogen, methyl, and ethyl;

[0021] Cy1 is selected from C 3-10 cycloalkyl, phenyl, C 7-10 aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally substituted with 1-5 R1 groups, wherein the R1 groups are selected from deuterium, oxoyl, -N=S(=O)-(C 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, -SCF3, -SF5, Cl, F, NH2, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-5 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Substitution with a deuterated alkoxy or 4-6 membered heterocyclic alkyl group; in some embodiments, Cy1 is selected from C 6-10 cycloalkyl, phenyl, C 7-10 aryl, 6-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally substituted with 1-4 R1 groups, wherein the R1 groups are selected from deuterium, oxoyl, -N=S(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, -SCF3, -SF5, Cl, F, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-4 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups;

[0022] In some implementations, Cy1 is selected from C 3-10 cycloalkyl, phenyl, C 7-10 The phenyl group is aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally surrounded by 1-4 atoms selected from deuterium, Cl, F, NH2, CN, OH, COOH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-4 groups selected from deuterium, halogen, NH2, CN, OH, COOH, C.1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups;

[0023] In some implementations, Cy1 is selected from C 6-10 cycloalkyl, phenyl, C 7-10 The phenyl group is aryl, 6-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally surrounded by 1-4 atoms selected from deuterium, Cl, F, NH2, CN, OH, COOH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-4 groups selected from deuterium, halogen, NH2, CN, OH, COOH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups;

[0024] In some implementations, Cy1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , The substance can be optionally replaced by 1-4 R1s, wherein the R1s are selected from deuterium, halogens, COOH, and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-4 alkenyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Substitution of deuterated alkoxy or aziridine groups;

[0025] In some implementations, Cy1 is selected from The substance can be optionally replaced by 1-4 R1s, wherein the R1s are selected from deuterium, Cl, F, COOH, and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-4 alkenyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Deuterated alkoxy, nitrogen-containing heterocyclic butyl, -N=S(=O)-(C 1-4 Alkyl)2, -SCF3, -SF5, -S-(C 1-6 Alkyl), C 2-4 alkynyl group, -S(=O)2-C 1-4 Substitution of alkyl, =CH2, =CHF, =CF2 groups;

[0026] In some embodiments, Cy1' is selected from the following groups optionally substituted with 1-4 R1 groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0027] L2 is selected from key, -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group, -C(=O)NH-, -NHC(=O)-; in some embodiments, L2 is selected from the bond, -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group; in some embodiments, L2 is selected from the group consisting of -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Alynyl group; in some embodiments, L2 is selected from the bond, -CONHSO2-; in some embodiments, L2 is selected from the bond; in some embodiments, L2 is selected from -CONHSO2-;

[0028] L 2’ Selected from -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -C(=O)NH-, -NHC(=O)-; in some embodiments, L 2’ Selected from -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-4 Alkylene, C 2-4 imidene group, C 2-4 etymynyl; in some implementations, L 2’ Selected from -C≡C-;

[0029] Cy2 is selected from C 3-6 The cycloalkyl, 5-10-membered heteroaryl, 5-membered heterocycloalkyl, 6-10-membered heterocycloalkyl, or none thereof, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl group is optionally substituted by 1-5 groups selected from R2, wherein R2 is selected from R, deuterium, halogen, oxo group, NH2, CN, OH, C. 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Deuterated alkyl groups, -N=S(=O)-(C 1-6 Alkyl)2, -SCF3, -SF5, -S-(C 1-6 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, -S(=O)2-C 1-6 Alkyl, =CH2, =CHF, =CF2, -C(=O)OC 1-6 Alkyl group substitution;

[0030] In some implementations, Cy2 is selected from C 3-6 The cycloalkyl, 5-6-membered heteroaryl, 5-membered heterocycloalkyl, 6-10-membered heterocycloalkyl or absent, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted by 1-5 R2 groups, wherein the R2 is selected from R, deuterium, halogen, NH2, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl groups, -N=S(=O)-(C 1-4 Alkyl)2, -SCF3, -SF5, -S-(C 1-4 Alkyl), C 2-4 alkenyl, C 2-4 alkynyl group, -S(=O)2-C 1-4 Alkyl, =CH2, =CHF, =CF2, -C(=O)OC 1-4 Alkyl group substitution; in some embodiments, Cy2 is selected from C 3-6 Cycloalkyl, 5-10-membered heteroaryl, 6-10-membered heterocycloalkyl or absent, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl group is optionally selected from 1-4 elements selected from R, deuterium, halogen, NH2, CN, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The deuterated alkyl group is substituted; when Cy2 is selected from tetrazolium, it is optionally substituted with R, deuterium, halogen, NH2, CN, OH, CH3, C. 1-6 Haloalkyl, C 1-6 Substitution of deuterated alkyl groups;

[0031] In some implementations, Cy2 is selected from C 3-6 Cycloalkyl, 5-6-membered heteroaryl, 6-10-membered heterocycloalkyl or absent, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl group is optionally selected from 1-4 of R, deuterium, halogen, NH2, CN, OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4The deuterated alkyl group is substituted; when Cy2 is selected from tetrazolium, it is optionally substituted with R, deuterium, halogen, NH2, CN, OH, CH3, C. 1-4 Haloalkyl, C 1-4 Substitution of deuterated alkyl groups;

[0032] In some implementations, Cy2 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Alternatively, it may not exist, but may be optionally substituted with 1-4 R2 groups, wherein the R2 is selected from R, deuterium, halogen, NH2, CN, OH, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, -C(=O)OC 1-2 Alkyl group substitution;

[0033] In some implementations, Cy2 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Alternatively, it may not exist, but may be optionally substituted with 1-4 R2 groups, wherein the R2 is selected from R, deuterium, halogen, NH2, CN, OH, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, -C(=O)OC 1-2 Alkyl group substitution;

[0034] In some embodiments, Cy2' is selected from the following groups optionally substituted with 1-4 R2 groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0035] In some implementations, Cy2 is selected from The elements selected are R, deuterium, halogen, NH2, CN, OH, CH3, and C. 1-2 Haloalkyl, C 1-2 Deuterated alkyl, -C(=O)OC 1-2 Alkyl group substitution;

[0036] R is selected from C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, C 6-10 aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the cycloalkyl or heteroaryl group is optionally surrounded by 1-5 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl groups are substituted; in some embodiments, R is selected from C. 3-6 cycloalkyl, -OC 3-6 cycloalkyl, C 6-10 aryl, 4-10-membered heterocyclic alkyl or 5-6-membered heteroaryl, wherein the cycloalkyl or heteroaryl group is optionally surrounded by 1-5 groups selected from halogen, oxo group, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Substitution of deuterated alkyl groups;

[0037] R is selected from C 3-6 Cycloalkyl or 5-10 heteroaryl groups, wherein the cycloalkyl or heteroaryl group is optionally surrounded by 1-4 groups selected from halogens, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Substitution of deuterated alkyl groups;

[0038] In some implementations, R is selected from C 3-6 Cycloalkyl or 5-6 heteroaryl groups, wherein the cycloalkyl or heteroaryl group is optionally selected from 1-4 halogens, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Substitution of deuterated alkyl groups;

[0039] In some implementations, R is selected from , , , , ;

[0040] R1 is selected from deuterium, Cl, COOH, and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-4 alkenyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2Deuterated alkoxy or azirrobutyl; in some embodiments, R1 is selected from deuterium, Cl, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-4 alkenyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Deuterated alkoxy or nitrogen-containing heterocyclic butyl;

[0041] In some implementation schemes, R 1’ Selected from deuterium, oxo group, -N=S(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, -SCF3, -SF5, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-4 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups;

[0042] X1 is selected from N;

[0043] Alternatively, R1 and R2, two R1s on the same atom, two R2s on the same atom, two R1s on different atoms, or two R2s on different atoms and the atoms to which they are attached, together form a 5-8 membered heterocyclic alkyl group or a C-shaped alkyl group. 5-8 Cycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with 1 to 4 groups selected from Rx;

[0044] In some implementation schemes, Selected from the following structures, which are optionally substituted with 1 to 4 groups selected from Rx: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0045] Cy3 is selected from the following structures that are optionally substituted with 1 to 4 groups selected from Rx: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0046] In some embodiments, Cy3 is selected from 1-4 molecules selected from halogens, cycloalkyl groups, and C. 1-6 The following structures are formed by the substitution of alkyl groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0047] In some implementations, Cy3 is selected from the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0048] In some implementations, Cy3 is selected from the following structures: ;

[0049] The Rx is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, =CH2, =CF2, =CHF, =CH(C) 1-3Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl groups, 4-8 membered heterocyclic alkyl groups optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 alkylamine group, C 3-6 Cycloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Substituted with alkyl groups;

[0050] t is selected from any integer between 0 and 5;

[0051] In some implementations, t is selected from 0, 1, 2, 3, 4; in some implementations, t is selected from 0, 1, 2, 3; in some implementations, t is selected from 0, 1, 2; in some implementations, t is selected from 0, 1; in some implementations, t is selected from 1.

[0052] m is selected from 0, 1, 2, 3, 4; in some implementations, m is selected from 0, 1, 2, 3; in some implementations, m is selected from 0, 1, 2; in some implementations, m is selected from 0, 1; in some implementations, m is selected from 1.

[0053] q is selected from 3 or 4; in some implementations, q is selected from 3.

[0054] The compound is not selected from the following structures:

[0055] .

[0056] The specific first technical solution involves compounds represented by general formulas (Ia), (I), and (Ib), their stereoisomers, or pharmaceutically acceptable salts.

[0057]

[0058] L1 is selected from -C(=O)NH-, -C(=S)NH-, -C(=Se)NH-, and -CR. a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx;

[0059] Each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy groups;

[0060] As an option, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl;

[0061] R x1 R x2 Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl;

[0062] R A R BEach is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy groups;

[0063] Cy1 is selected from C 3-10 cycloalkyl, phenyl, C 7-10 aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally substituted with 1-5 R1 groups, wherein the R1 groups are selected from deuterium, oxoyl, -N=S(=O)-(C 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, -SCF3, -SF5, Cl, F, NH2, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-5 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups;

[0064] L2 is selected from key, -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group or -C(=O)NH-, -NHC(=O)-;

[0065] Cy2 is selected from C 3-6The cycloalkyl, 5-10-membered heteroaryl, 5-membered heterocycloalkyl, 6-10-membered heterocycloalkyl, or none thereof, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl group is optionally substituted by 1-5 groups selected from R2, wherein R2 is selected from R, deuterium, halogen, oxo group, NH2, CN, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl groups, -N=S(=O)-(C 1-6 Alkyl)2, -SCF3, -SF5, -S-(C 1-6 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, -S(=O)2-C 1-6 Alkyl, =CH2, =CHF, =CF2, -C(=O)OC 1-6 Alkyl group substitution;

[0066] When Cy2 is selected from tetrazolium, it may be arbitrarily selected from R, deuterium, halogen, NH2, CN, OH, CH3, C. 1-6 Haloalkyl, C 1-6 Substitution of deuterated alkyl groups;

[0067] R is selected from C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, C 6-10 aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the cycloalkyl or heteroaryl group is optionally surrounded by 1-5 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Substitution of deuterated alkyl groups;

[0068] Alternatively, R1 and R2, two R1s on the same atom, two R2s on the same atom, two R1s on different atoms, or two R2s on different atoms and the atoms to which they are attached, together form a 5-8 membered heterocyclic alkyl group or a C-shaped alkyl group. 5-8 Cycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with 1 to 4 groups selected from Rx;

[0069] The Rx is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl groups, 4-8 membered heterocyclic alkyl groups optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 alkylamine group, C 3-6 Cycloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Substituted with alkyl groups;

[0070] t is selected from any integer between 0 and 5;

[0071] The compound is not selected from the following structures:

[0072] .

[0073] The second specific technical solution involves the compound shown in formula (Ib), its stereoisomers, or pharmaceutically acceptable salts.

