Aryl-fused compounds and use thereof

Abstract

Provided are aryl-fused compounds and the use thereof, belonging to the technical fields of chemistry and medicine. Particularly provided are aryl-fused compounds represented by formula I and the use thereof. Said compounds can target the RIPK1 enzyme, have the advantages of high activity and high selectivity, and also have excellent pharmacokinetic properties, thereby providing a pathway for the prevention and treatment of RIPK1 kinase-related diseases.

Description

Para-aryls and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of chemical medicine technology, and specifically relates to a para-aryl compound and uses thereof. BACKGROUND

[0002] Receptor-interacting protein kinases (RIPKs) are a group of threonine / serine protein kinases that play an important role in the regulation of innate immune signals, have a relatively conserved kinase domain, but have different non-kinase regions. The RIPK family contains seven members, which have different functional domains, but all share a homologous serine-threonine kinase domain with a catalytic site, in addition to RIPK2 which also has an additional tyrosine kinase activity. Currently, RIPK1, RIPK3 and mixed lineage kinase domain-like protein (MLKL) have been widely recognized as key therapeutic targets of necrotic machinery. Among the RIPK kinases, RIPK1 has become a pleiotropic regulator of inflammatory responses, which acts to directly modulate intracellular inflammatory signaling pathways or cause apoptosis or necrosis. RIPK1 is the first discovered member of the family and is also the one with more in-depth biological activity research in the family. RIPK1 can lead to the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-B (NF-κB) and is a key mediator of several signaling pathways leading to cell death. RIPK1 is composed of a carboxy-terminal death domain (DD), an amino-terminal kinase domain and an intermediate domain (ID) bridging the two. The ID structure contains a RIP homotypic interaction motif (RHIM). The DD domain of RIPK1 mediates direct binding to death receptors of the TNF receptor superfamily (including TNFR1, Fas and TRAIL) and to adaptor proteins (such as FADD or TRADD). After binding, an oligomeric protein complex can be formed which can regulate survival or cell death.

[0003] In TNF-stimulated cells, RIPK1 kinase executes pro-cell death and pro-inflammatory activities by activating RIPK1-dependent apoptosis and necrosis, which in turn affect TNF-induced intestinal epithelial cell death mechanisms. For example: TNF is one of the numerous genes implicated in the pathogenesis of NF-κB-stimulated inflammatory bowel disease (IBD), which encodes the prototypical inflammatory cytokine tumor necrosis factor, is a major pathogenic factor and therapeutic target for IBD. In addition, NF-κB signaling responds to a wide range of inflammatory and pro-death stimuli in human diseases, and its K63 ubiquitination modification process can inhibit cell death during embryonic development and inflammation by regulating the kinase activity of RIPK1, RIPK1 is a major regulator of NF-κB signaling and cell death response determinants. When multiple proteins encoding RIPK1 and regulating RIPK1 signal are genetically mutated, it can cause immune and autoimmune inflammatory diseases. These clinically identified mutations highlight the important role of RIPK1 in regulating innate immune responses and provide mechanistic insights into the functional role of RIPK1 in disease. In addition, in addition to its role downstream of TNF receptor 1, RIPK1 has been shown to be a key driver of inflammation downstream of various other pathways (FasL, TRAIL, TLR3 and TLR4).

[0004] Therefore, inhibiting RIP1 activation can have broad therapeutic potential for a variety of inflammatory diseases, and is a small molecule drug that can replace anti-tumor necrosis factor antibodies, and is suitable for treating tumor necrosis factor-driven autoimmune diseases. SUMMARY

[0005] The purpose of the present application is to provide a class of aryl compounds and uses thereof, which can be used as RIPK1 targeting compounds to achieve high selectivity, high efficiency in preventing or treating diseases related to the function of RIPK1.

[0006] In a first aspect, the present application provides a compound represented by formula I or a pharmaceutically acceptable form thereof, and the structure of formula I is as follows:

[0007] Wherein:

[0008] represents a single bond or a double bond represents a single bond or a double bond, which is determined by the groups of X1, X2, X3, Y1, Y2, Y3, Y4;

[0009] X1is selected from CR 3a or N, X2is selected from CR 3b or N, X3is selected from CR 3c or N;

[0010] R3a R 3b and R 3c It can be independently selected from hydrogen or halogen;

[0011] Y1 and Y2 are independently selected from C or N, and when one is N, the other is C (i.e., both Y1 and Y2 are C, or one is C and the other is N);