[0074]

[0075] L1 is selected from -C(=O)NH-, -C(=S)NH-, -C(=Se)NH-, and -CR. a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b-、-C(=O)NHS(=O)2-、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx;

[0076] Each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy groups;

[0077] As an option, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl;

[0078] R x1 R x2 Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl;

[0079] Cy1 is selected from C 3-10 cycloalkyl, phenyl, C 7-10 aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally substituted with 1-5 R1 groups, wherein the R1 groups are selected from deuterium, oxoyl, -N=S(=O)-(C 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, -SCF3, -SF5, Cl, F, NH2, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-5 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups;

[0080] L2 is selected from key, -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl group or -C(=O)NH-, -NHC(=O)-;

[0081] Cy2 is selected from C 3-6 The cycloalkyl, 5-10-membered heteroaryl, 5-membered heterocycloalkyl, 6-10-membered heterocycloalkyl, or none thereof, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl group is optionally substituted by 1-5 groups selected from R2, wherein R2 is selected from R, deuterium, halogen, oxo group, NH2, CN, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl groups, -N=S(=O)-(C 1-6 Alkyl)2, -SCF3, -SF5, -S-(C 1-6 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, -S(=O)2-C 1-6 Alkyl, =CH2, =CHF, =CF2, -C(=O)OC 1-6 Alkyl group substitution;

[0082] When Cy2 is selected from tetrazolium, it may be arbitrarily selected from R, deuterium, halogen, NH2, CN, OH, CH3, C. 1-6 Haloalkyl, C 1-6 Substitution of deuterated alkyl groups;

[0083] R is selected from C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, C 6-10 aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the cycloalkyl or heteroaryl group is optionally surrounded by 1-5 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Substitution of deuterated alkyl groups;

[0084] Alternatively, R1 and R2, two R1s on the same atom, two R2s on the same atom, two R1s on different atoms, or two R2s on different atoms and the atoms to which they are attached, together form a 5-8 membered heterocyclic alkyl group or a C-shaped alkyl group. 5-8 Cycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with 1 to 4 groups selected from Rx;

[0085] The Rx is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl groups, 4-8 membered heterocyclic alkyl groups optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 alkylamine group, C 3-6 Cycloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Substituted with alkyl groups;

[0086] The compound is not selected from the following structures:

[0087] .

[0088] Specifically, in the third technical solution, the compounds represented by formulas (Ia), (I), and (Ib), their stereoisomers or pharmaceutically acceptable salts,

[0089] L1 is selected from -C(=O)NH-, -C(=S)NH-, -C(=Se)NH-, and -CR. a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 1-6 Alkylene, C 2-4 imidene group, C 2-4 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx;

[0090] Each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy groups;

[0091] As an option, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl;

[0092] R x1 R x2 Each is independently selected from hydrogen, deuterium, and C. 1-4 alkyl;

[0093] Cy1 is selected from C 6-10 cycloalkyl, phenyl, C 7-10 aryl, 6-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally substituted with 1-4 R1 groups, wherein the R1 groups are selected from deuterium, oxoyl, -N=S(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, -SCF3, -SF5, Cl, F, NH2, CN, OH, COOH, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-4 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups;

[0094] L2 is selected from key, -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Alynyl group or -C(=O)NH-, -NHC(=O)-;

[0095] Cy2 is selected from C 3-6 The cycloalkyl, 5-6-membered heteroaryl, 5-membered heterocycloalkyl, 6-10-membered heterocycloalkyl or absent, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted by 1-5 R2 groups, wherein the R2 is selected from R, deuterium, halogen, NH2, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl groups, -N=S(=O)-(C 1-4 Alkyl)2, -SCF3, -SF5, -S-(C 1-4 Alkyl), C 2-4 alkenyl, C 2-4 alkynyl group, -S(=O)2-C 1-4 Alkyl, =CH2, =CHF, =CF2, -C(=O)OC 1-4 Alkyl groups are substituted; when Cy2 is selected from tetrazolium, it is optionally selected from R, deuterium, halogen, NH2, CN, OH, CH3, C. 1-4 Haloalkyl, C 1-4 Substitution of deuterated alkyl groups;

[0096] R is selected from C 3-6 cycloalkyl, -OC3-6 cycloalkyl, C 6-10 aryl, 4-10-membered heterocyclic alkyl or 5-6-membered heteroaryl, wherein the cycloalkyl or heteroaryl group is optionally surrounded by 1-5 groups selected from halogen, oxo group, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Substitution of deuterated alkyl groups;

[0097] Alternatively, R1 and R2, two R1s on the same atom, two R2s on the same atom, two R1s on different atoms, or two R2s on different atoms and the atoms to which they are attached, together form a 5-8 membered heterocyclic alkyl group or a C-shaped alkyl group. 5-8 Cycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with 1 to 4 groups selected from Rx;

[0098] The definitions of other functional groups are consistent with those of the first technical solution.

[0099] Specifically, in the fourth technical solution, the compounds represented by formulas (Ia), (I), and (Ib), their stereoisomers or pharmaceutically acceptable salts,

[0100] Cy1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , The substance can be optionally replaced by 1-4 R1s, wherein the R1s are selected from deuterium, halogens, COOH, and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-4 alkenyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2Substitution of deuterated alkoxy or aziridine groups;

[0101] Or Cy1 is selected from The substance can be optionally replaced by 1-4 R1s, wherein the R1s are selected from deuterium, Cl, F, COOH, and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-4 alkenyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Deuterated alkoxy, nitrogen-containing heterocyclic butyl, -N=S(=O)-(C 1-4 Alkyl)2, -SCF3, -SF5, -S-(C 1-6 Alkyl), C 2-4 alkynyl group, -S(=O)2-C 1-4 Substitution of alkyl, =CH2, =CHF, =CF2 groups;

[0102] Cy2 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Alternatively, it may not exist, but may be optionally substituted with 1-4 R2 groups, wherein the R2 is selected from R, deuterium, halogen, NH2, CN, OH, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, -C(=O)OC 1-2 Alkyl group substitution;

[0103] Or Cy2 is selected from The elements selected are R, deuterium, halogen, NH2, CN, OH, CH3, and C. 1-2 Haloalkyl, C 1-2 Substitution of deuterated alkyl groups;

[0104] R is selected from , , , , ;

[0105] As an option, Selected from the following structures, which are optionally substituted with 1 to 4 groups selected from Rx: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0106] The definitions of other functional groups are consistent with those of the first technical solution.

[0107] Specifically, in the fifth technical solution, the compounds represented by formulas (Ia), (I), and (Ib), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the compounds of formulas (Ia), (I), and (Ib) have the structures of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9).

[0108]

[0109] Cy1' is selected from the following groups that are substituted with 1 to 4 R1 groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0110] Cy2' is selected from any of the following groups substituted with 1 to 4 R2 groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0111] Cy3 is selected from the following structures that are optionally substituted with 1 to 4 groups selected from Rx: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0112] L 1’ Selected from -C(=S)NH-, -C(=Se)NH-, -CR a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 2-4 imidene group, C 2-4 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx;

[0113] Each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4Deuterated alkoxy groups;

[0114] As an option, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl;

[0115] R x1 Selected from hydrogen, R x2 Selected from methyl;

[0116] Or R x1 Selected from methyl, R x2 Selected from hydrogen;

[0117] L 2’ Selected from -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Alynyl group or -C(=O)NH-, -NHC(=O)-;

[0118] R 1’ Selected from deuterium, oxo group, -N=S(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, -SCF3, -SF5, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-4 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups;

[0119] X1 is selected from N;

[0120] m is selected from any integer between 0 and 5;

[0121] The definitions of other functional groups are consistent with those of the first technical solution.

[0122] Specifically, in the fifth technical solution, the compounds represented by formulas (Ia), (I), and (Ib), their stereoisomers or pharmaceutically acceptable salts thereof, wherein the compounds of formulas (Ia), (I), and (Ib) have the structures of formulas (I-1b), (I-2b), (I-3b), (I-4b), (I-5b), (I-6b), (I-7b), and (I-8b).

[0123]

[0124] The definitions of other functional groups are consistent with those of the first technical solution.

[0125] More specifically, the compounds of formula (I) described in this invention, their stereoisomers or pharmaceutically acceptable salts, are selected from, but not limited to, the structures in Tables 1 and 2 below:

[0126] Table 1

[0127]

[0128] Table 2

[0129] 。

[0130] The present invention also provides a pharmaceutical composition comprising the compound described in any of the foregoing technical solutions, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient. The present invention also provides a use, namely, the use of the compound described in any of the foregoing technical solutions, its stereoisomer or pharmaceutically acceptable salt, or the foregoing pharmaceutical composition in the preparation of a medicament for treating / preventing c-Kit-mediated diseases.

[0131] The c-Kit-mediated diseases described in this invention are selected from systemic mastocytosis, urticaria, and asthma.

[0132] The present invention also provides a method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the aforementioned compound, its stereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients and / or carriers, the therapeutically effective amount preferably being 1-1500 mg, the disease preferably being systemic mastocytosis, urticaria, or asthma.

[0133] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the mammals described in the present invention include humans.

[0134] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5 -500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5 -20mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-12 5mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-60 0mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20- 50mg, 20-40mg, 20-30mg; 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg , 50-125mg, 50-100mg; 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg.

[0135] This invention relates to a pharmaceutical composition or formulation comprising a therapeutically effective amount of the compound of the invention or its stereoisomers or pharmaceutically acceptable salts, and excipients and / or a carrier. The pharmaceutical composition may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, etc. The compounds of the present invention or their stereoisomers, or pharmaceutically acceptable salts thereof, in the following amounts: g, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg.

[0136] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention, its stereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients and / or carriers, the therapeutically effective amount preferably being 1-1500 mg, the disease preferably being systemic mastocytosis, urticaria, or asthma.

[0137] A method for treating a disease in a mammal. The method comprises administering a pharmaceutical compound, a stereoisomer of the invention, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients and / or carriers to a subject at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100- 1000mg / day, 200-1000mg / day, 25-800mg / day, 50-800mg / day, 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day. In some embodiments, the daily dose includes, but is not limited to, 1mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, and 1500mg / day.

[0138] This invention relates to a kit that may comprise a single-dose or multi-dose composition containing a compound of the present invention or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of the present invention or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is the same as the amount in the aforementioned pharmaceutical composition.

[0139] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0140] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0141] Synthetic route

[0142] Those skilled in the art can prepare the compounds of this invention by combining this literature with known organic synthesis techniques, using commercially available chemicals and / or compounds described in the chemical literature as starting materials. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energie Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0143] References and monographs in this field detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing such preparation methods for reference. Specific and similar reactants can be selectively identified through the American Chemical Society's Chemical Abstracts Index of Known Chemicals, which is available in most public and university libraries, as well as online. Known but not commercially available chemicals may optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services (e.g., those listed above).

[0144] the term

[0145] Unless otherwise specified in this invention, the terminology used in this invention has the following meanings:

[0146] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention all include their isotopes. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0147] In this article, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0148] "Halogenation" or "halogen substitution" refers to substitution by one or more halogen substituents selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted in the substituted group. Unless otherwise specified, the number of halogen substituents can be any integer between 1 and this upper limit. When the number of halogen substituents is greater than 1, the substitution can be by the same or different halogens. Common cases include 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0149] "Deuterium" refers to the hydrogen (H) isotope deuterium, which is synonymous with "D".

[0150] "Deuteration" or "deuterated product" refers to the situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, or alkynyl group is replaced by at least one deuterium atom. The upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced in the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and this upper limit, such as 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms, or 1 deuterium atom.

[0151] “C x-y A "group" refers to a group containing x to y carbon atoms, such as "C". 1-6 "Alkyl" refers to an alkyl group containing 1-6 carbon atoms, and "C0" usually refers to a bond.

[0152] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. It is typically an alkyl group with 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc., and the alkyl group may be further substituted with substituents.

[0153] "Alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, etc.

[0154] "Halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine, or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and this upper limit. Typically, alkyl groups are substituted by 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, they can be the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0155] "Alkoxy" or "alkyloxy" refers to -O-alkyl. For example, -OC 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 Alkyl or -OC 1-2Alkyl groups. Specific, non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy, etc.; the alkoxy groups may optionally be substituted with substituents.

[0156] "Haloalkoxy" refers to -O-haloalkyl. For example, -O-haloC 1-8 Alkyl, -O-halogenated C 1-6 Alkyl, -O-halogenated C 1-4 Alkyl or -O-halogenated C 1-2 Alkyl groups; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be replaced in the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substituents, 1-3 halogen substituents, 1-2 halogen substituents, or 1 halogen substituent. When the number of halogen substituents is greater than 1, the same or different halogens can be used for substitution. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0157] "Alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2... -Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group may optionally be further substituted with substituents.

[0158] "Alkenyl" refers to a straight-chain or branched divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Non-limiting examples include ethynylene groups, which may optionally be substituted with substituents.

[0159] "Alynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl; the alkynyl group may optionally be substituted with substituents.

[0160] "Imyynyl" refers to a straight-chain or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Non-limiting embodiments include ethynyl, propynyl, and butynyl, wherein the ethynyl group may optionally be substituted with substituents.

[0161] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain cyclic heteroatoms. Cycloalkyl groups can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic groups can be fused, spirocyclic, bridged, or combinations thereof. A bicyclic or polycyclic group may include one or more aromatic rings, but the ring system as a whole is not aromatic, and the linking site is on a non-aromatic ring. Typically, cycloalkyl groups contain 3 to 20 carbon atoms, more commonly 3 to 8 carbon atoms, and even more commonly 3 to 6 carbon atoms; when monocyclic, they contain 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms; when bicyclic or polycyclic, they contain 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, etc. , , , , , , , , , , , , In addition, cycloalkyl groups may optionally be substituted with substituents.

[0162] "Cycloalkylene" refers to the divalent group of a cycloalkyl group.

[0163] "Aryl" refers to an aromatic carbon ring that does not contain heteroatoms, including monocyclic aryl and fused-ring aryl. It typically contains 6 to 14 carbon atoms, and more commonly 6 to 10 carbon atoms. Non-limiting examples include phenyl, naphthyl, anthraceneyl, and phenanthreneyl groups, and the aryl group may optionally be substituted with substituents.

[0164] "Carbocyclic" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic carbon ring, including aryl and cycloalkyl groups. The carbon ring can be monocyclic, bicyclic, or polycyclic, including bridged rings, fused rings, and spirocyclic rings, as well as combinations thereof. Carbon rings typically have 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting embodiments, monocyclic carbon rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl, etc., and bicyclic bridged rings include... , , Etc., double-ring parallel rings include , , , , and etc., double-ring spiral rings include , , , , and In addition, the carbon ring can be optionally replaced by substituents.

[0165] "Heterocyclic alkyl" refers to a saturated or partially unsaturated non-aromatic carbon ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, P, Si, Se, S, or B and their oxidation states. Heterocyclic alkyl can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be bridged rings, fused rings, spirocyclic rings, or combinations thereof. Bicyclic or polycyclic rings may include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic, and the connecting sites are on non-aromatic rings. Typically, heterocyclic alkyl rings are 3 to 20-membered rings. When it is a monocyclic heterocyclic alkyl, it is usually 3 to 15-membered, or 3-10-membered, or 3-8-membered, or 3-6-membered rings; when it is a bicyclic or polycyclic heterocyclic alkyl, it is usually 5-12-membered, or 5-11-membered, or 6-9-membered rings. Non-limiting examples of heterocyclic alkyl groups include azirrobutyl, morpholino, piperazinyl, piperidinyl, tetrahydropyranyl, oxacyclobutyl, pyranyl, azirropentenyl, azirrohexenyl, oxacyclopentenyl, oxacyclohexenyl, etc., and the heterocyclic alkyl groups may optionally be substituted with substituents.

[0166] Unless otherwise specified, "heteroaromatic ring" or "heteroaryl" refers to an aromatic ring containing 1 to 4 heteroatoms selected from N, O, P, Si, Se, S, or B and their oxidation states. It can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be bridged rings, fused rings, spirocyclic rings, and combinations thereof. When it is bicyclic or polycyclic, it can be a fusion of a heteroaryl group and an aryl group, or a fusion of two heteroaryl groups, wherein either the heteroaryl group or the aryl group can be a connecting site. Non-limiting embodiments include furanyl, thiophene, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indoleyl, purineyl, etc. , , , , , The heteroaryl group can be optionally substituted with a substituent.

[0167] "Heterocycle" or "heterocyclic group" refers to a saturated or unsaturated, aromatic or non-aromatic ring containing one to four heteroatoms selected from N, O, P, Si, Se, S, or B and their oxidation states. It includes heteroaryl and heterocyclic alkyl groups. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles, or combinations thereof. They are typically 3- to 12-membered heterocycles, 5- to 12-membered heterocycles, or 5- to 7-membered heterocycles. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, piperazine, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, and 1,3-dithiayl. Dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazoyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazoyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl, , , , , , , , , In addition, heterocyclic rings can be optionally substituted by substituents.

[0168] "Hypo-heterocyclic group" refers to a divalent heterocyclic group that is substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic. Non-limiting examples include... , , , , wait.

[0169] A "spirocyclic ring" refers to a polycyclic group in which rings share a single carbon atom (called a spiro atom). It can contain 0 or more double or triple bonds and 0 to 5 heteroatoms selected from N, O, P, Si, Se, S, or B and their oxidation states. Spirocyclic rings are typically 6 to 14-membered, 6 to 12-membered, or 6 to 10-membered. Common spirocyclic rings include tri-spirotri- (representing a three-membered ring followed by a spirotri-membered ring), tri-spirotetra-, tri-spiropenta-, tri-spirohexa-, tetra-spirotetra-, tetra-spiropenta-, tetra-spirohexa-, penta-spiropenta-, or penta-spirohexa-. Non-limiting examples of spirocyclic rings include...

[0170] The spiroring may optionally be replaced by a substituent.

[0171] "Fused rings" or "fused rings" refer to polycyclic groups where rings share two adjacent ring atoms and a chemical bond. They may contain one or more double or triple bonds and can contain 0 to 5 heteroatoms selected from N, O, P, Si, Se, S, or B and their oxidation states. Fused rings are typically 5 to 20-membered, 5 to 14-membered, 5 to 12-membered, or 5 to 10-membered rings. Common fused ring types include trifused tetracyclic rings (representing fused rings formed by a three-membered and a four-membered ring; according to IUPC nomenclature, this could be a fused ring with either a three-membered or a four-membered ring as the base ring, and the same applies below), trifused pentacyclic rings, trifused hexacyclic rings, tetrafused tetracyclic rings, tetrafused pentacyclic rings, tetrafused hexacyclic rings, pentafused pentacyclic rings, pentafused hexacyclic rings, and hexafused hexacyclic rings. Non-limiting examples of fused rings include purines, quinolines, isoquinolines, benzopyrans, benzofurans, benzothiophenes, etc. The cyclic compound can be aromatic or non-aromatic, and optionally substituted with substituents.

[0172] A "bridged ring" refers to two rings sharing two non-adjacent ring atoms and may contain one or more double or triple bonds. Bridged rings can contain 0 to 5 heteroatoms selected from N, O, P, Si, Se, S, or B and their oxidation states. Typically, bridged rings have 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring atoms. Non-limiting examples of bridged rings include adamantane, etc.

[0173] .

[0174] Unless otherwise specified, "substitution" or "substituent" refers to any substitution occurring at a position permitted by chemical theory, with the number of substituents conforming to the rules of chemical bonding. Exemplary substituents include, but are not limited to: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Heteroalkyl, C 5-12 Aryl, 5-12 heteroaryl, hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1-6 Alkylthio, cyano, halogen, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, phosphonic acid, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2,-HC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 alkyl)2,-SO2NH(C 1-6 Alkyl group, -SO2NH2, -SO2C 1-6 Alkyl groups, etc.

[0175] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0176] "Pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, wherein the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0177] "Pharmaceutical composition" means one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or eutectics, mixed with other components, wherein the other components contain physiologically / pharmaceuticalally acceptable carriers and / or excipients.

[0178] "Carrier" refers to a system that does not cause significant stimulation to the organism and does not eliminate the biological activity and properties of the given compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0179] "Excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added to a pharmaceutical composition to improve its disposal or storage properties or to allow or promote the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (e.g. croscarmellose sodium); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Oils and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and / or polyanhydride; and (22) other non-toxic compatible substances used in pharmaceutical preparations.

[0180] "Isomers" include "stereoisomers" and "tautomers." Stereoisomers are isomers that exist in molecules where atoms or groups of atoms are connected in the same order but arranged differently in space. Stereoisomers include cis-trans isomers, optical isomers, and conformational isomers. Tautomers are molecules that can interconvert through a reversible chemical reaction called tautomerization, typically caused by the migration of hydrogen atoms and π bonds (double or triple bonds), resulting in a transformation from one functional group to another. Examples include the following paired compounds: aldehyde / ketone – enol, imine – enamine. Detailed Implementation

[0181] The technical solution of the present invention will be described in detail below with reference to the embodiments, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0182] Detection methods

[0183] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers in the following solvents: deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD). Tetramethylsilane (TMS) was used as the internal standard.

[0184] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0185] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM).

[0186] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for TLC have a diameter of 0.15 mm to 0.20 mm, and the diameter of the plates used for TLC separation and purification is 0.4 mm to 0.5 mm.

[0187] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0188] Example 1:

[0189]

[0190] Step 1: Dissolve 1A (3 g, 14.42 mmol) and 1B (1.52 g, 17.27 mmol) in DMF (30 mL), then add cesium carbonate (7.05 g, 21.62 mmol), and react at 100 °C for 3 h. After the reaction is complete, cool to room temperature, extract with ethyl acetate and water, combine the organic layers, wash with saturated brine, dry with anhydrous sodium sulfate, filter the insoluble matter, and purify by silica gel column chromatography to obtain a mixture of 1C-1 and 1C-2 (3.29 g, 77%). LC-MS (ESI): m / z = 297.2 [M+H] + .

[0191] Step 2: 1D (300 mg, 1.29 mmol, prepared according to the method disclosed in patent WO2013033070) and 1E (346 mg, 1.29 mmol) were dissolved in toluene (15 mL). A 1.6 M trimethylaluminum solution in toluene (2 mL) was slowly added dropwise under ice bath conditions, and the reaction was carried out at 80 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with water. The mixture was then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, filtered to remove the insoluble matter, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 1F (458 mg, 78%). LC-MS (ESI): m / z = 455.8 [M+H] + .

[0192] Step 3: 1F (458 mg, 1.00 mmol), a mixture of 1C-1 and 1C-2 (357 mg, 1.21 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol), and potassium carbonate (416 mg, 3.01 mmol) were dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (1 mL). The reaction was carried out under a nitrogen atmosphere at 80 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The crude product was purified by silica gel column chromatography. Subsequently, compounds 1-1 (75 mg, 14%), 1-2 (73 mg, 13%), 1-3 (67 mg, 12%), and 1-4 (65 mg, 12%) were prepared by SFC.

[0193] SFC separation method: Instrument: CAS-05-Prep-SFC-F, Column: AD column, Mobile phase: A for CO2; B for 0.1% NH3•H2O in isopropanol and acetonitrile, Flow rate: 140 mL / min, Column temperature: 25℃, Wavelength: 220 nm. Retention times: Compound 1-1: tR = 1.300 min; Compound 1-2: tR = 1.536 min; Compound 1-3: tR = 2.274 min; Compound 1-4: tR = 3.045 min.

[0194] Compound 1-1: LC-MS (ESI): m / z = 546.3 [M+H] + .

[0195] 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.82-8.78 (m, 1H), 8.74 (s,1H), 8.28-8.26 (m, 1H), 8.18 (s, 1H), 8.06-8.04 (m, 1H), 7.76-7.73 (m, 1H),7.47-7.44 (m, 1H), 7.27-7.24 (m, 1H), 5.38-5.19 (m, 1H), 5.16-5.14 (m, 1H),4.18-4.10 (m, 1H), 4.03-3.95 (m, 2H), 3.32-3.30 (m, 2H), 3.29 (s, 3H), 3.10-3.00 (m, 1H), 2.41 (s, 3H), 2.36 (s, 3H), 2.00-1.88 (m, 1H), 1.64-1.54 (m,1H).

[0196] Compounds 1-2: LC-MS (ESI): m / z = 546.3 [M+H] + .

[0197] 1¹H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.82-8.78 (m, 1H), 8.74 (s,1H), 8.28-8.26 (m, 1H), 8.18 (s, 1H), 8.06-8.04 (m, 1H), 7.76-7.73 (m, 1H),7.47-7.44 (m, 1H), 7.27-7.24 (m, 1H), 5.39-5.19 (m, 1H), 5.16-5.14 (m, 1H),4.19-4.10 (m, 1H), 4.04-3.95 (m, 2H), 3.32-3.30 (m, 2H), 3.29 (s, 3H), 3.10-3.00 (m, 1H), 2.41 (s, 3H), 2.36 (s, 3H), 2.00-1.88 (m, 1H), 1.64-1.54 (m,1H).