[0012] Y3 is selected from -CR 4a -、-C(O)-、-C(R 4b R 4c) -、-C(R 4b R 4c) C(R 4d R 4e) -、-C(R 4b R 4c) O-、-OC(R 4d R 4e) -、-NR 4f -Or N (the left key is connected to Y2, and the right key is connected to Y4);

[0013] Y4 is selected from -CR 5a -、-C(O)-、-C(R 5b R 5c) -、-C(R 5b R 5c) C(R 5d R 5e) -、-C(R 5b R 5c) O-、-OC(R 5d R 5e) -、-NR 5f -Or N (the left key is connected to Y3, and the right key is connected to Z);

[0014] R 4a and R 5a Independently selected from hydrogen, deuterium, halogen, 3-6 membered cycloalkyl, or C substituted with 0-3 substituents. 1-4 Alkyl; R 4a and R 5a In this context, the substituent is selected from hydrogen, deuterium, cyano, hydroxyl, amino, or halogen;

[0015] R 4b R 4c R 4d R 4e R 5b R 5c R 5d and R 5e Independently selected from hydrogen, deuterium, fluorine, 3-6 membered cycloalkyl groups, or C groups substituted with 0-3 substituents. 1-4 Alkyl; R4b , R 4c , R 4d , R 4e , R 5b , R 5c , R 5d and R 5e , wherein the substituents are selected from hydrogen, deuterium, or fluorine; or, R 4b and R 4c form, together with the atom to which they are attached, a 3-4 membered cycloalkyl;

[0016] R 4f and R 5f are independently selected from 3-6 membered cycloalkyl or C 1-4 alkyl substituted with 0-3 substituents selected from hydrogen, deuterium, or fluorine; 4f and R 5f , wherein the substituents are selected from hydrogen, deuterium, or fluorine;

[0017] Z is selected from C or N (Z is C or N, depending on the groups of X1, X2, X3, Y1, Y2, Y3, Y4);

[0018] R1is selected from hydrogen, deuterium, halogen, cyano, -N(R 6a R 6b ), -CON(R 6a R 6b ), -OR 6a , -SR 6a , -COR 6b , -COOR 6b , -NR 6a COR 6b , -NHCON(R 6a R 6b ), -SO2R 6a , -SO2N(R 6a R 6b ), or the following groups substituted with 0-6 substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered spirocycloalkyl, 5-10 membered heterospriocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; in R1, the substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4Fluoroalkoxy or 3-4 membered cycloalkyl; in R1, the 3-6 membered heterocycloalkyl, 5-10 membered heterospirocycloalkyl, 6-10 membered heterobridged cycloalkyl, and 5-10 membered heteroaryl contain 1-3 heteroatoms selected from at least one of N, S, and O;

[0019] R 6a and R 6b Independently selected from hydrogen, deuterium, or the following groups substituted with 0 to 6 substituents: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 Alkyne, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl; R 6a and R 6b In this context, the substituents are selected from: deuterium, halogens, -OH, -NH2, -CN, C. 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy or 3- to 4-membered cycloalkyl; R 6a and R 6b In this context, the 4-6 membered heterocyclic alkyl or 5-10 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S, and O;

[0020] Ring A is selected from 5-10 membered heteroaromatic rings or 5-10 membered heteroaromatic rings; in ring A, the 5-10 membered heteroaromatic ring or 5-10 membered heteroaromatic ring contains 1 to 4 heteroatoms selected from at least one of N, S, and O;

[0021] L is selected from or (In these structures, the bonds at the NH, N, and O ends are connected to the main cyclic acyl group, and the bonds at the other end are connected to the ring B).

[0022] R 7a and R 7b Independently selected from hydrogen, deuterium, or C atoms substituted with 0-3 substituents. 1-4 Alkyl; R 7a and R 7b In this context, the substituent is selected from deuterium, halogen, hydroxyl, or amino groups;

[0023] R 7c C is selected from hydrogen, deuterium, fluorine, cyano, hydroxyl, amino, or C groups substituted with 0-3 substituents. 1-4 Alkyl; R 7c In this context, the substituent is selected from deuterium, halogen, hydroxyl, or amino groups;

[0024] Ring B is selected from a phenyl ring or a 5-10 membered heteroaromatic ring; in Ring B, the 5-10 membered heteroaromatic ring contains 1-3 heteroatoms selected from at least one of N, S, O;

[0025] R2is selected from hydrogen, deuterium, halogen, cyano, amino, or the following groups substituted with 0-3 substituents: C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; in Ring B, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S, O;

[0026] n1is selected from 0, 1, 2, 3, 4, 5, or 6;

[0027] n2is selected from 0, 1, 2, 3, 4, 5, or 6;

[0028] n3is selected from 0, 1, 2, 3, 4, 5, or 6;

[0029] n4is selected from 0, 1, 2, or 3;

[0030] the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitroxide, isotopically labeled, metabolite, or prodrug.

[0031] In some embodiments of the application, R 4a and R 5a are independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, fluorinated methyl, or cyclopropyl;

[0032] R 4b , R 4c , R 4d , R 4e , R 5b , R 5c , R 5d , and R 5e are independently selected from hydrogen, deuterium, fluorine, chlorine, deuterated methyl, fluorinated methyl, or cyclopropyl; or, R 4b and R 4c form a cyclopropyl ring with the atom to which they are attached;

[0033] R 4f and R 5f are independently selected from hydrogen, deuterium, methyl, deuterated methyl, fluorinated methyl, or cyclopropyl.

[0034] In some embodiments of the application, at most one of X1, X2, X3is selected from N, R 4a , R 4b , and R4c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, fluorinated methyl, or cyclopropyl.

[0035] In some preferred embodiments of the application, the structural unit is selected from the following groups: or (these structures, the left end of the bond with the main ring alkyne, the right end of the bond with the main ring acyl group).

[0036] In some more preferred embodiments of the application, the structural unit is selected from the following groups: or (these structures, the left end of the bond with the main ring alkyne, the right end of the bond with the main ring acyl group).

[0037] In some embodiments of the application, R1is selected from hydrogen, deuterium, halogen, cyano, -NHR 6a , -OR 6a , -COR 6b , -NHCOR 6b , -NHCONHR 6a or the following groups substituted with 0-6 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, or 4-6 membered oxacycloalkyl; in R1, the substituents are selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl;

[0038] R 6a and R 6b are independently selected from hydrogen, deuterium, or the following groups substituted with 0-3 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered oxacycloalkyl, phenyl, or 5-6 membered heteroaryl; in R 6a and R 6b , the substituents are selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl; in R 6a and R 6b , the 5-6 membered heteroaryl contains 1-2 N heteroatoms.

[0039] In some preferred embodiments of the application, R1is selected from hydrogen, deuterium, halogen, cyano, -NHR 6a , -OR 6a , -COR 6b , -NHCOR 6b , -NHCONHR 6a or the following groups which are substituted with 0-3 substituents: methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, or oxetanyl; in R1, the substituents are selected from deuterium, fluorine, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy, fluoromethoxy, or cyclopropyl;

[0040] R 6a and R 6b are independently selected from hydrogen, deuterium, or the following groups which are substituted with 0-3 substituents: methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, oxetanyl, phenyl, or R 6a and R 6b , the substituents are selected from deuterium, fluorine, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy, fluoromethoxy, or cyclopropyl.

[0041] In some more preferred embodiments of the application, R1is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, deuterated methyl, fluorinated methyl, methoxy, deuterated methoxy, fluorinated methoxy, ethyl, cyclopropyl, cyclobutyl, oxetanyl, -NH2, or

[0042] In some embodiments of the application, ring A is selected from the following groups: or (wave line bond in ring A is connected to the main ring alkyne, and R1is attached to other positions on ring A);

[0043] R 8a and R 8b are independently selected from hydrogen, deuterium, -CON(R 9a R 9b ), -COR 9b , -COOR 9b or the following groups which are substituted with 0-6 substituents: C 1-6alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered spiro cycloalkyl, 5-10 membered hetero spiro cycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered hetero bridged cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; R 8a and R 8b wherein the substituents are selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl; R 8a and R 8b wherein the 3-6 membered heterocycloalkyl, 5-10 membered hetero spiro cycloalkyl, 6-10 membered hetero bridged cycloalkyl, 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, S, O;

[0044] R 9b is selected from the group consisting of hydrogen, deuterium, or the following group substituted with 0-3 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl; R 9b wherein the substituents are selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl; R 9b wherein the 4-6 membered heterocycloalkyl or 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, S, O.

[0045] In some preferred embodiments of the present application, R 8a and R 8b are independently selected from the group consisting of hydrogen, deuterium, -COR 9b or the following group substituted with 0-3 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, or 4-6 membered oxacycloalkyl; R 8a and R 8b wherein the substituents are selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl;

[0046] R 9b is selected from the group consisting of hydrogen, deuterium, or the following group substituted with 0-3 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered oxacycloalkyl, or phenyl; R9b In some embodiments, the substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3- to 4-membered cycloalkyl.