[0198] Compound 1-3: LC-MS (ESI): m / z = 546.3 [M+H] + .

[0199] 1 ¹H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.84-8.80 (m, 1H), 8.75 (s,1H), 8.21-8.19 (m, 1H), 8.05-8.04 (m, 1H), 7.85 (s, 1H), 7.76-7.73 (m, 1H),7.47-7.44 (m, 1H), 7.26-7.22 (m, 1H), 5.38-5.19 (m, 1H), 5.14-5.11 (m, 1H),4.20-3.95 (m, 3H), 3.38-3.31 (m, 2H), 3.29 (s, 3H), 3.08-3.00 (m, 1H), 2.49(s, 3H), 2.36 (s, 3H), 2.00-1.88 (m, 1H), 1.64-1.54 (m, 1H).

[0200] Compound 1-4: LC-MS (ESI): m / z = 546.3 [M+H] + .

[0201] 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.84-8.81 (m, 1H), 8.75 (s,1H), 8.21-8.19 (m, 1H), 8.05-8.04 (m, 1H), 7.85 (s, 1H), 7.77-7.73 (m, 1H),7.47-7.44 (m, 1H), 7.26-7.22 (m, 1H), 5.39-5.19 (m, 1H), 5.14-5.11 (m, 1H),4.20-3.96 (m, 3H), 3.38-3.31 (m, 2H), 3.29 (s, 3H), 3.10-3.00 (m, 1H), 2.49 (s, 3H), 2.36 (s, 3H), 2.00-1.88 (m, 1H), 1.64-1.54 (m, 1H).

[0202] Example 2:

[0203]

[0204] Step 1: 2A (0.6 g, 2.12 mmol), cyclopropanethyne (0.18 g, 3.0 mmol), Pd(PPh3)2Cl2 (0.21 g, 0.30 mmol), and triethylamine (0.6 g, 6.0 mmol) were dissolved sequentially in 20 mL of 1,4-dioxane under nitrogen protection and stirred at room temperature for 18 h. After the reaction was complete, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and purified by silica gel column chromatography to obtain 2B (0.41 g, 87.4%). LC-MS (ESI): m / z = 222.0 [M+H] + .

[0205] Step 2: Dissolve 2B (0.27 g, 1.22 mmol) and zinc powder (0.65 g, 10 mmol) in methanol (15 mL), then add ammonium chloride (0.54 g, 10 mmol) in portions, and stir the mixture at room temperature for 2 h. After the reaction is complete, filter the solution, concentrate the filtrate, and purify the residue by silica gel column chromatography to obtain 2C (0.22 g, 94.23%). LC-MS (ESI): m / z = 192.0 [M+H] + .

[0206] Step 3: Using 2C (0.22 g, 1.15 mmol) and 1E (0.32 g, 1.21 mmol) as raw materials, 2D (0.3 g, 63.0%) was obtained following the procedure in Step 2 of Example 1. LC-MS (ESI): m / z = 414.0 [M+H] + .

[0207] Step 4: Using 2D (0.30 g, 0.72 mmol), a mixture of 1C-1 and 1C-2 (0.25 g, 0.86 mmol) as starting materials, compound 2-1 (40 mg, 11%) and compound 2-2 (32 mg, 8.8%) were obtained according to the procedure in Step 3 of Example 1. LC-MS (ESI): m / z = 504.2 [M+H] + .

[0208] SFC separation method: Instrument: CAS-05-Prep-SFC-A, Column: AS column, Mobile phase: A for CO2; B for 0.1% NH3•H2O in isopropanol, Flow rate: 120 mL / min, Column temperature: 25℃, Wavelength: 220 nm. Retention time: Compound 2-1: tR = 2.088 min; Compound 2-2: tR = 2.295 min.

[0209] Compound 2-1: LC-MS (ESI): m / z = 504.2 [M+H] + .

[0210] 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.56-8.53 (m, 1H), 8.39 (s,1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.32-7.30 (m, 1H), 7.08-7.04(m, 2H), 4.41-4.38 (m, 1H), 4.28-4.23 (m, 2H), 3.46-3.38 (m, 5H), 2.57 (s,3H), 1.47-1.42 (m, 1H), 0.90-0.85 (m, 2H), 0.84-0.80 (m, 2H).

[0211] Compound 2-2: LC-MS (ESI): m / z = 504.2 [M+H] + .

[0212] 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.56-8.53 (m, 1H), 8.34 (s,1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.32-7.30 (m, 1H), 7.07-7.03(m, 2H), 4.37-4.26 (m, 1H), 4.28-4.23 (m, 2H), 3.49-3.35 (m, 5H), 2.56 (s,3H), 1.45-1.42 (m, 1H), 0.90-0.85 (m, 2H), 0.84-0.80 (m, 2H).

[0213] Example 3:

[0214]

[0215] Step 1: 3A (3 g, 23.17 mmol), di-tert-butyl dicarbonate (10.1 g, 46.33 mmol), and triethylamine (4.68 g, 46.33 mmol) were dissolved sequentially in tetrahydrofuran (30 mL), followed by the addition of 4-dimethylaminopyridine (565 mg, 4.63 mmol). The reaction was carried out overnight at room temperature. After the reaction was complete, the mixture was diluted with water, extracted twice with ethyl acetate, and the organic layers were combined. The extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain 3B (3.77 g, 71%). LC-MS (ESI): m / z = 230.1 [M+H] + .

[0216] Step 2: 3B (3.77 g, 16.46 mmol), zinc cyanide (5.80 g, 49.39 mmol), and BrettPhos-Pd-G3 (2.99 g, 3.29 mmol) were dissolved sequentially in DMF (30 mL) and reacted overnight at 80 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted twice with ethyl acetate, and the organic layers were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain 3C (2.06 g, 57%). LC-MS (ESI): m / z = 221.1 [M+H] + .

[0217] Step 3: 3C (2.06 g, 9.36 mmol), sodium azide (1.82 g, 28.09 mmol), and triethylamine hydrochloride (4.51 g, 32.77 mmol) were dissolved sequentially in toluene (25 mL) and reacted overnight at 90 °C. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted twice with ethyl acetate, and the organic layers were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain 3D (1.4 g, 57%). LC-MS (ESI): m / z = 264.1 [M+H] + .

[0218] Step 4: Dissolve 3D (1.3 g, 4.94 mmol) and cyclopropylboronic acid (849 mg, 9.89 mmol) in 1,2-dichloroethane (15 mL), then add copper acetate (987 mg, 4.94 mmol), sodium carbonate (1.05 g, 9.89 mmol), and 2,2'-bipyridine (771 mg, 4.94 mmol). React overnight at 60°C under an oxygen atmosphere. After the reaction is complete, cool to room temperature, dilute with water, extract twice with ethyl acetate, combine the organic layers, wash with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography to obtain 3E (570 mg, 38%). LC-MS (ESI): m / z = 304.1 [M+H] + .

[0219] Step 5: Dissolve 3E (570 mg, 1.88 mmol) in dichloromethane (5 mL), add 2 mL of 4 M dioxane solution of hydrogen chloride, and react at room temperature for 1 hour. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain crude 3F hydrochloride (380 mg), which was used directly in the next reaction without further purification. LC-MS (ESI): m / z = 204.1 [M+H] + .

[0220] Step 6: Using 3F (380 mg, 1.87 mmol) and 1E (504 mg, 1.87 mmol) as starting materials, 3G (218 mg, 27%) was synthesized following the steps in Step 2 of Example 1. LC-MS (ESI): m / z = 426.0 [M+H] + .

[0221] Step 7: Using 3G (218 mg, 0.51 mmol) and a mixture of 1C-1 and 1C-2 (504 mg, 0.61 mmol) as raw materials, the crude product was synthesized according to the steps in Step 3 of Example 1. Subsequently, compound 3-1 (31 mg, 12%) and compound 3-2 (26 mg, 10%) were prepared by SFC.

[0222] SFC separation method: Instrument: CAS-05-Prep-SFC-F, Column: AD column, Mobile phase: A for CO2; B for 0.1% NH3•H2O in ethanol and acetonitrile, Flow rate: 125 mL / min, Column temperature: 25℃, Wavelength: 220 nm. Retention time: Compound 3-1: tR = 1.328 min; Compound 3-2: tR = 1.674 min.

[0223] Compound 3-1: LC-MS (ESI): m / z = 516.2 [M+H] + .

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.71 (s, 1H), 8.84-8.80(m, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.93-7.89 (m, 2H), 7.29-7.25 (m, 1H),5.17-5.15 (m, 1H), 4.52-4.45 (m, 1H), 4.16-4.10 (m, 1H), 4.03-3.95 (m, 2H),3.35-3.31 (m, 2H), 3.29 (s, 3H), 2.42 (s, 3H), 1.45-1.39 (m, 2H), 1.32-1.26 (m, 2H).

[0225] Compound 3-2: LC-MS (ESI): m / z = 516.2 [M+H] + .

[0226] 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.71 (s, 1H), 8.86-8.82(m, 1H), 8.39 (s, 1H), 7.93-7.86 (m, 3H), 7.29-7.25 (m, 1H), 5.15-5.12 (m,1H), 4.52-4.45 (m, 1H), 4.19-4.05 (m, 2H), 4.03-3.95 (m, 1H), 3.38-3.32 (m,2H), 3.29 (s, 3H), 2.50 (s, 3H), 1.45-1.39 (m, 2H), 1.32-1.26 (m, 2H).

[0227] Example 4:

[0228]

[0229] Step 1: Compound 4B (0.5 g, 25%) was prepared from compound 4A (1 g, 5.56 mmol) according to the method disclosed in patent CN118108711. LC-MS (ESI): m / z = 360.1 [M+H] + .

[0230] Step 2: Compound 4B (0.5 g, 1.39 mmol) was dissolved in sulfuric acid (5 mL), and potassium nitrate (0.7 g, 6.95 mmol) was added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, the solution was poured into ice water, and the pH was adjusted to neutral by adding saturated sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The combined organic phases were concentrated, and the residue was purified by column chromatography to obtain compound 4C (0.3 g, 57%). LC-MS (ESI): m / z = 251.1 [M+H] + .

[0231] Step 3: Using compound 4C (0.3 g, 1.2 mmol) as the starting material, compound 4D (0.12 g, 35%) was synthesized according to the method described in Step 4 of Example 3. LC-MS (ESI): m / z = 291.1 [M+H] + .

[0232] Step 4: Using compound 4D (1 g, 3.45 mmol) as the starting material, compound 4E (0.85 g, 95%) was synthesized according to the method described in step 2 of Example 2. LC-MS (ESI): m / z = 261.1 [M+H] + .

[0233] Step 5: Using compound 4E (0.85 g, 3.28 mmol) as a starting material, compound 4F (0.98 g, 62%) was synthesized according to the method described in step 2 of Example 1. LC-MS (ESI): m / z = 485.1 [M+H] + .

[0234] Step 6: Using compound 4F (0.3 g, 0.62 mmol) and 1C (containing two isomers, 1C-1 and 1C-2) (504 mg, 0.61 mmol) as starting materials, compound 4 was synthesized according to the method described in step 3 of Example 1. Subsequently, two isomers, compound 4-1 (62.1 mg, 17%, retention time 1.537 min) and compound 4-2 (36.9 mg, 10%, retention time 1.961 min), were prepared by SFC. LC-MS (ESI): m / z = 575.2 [M+H] + .

[0235] Analytical methods: Instrument name: CAS-05-ANA-SFC-D; Column: IK column; Mobile phase: A for CO2; B for 0.05% MNH3 in methanol and acetonitrile; Flow rate: 3 mL / min; Column temperature: 35℃; Absorption wavelength: 220 nm.

[0236] Compound 4-1: 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.84-8.77 (m,1H), 8.76 (s, 1H), 8.28 (d, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H),7.27 (dd, 1H), 5.15 (d, 1H), 4.17-4.05 (m, 2H), 4.05-3.93 (m, 2H), 3.31-3.30(m, 3H), 3.29 (s, 3H), 3.04 (t, 2H), 2.91 (t, 2H), 2.42 (s, 3H), 1.26- 1.19(m, 3H), 1.12-1.06 (m, 2H).