[0047] In some more preferred embodiments of the application, R 8a and R 8b are independently selected from hydrogen, deuterium, -COR 9b or the following groups substituted with 0-3 substituents: methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, or oxetanyl; R 8a and R 8b In some embodiments, the substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy, fluoromethoxy, or cyclopropyl.

[0048] R 9b is selected from hydrogen, deuterium, or the following groups substituted with 0-3 substituents: methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, oxetanyl, phenyl, or R 9b In some embodiments, the substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, methoxy, fluoromethoxy, or cyclopropyl.

[0049] In some most preferred embodiments of the application, R 8a and R 8b are independently selected from hydrogen, deuterium, methyl, fluoromethyl, deuteromethyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, oxetanyl, or

[0050] In some embodiments of the application, the structural unit is selected from the following groups: or

[0051] In some embodiments of the application, R 7a and R 7b are independently selected from hydrogen, deuterium, methyl, deuteromethyl, fluoromethyl, or hydroxymethyl; n3 is selected from 0, 1, 2, or 3; n4 is selected from 1.

[0052] In some preferred embodiments of the application, L is selected from or (these structural units, the bond at the left end is connected to the main ring alkyne, the bond at the right end is connected to the main ring acyl group).

[0053] In some embodiments of the application, n1 is selected from 0, 1, 2 or 3; n2 is selected from 0, 1, 2 or 3.

[0054] In some embodiments of the application, ring B is selected from a benzene ring, a pyridine ring or a pyrazine ring; R2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, amino, methyl, fluoromethyl, deuteromethyl, methoxy, fluoromethoxy, deuteromethoxy, thiomethyl or fluorothiomethyl.

[0055] In some preferred embodiments of the application, the structural unit is selected from the following groups: or

[0056] The application also provides some specific compounds of the above-mentioned formula I, which are selected from: or In some embodiments of the application, the structural unit is selected from the following groups: …… is also selected from the following groups: or (these structures, the bond at the left end is connected to the main ring alkyne, the bond at the right end is connected to the main ring acyl group).

[0057] In some preferred embodiments of the application, the structural unit is selected from the following groups: …… is also selected from the following groups: or (these structures, the bond at the left end is connected to the main ring alkyne, the bond at the right end is connected to the main ring acyl group).

[0058] In some embodiments of the application, R1 is selected from hydrogen, deuterium, fluorine, chlorine, cyano…… in addition to the above-mentioned

[0059] In some embodiments of the application, ring A is selected from the above-mentioned … , and ring A is also selected from the group consisting of: or (in ring A, the bond of the wavy line is connected to the main ring alkyne group, and R1is connected to other position of ring A).

[0060] In some embodiments of the present application, the structural unit is selected from the group consisting of: … , and ring A is also selected from the group consisting of: or

[0061] In some embodiments of the present application, R 7a and R 7b are independently selected from the group consisting of hydrogen, deuterium, methyl, deuterated methyl, fluorinated methyl, or hydroxymethyl, in addition to being independently selected from the group consisting of ethyl, cyclopropyl, or R 7a and R 7b are independently selected from the group consisting of ethyl, cyclopropyl, or R 7a and R 7b are connected to form a cyclopropane.

[0062] In some preferred embodiments of the present application, L is selected from the group consisting of: … , in addition to being selected from the group consisting of: or (in these structural units, the bond at the NH, N, and O end is connected to the main ring acyl group, and the bond at the other end is connected to ring B).

[0063] In some embodiments of the present application, ring B is selected from the group consisting of a benzene ring, a pyridine ring, or a pyrazine ring, in addition to being selected from a thiazole ring.

[0064] In some preferred embodiments of the present application, the structural unit is selected from the group consisting of: … , in addition to being selected from the group consisting of: or

[0065] The present application also provides some specific compounds of the above-mentioned formula I, which are selected from the group consisting of: or

[0066] In some embodiments of the application, the structural unit In addition to being selected from the above In addition to being selected from the above In addition to being selected from the above In addition to being selected from the above In addition to being selected from the above In addition to being selected from the above

[0067] In some embodiments of the application, the structural unit In addition to being selected from the above In addition to being selected from the above In addition to being selected from the above In addition to being selected from the above In addition to being selected from the above

[0068] The present application also provides some specific compounds of the above Formula I, which are selected from: The present application also provides some specific compounds of the above Formula I, which are selected from:

[0069] In a second aspect, the present application provides a pharmaceutical composition comprising a compound of the above Formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopically-labeled, metabolite, or prodrug thereof, as an active ingredient in association with a pharmaceutically acceptable carrier.