[0237] Compound 4-2: 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.82 (d, 1H), 8.77 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.55 (s, 1H), 7.25(d, 1H), 5.12 (d, 1H), 4.20-3.94 (m, 4H), 3.34 (d, 3H), 3.29 (s, 3H), 3.04(d, 2H), 2.91 (t, 2H), 2.50 (s, 3H), 1.23-1.21 (s, 3H), 1.10-1.08 (m, 2H).

[0238] Example 5:

[0239]

[0240] Step 1: Compound 1C (containing 1C-1 and 1C-2) (1.2 g, 4.05 mmol) and compound 1E (1.20 g, 4.46 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). Pd(dppf)Cl2 dichloromethane complex (0.32 g, 0.4 mmol) and potassium carbonate (0.85 g, 5.15 mmol) were added. After stirring thoroughly, the mixture was reacted at 100 °C for 18 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, poured into water, and extracted three times with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain 5A (containing 5A-1 and 5A-2) (0.82 g, yield 56.5%). LC-MS (ESI): m / z = 359.1 [M+H] + .

[0241] Step 2: Using 5B (1.0 g, 3.53 mmol) as the starting material, 5C (0.82 g, 91.70%) was obtained following the procedure in Step 2 of Example 2. LC-MS (ESI): m / z = 254.1 [M+H] + .

[0242] Step 3: Dissolve 5C (0.82 g, 3.24 mmol) in toluene (20 mL), add 2,5-hexanedione (1.85 g, 16.18 mmol) to the solution, stir well, then add p-toluenesulfonic acid (0.086 g, 0.5 mmol), and react at 100 °C for 3 hours. Cool to room temperature, add EA to the reaction system, wash the organic phase three times with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the residue by column chromatography to obtain 5D (660 mg, 61.53%). LC-MS (ESI): m / z = 332.1 [M+H] + .

[0243] Step 4: In a microwave-safe tube, 5D (0.66 g, 1.99 mmol) was dissolved in dioxane (3 mL). 1-Cyclopropylimidazolium-2-one (0.3 g, 2.39 mmol), CuI (38 mg, 0.2 mmol), and sodium tert-butoxide (0.24 g, 2.5 mmol) were added to the solution. After purging with nitrogen, the mixture was heated to 110 °C and microwaved for 2 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic phase was washed three times with saturated brine, dried, filtered, and concentrated. The residue was purified by column chromatography to obtain 5E (500 mg, 76.16%). LC-MS (ESI): m / z = 330.1 [M+H] + .

[0244] Step 5: Dissolve 5E (500 mg, 1.52 mmol) in ethanol (20 mL), add hydroxylamine hydrochloride (1.06 g, 15.2 mmol) and water (10 mL), and react at 80 °C for 20 hours. Cool to room temperature, pour the reaction solution into water, extract three times with ethyl acetate, wash the combined organic phases twice with saturated brine, dry to anhydrous sodium sulfate, filter, concentrate, and purify the residue by column chromatography to obtain 5F (360 mg, 94.34%). LC-MS (ESI): m / z = 252.1 [M+H] + .

[0245] Step 6: Using 5F (0.27 g, 1.07 mmol) and 5A (containing 5A-1 and 5A-2) (0.40 g, 1.13 mmol) as starting materials, compound 5-1 (54.9 mg, 9.1%) and compound 5-2 (104.2 mg, 17.22%) were obtained according to the procedure in Step 2 of Example 1. LC-MS (ESI): m / z = 564.2 [M+H] +.

[0246] SFC separation method: Instrument: CAS-05-Prep-SFC-E, Column: AS column, Mobile phase: A for CO2; B for 0.1% NH3•H2O in ethanol and acetonitrile, Flow rate: 125 mL / min, Column temperature: 25℃, Wavelength: 220 nm. Retention time: Compound 5-1: tR = 1.118 min; Compound 5-2: tR = 1.428 min. LC-MS (ESI): m / z = 564.2 [M+H] + .

[0247] Compound 5-1: 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.80-8.78 (m,1H), 8.73 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.91-7.90 (m, 1H), 7.48-7.42(m, 2H), 7.26-7.24 (m, 1H), 5.15-5.14 (m, 1H), 4.15-4.11 (m, 1H), 4.00-3.97(m, 2H), 3.77-3.74 (m, 2H), 3.45-3.41 (m, 4H), 3.36-3.31 (m, 3H), 2.56-2.55 (m, 1H), 2.40 (s, 3H), 0.67-0.65 (m, 4H).

[0248] Compound 5-2: 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.82-8.80 (m,1H), 8.74 (s, 1H), 8.18 (s, 1H), 7.91-7.90 (m, 1H), 7.85 (s, 1H), 7.48-7.42(m, 2H), 7.25-7.23 (m, 1H), 5.13-5.11 (m, 1H), 4.18-4.05 (m, 2H), 4.00-3.97(m, 1H), 3.77-3.74 (m, 2H), 3.45-3.41 (m, 4H), 3.36-3.29 (m, 3H), 2.57-2.54 (m, 1H), 2.23 (s, 3H), 0.67-0.65 (m, 4H).

[0249] Example 6:

[0250]

[0251] Step 1: 6A (10 g, 39.30 mmol), pinacol diboronate (10.98 g, 43.23 mmol), potassium acetate (5.79 g, 58.95 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (1.44 g, 1.97 mmol) were dissolved sequentially in 1,4-dioxane (100 mL). The mixture was heated to 80 °C and reacted overnight under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 6B (20 g).

[0252] Step 2: 6B crude product (15 g), 6C (synthesized according to the method described in patent WO2022155941) (3 g, 12.81 mmol), potassium carbonate (4.42 g, 32.02 mmol), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (0.94 g, 1.28 mmol) were dissolved in a mixed solvent of 1,4-dioxane (80 mL) and water (10 mL). The mixture was heated to 100 °C overnight under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain 6D (0.9 g, 22.75%). LC-MS (ESI): m / z = 309 [M+H] + .

[0253] Step 3: 6D (800 mg, 2.59 mmol), iron powder (725 mg, 12.95 mmol), and ammonium chloride (686 mg, 12.95 mmol) were dissolved in a mixed solvent of ethanol (10 mL) and water (10 mL), and reacted at 70 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, and the organic layers were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain 6E (500 mg, 69%). LC-MS (ESI): m / z = 279 [M+H] + .

[0254] Step 4: 6E (300 mg, 1.08 mmol) and 6F-1 and 6F-2 (synthesized according to the method described in patent WO2024118887) (371 mg, 1.08 mmol) were dissolved in dry toluene (20 mL), followed by the addition of trimethylaluminum (3.24 mmol), and reacted overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted three times with dichloromethane / methanol (v / v) = 10 / 1. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 6. Subsequently, compounds 6-1 (160 mg, retention time 1.350 min, 25%) and 6-2 (88 mg, retention time 1.924 min, 14%) were prepared by SFC. LC-MS(ESI): m / z = 591.2 [M+H] + .

[0255] SFC analysis method: Instrument: CAS-05-ANA-SFC-C, Column: IK column, Mobile phase: A for CO2; B for 0.05% DEA in ethanol and acetonitrile, Flow rate: 3 mL / min, Column temperature: 35℃, Wavelength: 220 nm.

[0256] Compound 6-1: 1 HNMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.79 (d, 1H), 8.72(s, 1H), 8.26-8.25 (m, 1H), 8.18 (s, 1H), 7.45 (s, 1H), 7.26-7.24 (m, 1H),7.17 (s, 1H), 5.39 (s, 2H), 5.16 (d, 1H), 4.17-4.10 (m, 1H), 4.04-3.92 (m,2H), 3.30-3.29 (m, 2H), 3.29 (s, 3H), 2.48-2.44 (m, 1H), 2.40 (s, 3H), 1.21-1.12 (m, 2H), 1.07-0.98 (m, 2H).

[0257] Compound 6-2: 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.81 (d, 1H),8.73 (s, 1H), 8.18 (d, 1H), 7.85 (s, 1H), 7.45 (s, 1H), 7.25-7.23 (m, 1H),7.17 (s, 1H), 5.39 (s, 2H), 5.13 (d, 1H), 4.18-4.14 (m, 1H), 4.10-4.05 (m,1H), 4.02-3.96(m, 1H), 3.38-3.31 (m, 2H), 3.29 (s, 3H), 2.49-2.43 (m, 4H), 1.21-1.11 (m, 2H), 1.06-0.97 (m, 2H).

[0258] Example 7:

[0259]

[0260] Step 1: 7A (3 g, 24.98 mmol, synthesized according to the method described in patent WO2022122044) and DIPEA (9.69 g, 74.94 mmol) were dissolved in dichloromethane (50 mL). Trifluoroacetic anhydride (10.57 g, 37.47 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to rise to room temperature and stirred for 1 hour. After the reaction was complete, a saturated sodium bicarbonate aqueous solution was added to quench the reaction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrated filtrate was used directly in the next reaction step.

[0261] Step 2: Dissolve 7C (1.5 g, 3.79 mmol, synthesized according to the method described in patent WO2024118887) and 7B (4.78 g, 18.95 mmol) in acetonitrile (60 mL), then add cesium carbonate (3.09 g, 9.47 mmol), and heat to 65°C under a nitrogen atmosphere. o Stir overnight at C. After the reaction is complete, filter, concentrate the reaction solution, and purify by silica gel column chromatography to obtain the target compound 7D (0.28 g, 15%). LC-MS (ESI): m / z = 498.2 [M+H] + .

[0262] Step 3: Using compound 7D (0.28 g, 0.56 mmol) as the starting material, compound 7E (0.19 g, 100%) was synthesized according to the method described in step 5 of Example 3. LC-MS (ESI): m / z = 298.2 [M+H] + .

[0263] Step 4: Dissolve 7E (0.21 g, 0.64 mmol) and pyridine (0.25 g, 3.20 mmol) in dichloromethane (20 mL). Add 7F (0.25 g, 0.96 mmol, synthesized according to the method described in patent WO2024118887) in dichloromethane (5 mL) dropwise under ice bath conditions. After the addition is complete, stir overnight at room temperature. Once the reaction is complete, quench the reaction with saturated sodium bicarbonate solution, followed by extraction. Extract the aqueous phase twice with the organic phase. Dry the combined organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by silica gel column chromatography to obtain the target compound 7G (0.17 g, 52%). LC-MS (ESI): m / z = 520.0 [M+H] + .

[0264] Step 5: Using 7G (170 mg, 0.33 mmol) and 1C (containing 1C-1 and 1C-2) (196 mg, 0.66 mmol) as starting materials, compound 7 was synthesized according to the method in step 3 of Example 1. Compound 7-1 (30 mg, 15%) and compound 7-2 (20 mg, 10%) were further prepared by SFC separation. LC-MS (ESI): m / z = 610.4 [M+H] + .

[0265] HPLC analysis method: Instrument: CAS-05-Prep-SFC-F; Column: AD column; Mobile phase: A for CO2; B for 0.1% NH3•H2O in ethanol and acetonitrile; Flow rate: 125 mL / min; Column temperature: 25℃; Wavelength: 220 nm. Retention time: Compound 7-1: tR = 1.183 min; Compound 7-2: tR = 1.612 min.

[0266] Compound 7-1: 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.84-8.80 (m,1H), 8.79 (s, 1H), 8.43 (d, 1H), 8.29-8.25 (m, 1H), 8.21 (s, 1H), 7.96-7.92(m, 1H), 7.79-7.74 (m, 1H), 7.31-7.26 (m, 1H), 5.80-5.69 (m, 1H), 5.16 (d,1H), 4.19-4.09 (m, 1H), 4.05-3.93 (m, 2H), 3.53-3.37 (m, 4H), 3.32-3.31 (m,1H), 3.30-3.29 (m, 1H), 3.29 (s, 3H), 2.42 (s, 3H).

[0267] Compound 7-2: 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.86-8.82 (m,1H), 8.80 (s, 1H), 8.43 (d, 1H), 8.23-8.18 (m, 1H), 7.98-7.93 (m, 1H), 7.87(s, 1H), 7.79-7.74 (m, 1H), 7.29-7.23 (m, 1H), 5.80-5.69 (m, 1H), 5.13 (d,1H), 4.20-4.03 (m, 2H), 4.03-3.94 (m, 1H), 3.52-3.39 (m, 4H), 3.38-3.31 (m, 2H), 3.29 (s, 3H), 2.49 (s, 3H).

[0268] Example 8:

[0269]

[0270] Step 1: Using compound 8A (400 mg, 1.58 mmol) and compound 8B (325 mg, 1.14 mmol) as starting materials, compound 8C (290 mg, 78.65%) was obtained by following the procedure in Step 2 of Example 6. LC-MS (ESI): m / z = 234.0 [M+H] + .

[0271] Step 2: Using compound 8C (220 mg, 0.94 mmol) and compound 5A (containing 5A-1 and 5A-2) (333 mg, 0.94 mmol) as starting materials, compound 8 (140 mg, 27.24%) was obtained according to the procedure in step 4 of Example 6. Further chiral resolution yielded compound 8-1: 74 mg; compound 8-2: 37 mg. LC-MS (ESI): m / z = 546.2 [M+H] + .

[0272] Analytical methods: Instrument: CAS-05-ANA-SFC-D; Column: IK column; Mobile phase: A is carbon dioxide; B is 0.05% ammonia (ethanol and acetonitrile); Flow rate: 3 mL / min; Column temperature: 35℃; Detection wavelength: 220 nm. Retention time: Compound 8-1: 1.749 min; Compound 8-2: 2.052 min.

[0273] Compound 8-1: 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.82-8.77 (m,1H), 8.76 (s, 1H), 8.32-8.29 (m, 1H), 8.27-8.25 (m, 1H), 8.18 (s, 1H), 7.91-7.87 (m, 1H), 7.82-7.79 (m, 1H), 7.54-7.47 (m, 2H), 7.29-7.22 (m, 1H), 5.16-5.11 (m, 1H), 4.17-4.09 (m, 1H), 4.02-3.95 (m, 2H), 3.78-3.71 (m, 1H), 3.31 (s, 2H), 3.28 (s, 3H), 2.40 (s, 3H), 1.11-1.04 (m, 2H), 1.01-0.94 (m, 2H).

[0274] Compound 8-2: 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.83-8.80 (m,1H), 8.76 (s, 1H), 8.32-8.29 (m, 1H), 8.20-8.17 (m, 1H), 7.91-7.87 (m, 1H),7.84 (s, 1H), 7.82-7.79 (m, 1H), 7.54- 7.47 (m, 2H), 7.26-7.22 (m, 1H), 5.14-5.09 (m, 1H), 4.18-4.04 (m, 2H), 4.02-3.94 (m, 1H), 3.79- 3.70 (m, 1H), 3.37-3.30 (m, 2H), 3.28 (s, 3H), 2.48 (s, 3H), 1.11-1.05 (m, 2H), 1.01-0.95 (m, 2H).

[0275] Example 9:

[0276]

[0277] Step 1: 9A (1.2 g, 5.66 mmol), prepared according to the method described in patent WO2023096850, along with 8A (1.43 g, 5.66 mmol), Pd(dppf)Cl2 (448 mg, 0.56 mmol), and potassium carbonate (2.34 g, 16.98 mmol), were dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (4 mL). The reaction was carried out under a nitrogen atmosphere at 80 °C for 16 h. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the target compound 9B (0.7 g, 48% yield). LC-MS (ESI): m / z = 260.1 [M+H] + .

[0278] Step 2: Using 9B (0.7 g, 2.7 mmol) and 1E (0.87 g, 3.24 mmol) as raw materials, 9C (0.6 g, 46% yield) was obtained following the procedure described in Step 2 of Example 1. LC-MS (ESI): m / z = 482.1 [M+H] + .

[0279] Step 3: Using 9C (0.3 g, 0.62 mmol) and 1C (containing 1C-1 and 1C-2) (0.18 g, 0.62 mmol) as raw materials, compound 9-1 (80 mg, 22%) and compound 9-2 (60 mg, 17%) were obtained by referring to the operation method in step 3 of Example 1.

[0280] SFC separation method: Instrument: CAS-05-Prep-SFC-F, Column: IK column, Mobile phase: A for CO2; B for 0.1% NH3•H2O in methanol and acetonitrile, Flow rate: 130 mL / min, Column temperature: 25℃, Wavelength: 220 nm. Retention time: Compound 9-1: tR = 1.541 min; Compound 9-2: tR = 1.868 min.

[0281] Compound 9-1: LC-MS (ESI): m / z = 572.2 [M+H] + .

[0282] 1 H NMR (400 MHz, CDCl3) δ 8.69-8.68 (m, 1H), 8.53-8.52 (m, 1H), 8.36(s, 1H), 8.31 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.40-7.38 (m, 1H), 7.16-7.12 (m, 1H), 7.07-7.05 (m, 1H), 4.34-4.29 (m, 1H), 4.21-4.16 (m, 4H), 3.45-3.36 (m, 5H), 3.19 (s, 2H), 2.53 (s, 3H), 1.85-1.75 (m, 1H), 0.90 (s, 4H).

[0283] Compound 9-2: LC-MS (ESI): m / z = 572.2 [M+H] + .

[0284] 1H NMR (400 MHz, CDCl3) δ 8.66-8.65 (m, 1H), 8.55-8.53 (m, 1H), 8.32-8.30 (m, 2H), 8.16 (s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.38-7.35 (m, 1H),7.14-7.12 (m, 1H), 7.05-7.03 (m, 1H), 4.30-4.20 (m, 3H), 4.11 (s, 2H), 3.48-3.44 (m, 1H), 3.41 (s, 3H), 3.38-3.35 (m, 1H), 3.17 (s, 2H), 2.54 (s, 3H), 1.47-1.25 (m, 1H), 0.89-0.88 (m, 4H).

[0285] Example 10:

[0286]

[0287] Step 1: Dissolve 10A (5.0 g, 22.28 mmol) in tetrahydrofuran (100 mL), then add triethylamine (6.76 g, 66.84 mmol) and di-tert-butyl dicarbonate (12.16 g, 55.7 mmol) sequentially, stirring until homogeneous. Then add DMAP (0.54 g, 4.46 mmol) and react overnight at room temperature. Concentrate the reaction solution, and purify the crude product by silica gel column chromatography to obtain 10B (7.2 g, 76%).

[0288] 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H), 7.24 (d, 1H), 1.43 (s, 18H).

[0289] Step 2: 10B (1.05 g, 2.47 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the sequential addition of 10C (0.52 g, 2.27 mmol), cesium carbonate (1.2 g, 4.94 mmol), and Ruphos-Pd-G3 (0.41 g, 0.49 mmol). After thorough stirring, the mixture was purged with nitrogen and then heated to 100 °C overnight. After complete reaction, the mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain 10D (0.71 g, 66%). LC-MS (ESI): m / z = 435.1 [M+H] + .

[0290] Step 3: Dissolve 10D (1.0 g, 2.30 mmol) in hydrogen chloride solution (10 mL, 4 M in 1,4-dioxane) and stir at room temperature for 2 hours. Concentrate to remove most of the solvent, add ethyl acetate and saturated sodium bicarbonate aqueous solution, stir and extract, separate the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography to obtain compound 10E (0.7 g, 90%). LC-MS (ESI): m / z = 335.0 [M+H] + .

[0291] Step 4: Using 10E (500 mg, 1.50 mmol) and 1E (403 mg, 1.50 mmol) as starting materials, 10F (620 mg, 74%) was synthesized following the steps in Step 2 of Example 1. LC-MS (ESI): m / z = 557.1 [M+H] + .

[0292] Step 5: Using 10F (300 mg, 0.54 mmol) and 1C (containing 1C-1 and 1C-2) (159 mg, 0.54 mmol) as raw materials, compound 10 (containing two isomers, compound 10-1 and compound 10-2) was synthesized according to the steps in step 3 of Example 1. Subsequently, compound 10-1 (92 mg, 26%) and compound 10-2 (72 mg, 21%) were prepared by SFC.

[0293] SFC separation method: Instrument: CAS-05-Prep-SFC-G, Column: OX column, Mobile phase: A for CO2; B for 0.1% NH3H2O ​​in methanol and acetonitrile, Flow rate: 140 mL / min, Column temperature: 25℃, Wavelength: 220 nm. Retention time: Compound 10⁻¹: tR = 0.955 min; Compound 10⁻²: tR = 1.920 min.

[0294] Compound 10-1: LC-MS (ESI): m / z = 647.2 [M+H] + .

[0295] 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.81-8.78 (m, 1H), 8.72 (s,1H), 8.26-8.23 (m, 1H), 8.18 (s, 1H), 7.82-7.80 (m, 1H), 7.57-7.53 (m, 1H),7.40-7.36 (m, 1H), 7.27-7.24 (m, 1H), 5.17-5.15 (m, 1H), 4.35 (s, 2H), 4.19-4.10 (m, 3H), 4.01-3.94 (m, 2H), 3.62-3.58 (m, 2H), 3.31-3.29 (m, 2H), 3.29 (s, 3H), 2.40 (s, 3H).

[0296] Compound 10⁻²: LC-MS (ESI): m / z = 647.2 [M+H] + .

[0297] 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.83-8.80 (m, 1H), 8.73 (s,1H), 8.18-8.16 (m, 1H), 7.85 (s, 1H), 7.82-7.80 (m, 1H), 7.57-7.53 (m, 1H),7.40-7.36 (m, 1H), 7.26-7.22 (m, 1H), 5.15-5.13 (m, 1H), 4.35 (s, 2H), 4.19-4.13 (m, 3H), 4.11-4.05 (m, 1H), 4.02-3.96 (m, 1H), 3.62-3.58 (m, 2H), 3.37-3.35 (m, 2H), 3.29 (s, 3H), 2.48 (s, 3H).

[0298] Example 11:

[0299]

[0300] Step 1: Compound 11A (1.10 g, 5.01 mmol), cyclopropylamine (0.29 g, 5.01 mmol), and N-methylimidazole (0.82 g, 10.02 mmol) were dissolved sequentially in dichloromethane (25 mL). TCFH (2.81 g, 10.02 mmol) was added in portions. After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was diluted with water, extracted twice with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography to obtain compound 11B (0.72 g, 55%). LC-MS (ESI): m / z = 259.0 [M+H] + .

[0301] Step 2: Compound 11B (0.72 g, 2.77 mmol) was dissolved in methanol (30 mL), followed by the addition of zinc powder (3.62 g, 55.4 mmol) and ammonium chloride (2.96 g, 55.4 mmol). After the addition was complete, the mixture was reacted at room temperature for 2 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 11C (600 mg), which could be used directly in the next step without further purification. LC-MS (ESI): m / z = 229.0 [M+H] + .

[0302] Step 3: Using compound 11C (160 mg, 0.7 mmol) and compound 5A (containing 5A-1 and 5A-2) (0.17 g, 0.47 mmol) as starting materials, compound 11 (containing compounds 11-1 and 11-2) was synthesized according to the method in step 2 of Example 1. Subsequently, compounds 11-1 (30 mg, 11.69%) and 11-2 (31 mg, 12.08%) were prepared by SFC. LC-MS (ESI): m / z = 541.3 [M+H] + .

[0303] Analytical conditions: Instrument name: CAS-05-ANA-SFC-D; Column: C2 column; Mobile phase: A for CO2; B for 0.05% MNH3 in ethanol and acetonitrile; Gradient: B for 50%; Flow rate: 3 mL / min; Column temperature: 35℃; Absorption wavelength: 220 nm. Retention time: Compound 11-1: 0.763 min, Compound 11-2: 1.129 min.

[0304] Compound 11-1: 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.81-8.79 (d,1H), 8.73 (s, 1H), 8.47-8.46 (d, 1H), 8.25-8.24 (d, 1H), 8.19 (s, 1H), 7.79-7.77 (d, 1H), 7.66-7.64 (d, 1H), 7.28-7.25 (m, 1H), 5.16-5.15 (d, 1H), 4.15-4.13 (d, 1H), 4.03-3.97 (m, 2H), 3.32-3.31 (m, 1H), 3.29 (s, 3H), 2.88-2.81 (m, 1H), 2.40 (s, 3H), 2.03-1.95 (m, 1H), 0.73-0.68 (m, 2H), 0.57-0.53 (m, 2H).