[0070] It is a further object of the present application to provide a method of preparing the pharmaceutical composition of the present application, which comprises combining any of the compounds of Formula I, or a pharmaceutically acceptable form thereof, or mixtures thereof, with one or more pharmaceutically acceptable carriers.

[0071] The pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present application are pharmaceutically acceptable carriers, and examples of suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (2005).

[0072] In a third aspect, the present application provides the use of a compound of the above Formula I, and related specific compounds, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present application, for the manufacture of a RIPK1 inhibitor.

[0073] The present application provides the use of a compound of Formula I, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for preventing and / or treating a RIPK1 kinase related disease.

[0074] The present application provides a method for preventing or treating a RIPK1 kinase related disease, comprising administering to an individual in need thereof a compound of Formula I, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present application.

[0075] The present application provides a compound of Formula I, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present application, for use in preventing or treating a RIPK1 kinase related disease.

[0076] The present application provides a method of using a compound of Formula I, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present application, in combination with another therapeutic method, including but not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof, for preventing or treating a RIPK1 kinase related disease.

[0077] In some embodiments, the use described above, the RIPK1 kinase related disease is a disease sensitive or responsive to RIPK1 enzyme inhibition.

[0078] In some embodiments, the use described above, the RIPK1 kinase related disease is an inflammatory disease, an immune disease, a nervous system disease, or a tumor.

[0079] In some preferred embodiments, the use described above, the RIPK1 kinase related disease is amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, Parkinson's disease, spinal muscular atrophy, stroke, human immunodeficiency virus associated dementia, autism, schizophrenia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic onset juvenile idiopathic arthritis, psoriasis, dermatitis, systemic lupus erythematosus, systemic inflammatory response syndrome, pancreatitis, encephalitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, ulcerative colitis, Crohn's disease, retinal degenerative disease, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, Sjogren's syndrome, systemic scleroderma, solid organ ischemia-reperfusion injury, cerebral ischemia, ischemic heart disease, acute kidney injury, ischemic brain injury, sepsis, diabetes, or atherosclerosis.

[0080] In some preferred embodiments, in the above uses, the RIPK1 kinase-related disease is leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, renal cancer, nasopharyngeal carcinoma, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestinal cancer, gallbladder cancer, pediatric tumor, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor, or myeloma.

[0081] Advantages of the present application:

[0082] The present application provides a class of biaryl compounds and uses thereof, which can be used as high-activity and high-selectivity RIPK1 kinase inhibitors, and can achieve at least one of the following technical effects: (1) significant inhibition of RIPK1 kinase; (2) selective inhibition of RIPK1 kinase; (3) excellent inhibition of necrosis of human HT29 cells and mouse L929 cells; (4) excellent pharmacokinetic properties (such as good bioavailability, appropriate half-life and duration of action); (5) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0083] Definitions of terms:

[0084] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terms "comprising," "comprises," "including," "includes" or "having," "has" and "containing," "contains" and other variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Those skilled in the art will appreciate that terms such as "comprising" are to be construed as encompassing "consisting of."

[0085] In the present application, "a", "an", "the", "at least one", and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

[0086] When a range of values is disclosed, any value or subrange within that range is specifically included as is any range encompassed therein. In particular, each range of values of the values disclosed herein (in the form "about a to b", or equivalently, "approximately a to b", or equivalently, "about a-b") is to be construed as indicating each individual value and range within the broader range.

[0087] For example, the expression "C 1-4 " is to be understood as encompassing any sub-range therein and each individual value, such as C 2-4 , C 3-4 , C 1-2 , C 1-3 , C 1-4 , etc., as well as C1, C2, C3, C4, etc. For another example, the expression "6-10 membered" is to be understood as encompassing any sub-range therein and each individual value, such as 6-7 membered, 6-8 membered, 6-7 membered, etc., as well as 6, 7, 8, 9, 10 membered, etc.

[0088] In the present application, unless otherwise indicated, halogen means fluorine, chlorine, bromine or iodine.