[0305] Compound 11-2: 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.83-8.81 (d,1H), 8.74 (s, 1H), 8.47-8.46 (d, 1H), 8.17 (d, 1H), 7.85 (s, 1H), 7.78-7.77(d, 1H), 7.66-7.64 (d, 1H), 7.26-7.24 (m, 1H), 5.14-5.12 (d, 1H), 4.18-4.05(m, 2H), 4.02-3.95(m, 1H), 3.37-3.33 (m, 1H), 3.29 (s, 3H), 2.87-2.81 (m,1H), 2.48 (s, 3H), 2.03-1.95 (m, 1H), 0.73-0.68 (m, 2H), 0.57-0.54 (m, 2H).

[0306] Example 12:

[0307]

[0308] Step 1: Using 10B (5 g, 11.79 mmol) as the starting material, 12A (3.4 g, 70%) was synthesized following the steps in Step 1 of Example 2.

[0309] Step 2: Using 12A (3.4 g, 8.31 mmol) as the starting material, 12B (1.51 g, 87%) was synthesized following the steps in Step 3 of Example 10. LC-MS (ESI): m / z = 210.1 [M+H] + .

[0310] Step 3: Using 12B (292 mg, 1.40 mmol) and 5A (containing 5A-1 and 5A-2) (500 mg, 1.40 mmol) as raw materials, compound 12 (containing two isomers, compound 12-1 and compound 12-2) was synthesized according to the steps of step 2 in Example 1. Subsequently, compound 12-1 (131 mg, 18%) and compound 12-2 (98 mg, 13%) were prepared by SFC.

[0311] SFC separation method: Instrument: CAS-05-Prep-SFC-G, Column: IC column, Mobile phase: A for CO2; B for 0.1% NH3H2O ​​in methanol and acetonitrile, Flow rate: 130 mL / min, Column temperature: 25℃, Wavelength: 220 nm. Retention time: Compound 12-1: tR = 0.845 min; Compound 12-2: tR = 1.178 min.

[0312] Compound 12-1: LC-MS (ESI): m / z = 522.3 [M+H] + .

[0313] 1 H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.82-8.78 (m, 1H), 8.73 (s,1H), 8.26-8.23 (m, 1H), 8.19 (s, 1H), 7.71-7.67 (m, 1H), 7.65-7.60 (d, J =9.1 Hz, 1H), 7.28-7.24 (m, 1H), 5.18-5.14 (m, 1H), 4.19-4.10 (m, 1H), 4.04-3.95 (m, 2H), 3.35-3.30 (m, 2H), 3.29 (s, 3H), 2.41 (s, 3H), 1.66-1.57 (m,1H), 0.97-0.91 (m, 2H), 0.82-0.76 (m, 2H).

[0314] Compound 12-2: LC-MS (ESI): m / z = 522.3 [M+H] + .

[0315] 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.84-8.80 (m, 1H), 8.74 (s,1H), 8.18-8.16 (m, 1H), 7.86 (s, 1H), 7.71-7.67 (m, 1H), 7.65-7.60 (m, 1H),7.28-7.23 (m, 1H), 5.16-5.12 (m, 1H), 4.19-4.04 (m, 2H), 4.03-3.96 (m, 1H),3.38-3.34 (m, 2H), 3.29 (s, 3H), 2.49 (s, 3H), 1.66-1.57 (m, 1H), 0.97-0.91(m, 2H), 0.82-0.77(m, 2H).

[0316] Example 13:

[0317]

[0318] Step 1: Compound 13A (5.0 g, 23.8 mmol), cyclopropylboronic acid (4.10 g, 47.78 mmol), and sodium carbonate (6.33 g, 59.73 mmol) were dissolved sequentially in dichloroethane (100 mL). Then, 2-(2-pyridyl)pyridine (8.21 g, 52.56 mmol) and copper acetate (6.51 g, 35.84 mmol) were added. The mixture was stirred at room temperature for 40 hours under an oxygen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography to obtain 13B (3.4 g, 57%). LC-MS (ESI): m / z = 250.1 [M+H] + .

[0319] Step 2: Using compound 13B (3.0 g, 12.03 mmol) as the starting material, 13C (1.5 g, 83% yield) was synthesized following the steps in Step 5 of Example 3. LC-MS (ESI): m / z = 150.1 [M+H] + .

[0320] Step 3: Using compounds 13C (0.7 g, 4.71 mmol) and 10B (2.0 g, 4.71 mmol) as starting materials, 13D (0.32 g, 17%) was synthesized following the steps in Step 2 of Example 10. LC-MS (ESI): m / z = 393.1 [M+H] + .

[0321] Step 4: Using 13D (0.3 g, 0.74 mmol) as the starting material, 13E (102 mg, yield 44%) was synthesized following the steps in Step 3 of Example 10. LC-MS (ESI): m / z = 293.0 [M+H] + .

[0322] Step 5: Using 13E (102 mg, 0.35 mmol) and 5A (containing 5A-1 and 5A-2) (125 mg, 0.35 mmol) as starting materials, compound 13 (containing two isomers, compound 13-1 and compound 13-2) (122 mg, 58%) was synthesized following the steps in Step 2 of Example 1. Subsequently, compound 13-1 (17 mg, 8%) and compound 13-2 (14 mg, 7%) were prepared by SFC. SFC separation method: Instrument: CAS-05-Prep-SFC-F, Column: IC column, Mobile phase: A for CO2; B for 0.1% NH3H2O ​​in ethanol and acetonitrile, Flow rate: 120 mL / min, Column temperature: 25℃, Wavelength: 220 nm. Retention time: Compound 13-1: tR = 1.015 min; Compound 13-2: tR = 1.381 min.

[0323] Compound 13-1: LC-MS (ESI): m / z = 605.3 [M+H] + .

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.81-8.77 (m, 1H), 8.72 (s,1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.40-7.35 (m, 1H), 7.27-7.22(m, 1H), 7.03-6.98 (m, 1H), 5.17-5.14 (m, 1H), 4.50 (s, 4H), 4.17-4.09 (m,1H), 4.02-3.94 (m, 2H), 3.74-3.66 (m, 1H), 3.31-3.26 (m, 5H), 2.40 (s, 3H), 1.07-1.01 (m, 2H), 0.99-0.92 (m, 2H).

[0325] Compound 13-2: LC-MS (ESI): m / z = 605.4 [M+H] + .

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.83-8.79 (m, 1H), 8.73 (s,1H), 8.18 (s, 1H), 7.84 (s, 1H), 7.62 (s, 1H), 7.41-7.35 (m, 1H), 7.25-7.21(m, 1H), 7.03-6.97 (m, 1H), 5.15-5.11 (m, 1H), 4.50 (s, 4H), 4.21-4.04 (m,2H), 4.03-3.95 (m, 1H), 3.74-3.66 (m, 1H), 3.37-3.32 (m, 2H), 3.29 (s, 3H), 2.48 (s, 3H), 1.07-1.01 (m, 2H), 0.99-092 (m, 2H).

[0327] Biological testing

[0328] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0329] 1. Kit kinase activity test

[0330] The compound was serially diluted using DMSO in a 384 PP Plate compound dilution plate. 0.1 μL of the compound was transferred to each well of a 384-well plate using an Echo 655 microplate, ensuring a final DMSO concentration of 1% (double replicate). 5 μL of 2× kinase solution was added to each well of the 384-well plate, and the plates were centrifuged at 1000 rpm for 1 minute. The plates were incubated at 25°C for 10 minutes. 5 μL of a 2× ATP and TK substrate mixture was added to each well, and the plates were centrifuged at 1000 rpm for 1 minute. The plates were incubated at 25°C for 60 minutes. 10 μL of kinase assay reagent was added to each well, and the plates were centrifuged at 1000 rpm for 1 minute. The plates were incubated at 25°C for 60 minutes. Fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) were read using a BMG (PHERAstar FSX) microplate reader. Wells containing 1% DMSO, enzyme, substrate, and ATP were designated as High Control, while wells containing 1% DMSO, substrate, ATP, and buffer were designated as Low Control. The percentage of inhibition of the compound-treated wells was normalized between High Control and Low Control (%inhibition = 100 * (ave High Control - cpd well) / (ave High Control - ave Low Control)). Data analysis was then performed using GraphPad 8 software, and the IC50 of the compounds was obtained using a nonlinear fitting formula. 50 (Half-maximal inhibitory concentration), IC50 50 This is the compound concentration corresponding to an inhibition rate of 50%.

[0331] The compounds of the present invention, such as those in the examples, have an IC50 of less than 500 nM against c-Kit kinase inhibitory activity. 50 IC50 values ​​for some preferred compounds 50 <500 nM, IC50 of some preferred compounds 50 <200 nM, IC50 of some preferred compounds 50 <100 nM, IC50 of some preferred compounds 50 <50 nM. Experimental results for some specific compounds are shown in Table 1, where A represents IC50. 50 <50 nM; B indicates 50 nM ≤ IC 50 <100nM, C represents 100nM≤IC 50 .

[0332] Table 1. Inhibitory activity of compounds against c-Kit kinase

[0333] compound <![CDATA[EC 50 ]]> compound <![CDATA[EC 50 ]]> Compound 1-1 A Compounds 1-2 A Compounds 1-3 A Compounds 1-4 A Compound 2-1 A Compound 2-2 A Compound 4-1 A Compound 4-2 A Compound 6-1 A Compound 6-2 A Compound 7-1 A Compound 7-2 A Compound 8-1 A Compound 8-2 A Compound 10-1 A Compound 10-2 A Compound 11-1 A Compound 11-2 A Compound 12-1 A Compound 12-2 A Compound 13-1 A Compound 13-2 A

[0334] Conclusion: The compounds of the present invention, such as those in the examples, exhibit high inhibitory activity against c-Kit kinase.

[0335] 2. M-07e cell proliferation experiment

[0336] M-07e cells were cultured to a suitable density in Culture Medium. Both suspension and adherent cells were collected. After washing the cells twice with Seeding Medium, they were counted. A cell suspension was prepared and seeded into 96-well plates according to the seeding conditions in the table below. The plates were incubated overnight at 5% CO2 and 37°C. Ten cell-only wells were also seeded simultaneously, bringing the total volume of the 96-well plate to 100 μL. The Luminescence signal was measured the day after drug addition and used as the signal value without SCF stimulation (average value denoted as Ave_L). 10 µL of hSCF (diluted with Seeding Medium) was added to the cell culture plate to a final concentration of 10 ng / mL. The compound was serially diluted in DMSO, then diluted 1:100 with Seeding Medium (10× working solution), and finally 10 µL was added to the cell culture plate. The final concentration in DMSO was 0.1%, and the plates were incubated at 5% CO2 and 37°C for 72 h. The CellCounting-Lite 2.0 Luminescent Cell Viability Assay reagent (CTG reagent) was equilibrated with the cell culture plate at room temperature for 30 min. After equilibration for 30 min, 100 µL of CTG was added to the cell culture plate and shaken for 2 min. The plate was then incubated at room temperature in the dark for 10 min, and the Luminescence signal value was read using BMG (PHERAstar FSX).

[0337]

[0338] Data analysis calculates the inhibition rate using the following formula, and the absolute IC is calculated by fitting a four-parameter logistic model. 50 value.

[0339] % Inhibition=(Ave_H-Sample) / (Ave_H-Ave_L)*100%.

[0340] in:

[0341] Sample: Sample well reading;

[0342] Ave_L: Average reading of the aperture without SCF stimulation;

[0343] Ave_H: Average value of the DMSO processing aperture readings;

[0344] The IC of the compound is obtained using the following nonlinear fitting formula. 50 (Half-maximal inhibitory concentration):

[0345] Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0346] X: Compound concentration

[0347] Y: Cell inhibition rate (% Inhibition)

[0348] The compounds of the present invention, such as those in the examples, have an IC50 of less than 500 nM against the proliferation inhibitory activity of M-07e cells. 50 IC50 values ​​for some preferred compounds 50 <500 nM, IC50 of some preferred compounds 50 <300 nM, IC50 of some preferred compounds 50 <100 nM, IC50 of some preferred compounds 50 <10 nM. Experimental results for some specific compounds are shown in Table 3, where A represents IC50. 50 <10 nM; B indicates 10 nM ≤ IC 50 <100nM, C represents 100nM≤IC 50 .

[0349] Table 3. Inhibitory activity of compounds on M-07e cell proliferation

[0350] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> Compound 1-1 A Compounds 1-2 A Compounds 1-3 A Compounds 1-4 A Compound 2-1 A Compound 2-2 A Compound 6-1 A Compound 6-2 A Compound 8-1 A Compound 8-2 A Compound 9-1 A Compound 11-1 A Compound 11-2 A Compound 12-1 A Compound 12-2 A Compound 13-1 A Compound 13-2 A

[0351] Conclusion: The compounds of the present invention, such as those in the examples, exhibit high inhibitory activity against the proliferation of M-07e cells.

[0352] 3. Detection of ckit phosphorylation level using ELISA method

[0353] M-07e cells were cultured to a suitable density in Culture Medium. Both suspension and adherent cells were collected. After washing the cells twice with Seeding Medium, they were counted. A cell suspension was prepared and seeded into 96-well plates according to the conditions in the table below. The plates were incubated at 37°C for 1 hour. The compound was serially diluted using DMSO in a dilution plate. 5 μL of the diluted compound (after a second dilution with Seeding Medium) was added to each well, ensuring a final DMSO concentration of 1%. The plates were incubated at 37°C for 1 hour. 5 μL of hSCF (Acro, catalog number SCF-H5219) diluted with Seeding Medium was added to each 96-well plate (final concentration 200 ng / ml). The plates were incubated at 37°C for 2 minutes. The cell pellet was collected by centrifugation at 2000 rpm for 1 minute. 100 μL / well of cell lysis buffer was added to the cell pellet, and the plates were lysed by shaking at 4°C for 40 minutes. The 96-well plates were then centrifuged at 2000 rpm at 4°C for 5 minutes. The intracellular ckit phosphorylation level was then detected using ELISA. 80 μL / well of cell lysate was transferred to a 96-well ELISA plate and incubated at 37°C for 2 hours. The remaining steps were performed according to the PathScan® Phospho-c-Kit (Tyr719) Sandwich ELISA Kit instructions. After adding the stop solution in the final ELISA step, the fluorescence signal at 450 nm was read on a BMG (PHERAstar FSX) microplate reader.

[0354]

[0355] Data analysis calculates the inhibition rate in Excel using the following formula, and then calculates the absolute IC by fitting a four-parameter logistic model. 50 value.

[0356] % Inhibition=(Ave_H-Sample) / (Ave_H-Ave_L)*100%.

[0357] in:

[0358] Sample: Sample well reading;

[0359] Ave_L: Average reading of the aperture without SCF stimulation;

[0360] Ave_H: Average value of the DMSO processing aperture readings;

[0361] The IC of the compound is obtained using the following nonlinear fitting formula. 50 (Half-maximal inhibitory concentration):

[0362] Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0363] X: Compound concentration

[0364] Y: Cell inhibition rate (% Inhibition)

[0365] The compounds of the present invention, such as those in the examples, have an IC50 of less than 500 nM against ckit phosphorylation inhibition in M-07e cells. 50 IC50 values ​​for some preferred compounds 50 <500 nM, IC50 of some preferred compounds 50 <300 nM, IC50 of some preferred compounds 50 <100 nM, IC50 of some preferred compounds 50 <10 nM. Experimental results for some specific compounds are shown in Table 5, where A represents IC50. 50 <10 nM; B indicates that 10 nM ≤ IC 50 <100nM, C represents 100nM≤IC 50 .

[0366] Table 5. Inhibitory activity of compounds against ckit phosphorylation in M-07e cells

[0367] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> Compound 1-1 A Compounds 1-2 A Compounds 1-3 A Compounds 1-4 A Compound 2-1 A Compound 2-2 A Compound 6-1 A Compound 6-2 A Compound 8-1 A Compound 8-2 A Compound 11-1 A Compound 11-2 A Compound 12-1 A Compound 12-2 A Compound 13-1 A Compound 13-2 A

[0368] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibit high inhibitory activity against ckit phosphorylation in M-07e cells.

Claims

1. A compound of formula (Ib), its stereoisomer or pharmaceutically acceptable salt, L1 is selected from -C(=O)NH-, -C(=S)NH-, -C(=Se)NH-, and -CR. a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx; Each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy groups; As an option, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl; R x1 R x2 Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl; Cy1 is selected from C 3-10 cycloalkyl, phenyl, C 7-10 aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally substituted with 1-5 R1 groups, wherein the R1 groups are selected from deuterium, oxoyl, -N=S(=O)-(C 1-6 Alkyl)2、-S(=O)2-C 1-6 Alkyl, -SCF3, -SF5, Cl, F, NH2, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-5 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups; L2 is selected from key, -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, -C(=O)NH-, -NHC(=O)-; Cy2 is selected from C 3-6 The cycloalkyl, 5-10-membered heteroaryl, 5-membered heterocycloalkyl, 6-10-membered heterocycloalkyl, or none thereof, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl group is optionally substituted by 1-5 groups selected from R2, wherein R2 is selected from R, deuterium, halogen, oxo group, NH2, CN, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl groups, -N=S(=O)-(C 1-6 Alkyl)2, -SCF3, -SF5, -S-(C 1-6 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, -S(=O)2-C 1-6 Alkyl, =CH2, =CHF, =CF2, -C(=O)OC 1-6 Alkyl group substitution; When Cy2 is selected from tetrazolium, it may be arbitrarily selected from R, deuterium, halogen, NH2, CN, OH, CH3, C. 1-6 Haloalkyl, C 1-6 Substitution of deuterated alkyl groups; R is selected from C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, C 6-10 aryl, 4-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the cycloalkyl or heteroaryl group is optionally surrounded by 1-5 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Substitution of deuterated alkyl groups; Alternatively, R1 and R2, two R1s on the same atom, two R2s on the same atom, two R1s on different atoms, or two R2s on different atoms and the atoms to which they are attached, together form a 5-8 membered heterocyclic alkyl group or a C-shaped alkyl group. 5-8 Cycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with 1 to 4 groups selected from Rx; The Rx is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl) (C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl groups, 4-8 membered heterocyclic alkyl groups optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 alkylamine group, C 3-6 Cycloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Substituted with alkyl groups; The compound is not selected from the following structures: 。 2. The compound of formula (Ib) according to claim 1, its stereoisomer or pharmaceutically acceptable salt, L1 is selected from -C(=O)NH-, -C(=S)NH-, -C(=Se)NH-, and -CR. a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 1-6 Alkylene, C 2-4 imidene group, C 2-4 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx; Each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy groups; As an option, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl; R x1 R x2 Each is independently selected from hydrogen, deuterium, and C. 1-4 alkyl; Cy1 is selected from C 6-10 cycloalkyl, phenyl, C 7-10 aryl, 6-10-membered heterocyclic alkyl, or 5-10-membered heteroaryl, wherein the phenyl group is optionally substituted with 1-4 R1 groups, wherein the R1 groups are selected from deuterium, oxoyl, -N=S(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, -SCF3, -SF5, Cl, F, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-4 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups; L2 is selected from key, -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -C(=O)NH-, -NHC(=O)-; Cy2 is selected from C 3-6 The cycloalkyl, 5-6-membered heteroaryl, 5-membered heterocycloalkyl, 6-10-membered heterocycloalkyl or absent, wherein the cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1-5 R2 groups, wherein the R2 is selected from R, deuterium, halogen, NH2, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl groups, -N=S(=O)-(C 1-4 Alkyl)2, -SCF3, -SF5, -S-(C 1-4 Alkyl), C 2-4 alkenyl, C 2-4 alkynyl group, -S(=O)2-C 1-4 Alkyl, =CH2, =CHF, =CF2, -C(=O)OC 1-4 Alkyl groups are substituted; when Cy2 is selected from tetrazolium, it is optionally selected from R, deuterium, halogen, NH2, CN, OH, CH3, C. 1-4 Haloalkyl, C 1-4 Substitution of deuterated alkyl groups; R is selected from C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, C 6-10 aryl, 4-10-membered heterocyclic alkyl or 5-6-membered heteroaryl, wherein the cycloalkyl or heteroaryl group is optionally surrounded by 1-5 groups selected from halogen, oxo group, NH2, CN, OH, =CH2, =CHF, =CF2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Substitution of deuterated alkyl groups; Alternatively, R1 and R2, two R1s on the same atom, two R2s on the same atom, two R1s on different atoms, or two R2s on different atoms and the atoms to which they are attached, together form a 5-8 membered heterocyclic alkyl group or a C-shaped alkyl group. 5-8 Cycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally substituted with 1 to 4 groups selected from Rx.

3. The compound according to claim 2, wherein its stereoisomer or pharmaceutically acceptable salt, Cy1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , The substance can be optionally replaced by 1-4 R1s, wherein the R1s are selected from deuterium, halogens, COOH, and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-4 alkenyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Substitution of deuterated alkoxy or aziridine groups; Or Cy1 is selected from The substance can be optionally replaced by 1-4 R1s, wherein the R1s are selected from deuterium, Cl, F, COOH, and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, C 2-4 alkenyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 1-2 Deuterated alkoxy, nitrogen-containing heterocyclic butyl, -N=S(=O)-(C 1-4 Alkyl)2, -SCF3, -SF5, -S-(C 1-6 Alkyl), C 2-4 alkynyl group, -S(=O)2-C 1-4 Substitution of alkyl, =CH2, =CHF, =CF2 groups; Cy2 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Alternatively, it may not exist, but may be optionally substituted with 1-4 R2 groups, wherein the R2 is selected from R, deuterium, halogen, NH2, CN, OH, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Deuterated alkyl, -C(=O)OC 1-2 Alkyl group substitution; Or Cy2 is selected from The elements selected are R, deuterium, halogen, NH2, CN, OH, CH3, and C. 1-2 Haloalkyl, C 1-2 Substitution of deuterated alkyl groups; R is selected from , , , , ; As an option, Selected from the following structures, which are optionally substituted with 1 to 4 groups selected from Rx: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

4. The compound according to claim 1, wherein its stereoisomer or pharmaceutically acceptable salt has the structure of formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9). Cy1' is selected from the following groups that are substituted with 1 to 4 R1 groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Cy2' is selected from any of the following groups substituted with 1 to 4 R2 groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Cy3 is selected from the following structures that are optionally substituted with 1 to 4 groups selected from Rx: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; L 1’ Selected from -C(=S)NH-, -C(=Se)NH-, -CR a R b NH-, -CR a R b C(=O)NH-, -S(=O)2NH-, -CR a R b -, -NHS(=O)2-, -NHC(=O)NH-, -NHC(=O)O-, -C(=O)NHCR a R b -、-C(=O)NHS(=O)2-、C 2-4 imidene group, C 2-4 The alkylene group, alkenylene group, or alkynylene group may optionally be substituted with 1 to 5 groups selected from Rx; Each R a R b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy groups; As an option, R a R b Together with the atoms they are attached to, they form C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl; R x1 Selected from hydrogen, R x2 Selected from methyl; or R x1 Selected from methyl, R x2 Selected from hydrogen; L 2’ Selected from -CONHSO2-, -NR a -, -O-, -C(=O), -NHC(=O)O-,C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, -C(=O)NH-, -NHC(=O)-; R 1’ Selected from deuterium, oxo group, -N=S(=O)-(C 1-4 Alkyl)2、-S(=O)2-C 1-4 Alkyl, -SCF3, -SF5, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 The cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with 1-4 groups selected from deuterium, halogen, oxo group, NH2, CN, OH, COOH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Substitution with deuterated alkoxy or 4-6 membered heterocyclic alkyl groups; X1 is selected from N; m is selected from any integer between 0 and 5; q is selected from 3 or 4.

5. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures in Table 1 or Table 2.

6. A pharmaceutical composition comprising the compound of any one of claims 1-5 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

7. Use of the compound of any one of claims 1-5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the composition of claim 6, in the preparation of a medicament for the treatment / prevention of c-Kit-mediated diseases.

8. The use according to claim 7, wherein the c-Kit-mediated disease is selected from systemic mastocytosis, urticaria, and asthma.

9. A pharmaceutical composition or pharmaceutical preparation comprising 1-1500 mg of the compound of any one of claims 1-5 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

10. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-5 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, preferably 1-1500 mg, wherein the disease is selected from systemic mastocytosis, urticaria, and asthma.

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