[0089] In the present application, unless otherwise indicated, "alkyl" includes straight-chain or branched-chain monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, isopropyl, n-butyl, t-butyl, 2-pentyl, neopentyl, n-hexyl, 2-methylpentyl, etc. Similarly, "C 1-4 " in "C 1-4 " means a straight-chain or branched-chain group containing 1, 2, 3 or 4 carbon atoms.

[0090] In the present application, unless otherwise indicated, "cycloalkyl" means saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon groups. Common cycloalkyl groups include, but are not limited to, monocyclic cycloalkyl groups such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.; or bicyclic cycloalkyl groups including fused, bridged or spirocyclic groups such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, decahydronaphthyl, etc. For example, "3-12 membered cycloalkyl" means a cycloalkyl group having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12).

[0091] In the present application, unless otherwise indicated, "heterocycloalkyl" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged, or spirocyclic) non-aromatic radical whose ring atoms are composed of carbon atoms and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl group can be attached to the remainder of the molecule through any one of the ring atoms, if valence requirements are met. For example, "3-8 membered heterocycloalkyl" refers to a heterocycloalkyl group having 3 to 8 ring atoms. Common heterocycloalkyl groups include, but are not limited to, oxiranyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, sulfolanyl, and the like.

[0092] In the present application, unless otherwise indicated, "haloalkyl" refers to an alkyl group as described above in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C1-6haloalkyl" refers to a C1-6alkyl group as described above in which one or more hydrogen atoms are replaced by a halogen. Examples of haloalkyl groups include, for example, -CH2F, -CHF2, -CF3, -CC13, -C2F5, -C2C15, -CH2CF3, -CH2C1, or -CH2CH2CF3, and the like. 1-6 In the present application, unless otherwise indicated, "haloalkyl" refers to an alkyl group as described above in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C 1-6 In the present application, unless otherwise indicated, "haloalkyl" refers to an alkyl group as described above in which one or more hydrogen atoms are replaced by a halogen. For example, the term "C

[0093] In the present application, unless otherwise indicated, "aryl" or "aromatic ring" refers to a fully carbon monocyclic or fused polycyclic (such as bicyclic) aromatic radical or aromatic ring having a conjugated pi-electron system. As used herein, the term "6-10 membered aryl" refers to an aromatic radical containing 6-10 carbon atoms. Examples thereof include, but are not limited to, phenyl and naphthyl, and the like.

[0094] In the present application, unless otherwise indicated, "heteroaryl" or "heteroaromatic ring" refers to an aromatic ring having a conjugated pi-electron system in which one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P, and S, with the remaining ring atoms being C. A heteroaryl or heteroaromatic ring can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, in particular, 5, 6, 9, 10 ring atoms. Examples of heteroaryl groups are, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like; the term also encompasses the case where the heteroaryl or heteroaromatic ring can be optionally further fused to an aryl, or heteroaryl ring, forming a fused ring.

[0095] In the present application, unless otherwise indicated, "substituted" means that one or more hydrogen atoms on the designated atom is replaced with the same or different substituent. Typical substituents include, but are not limited to, halogen (F, Cl, Br, or I), hydroxyl, amine, C 1-8 alkyl, C 3-7 cycloalkyl, -OR', -SR', =0, =S, -C(O)R', -C(S)R', =NR', -C(O)OR', -C(S)OR', -NR'R", -C(O)NR'R", cyano, nitro, -S(O)2R', -O-S(O)2OR', -O-S(O)2R', -OP(O)(OR')(OR"); wherein R' and R" are independently selected from -H, C 1-8 alkyl, C 1-8 haloalkyl.

[0096] The present application also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present application include, but are not limited to, isotopes of hydrogen, such as deuterium ( 2 H), tritium ( 3 H); isotopes of carbon, such as 13 C and 14 C); isotopes of chlorine, such as 37 Cl); isotopes of iodine, such as 125 I); isotopes of nitrogen, such as 13 N and 15 N); isotopes of oxygen, such as 17 O and 18 O); isotopes of phosphorus, such as 32 P); and isotopes of sulfur, such as 34 S).

[0097] In the present application, "polymorph" refers to the different solid crystalline phases of certain compounds of the present application that exist in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present application can exist in more than one crystalline form, and the present application is intended to encompass all such polymorphs and mixtures thereof. In general, the process of crystallization results in the formation of solvates of the compounds of the present application. The term "solvate" as used herein refers to an aggregate that comprises one or more molecules of a compound of the present application with one or more molecules of solvent. The solvent can be water, in which case the solvate is a hydrate, or an organic solvent. Thus, the compounds of the present application can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesqui-hydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms.

[0098] In the present application, "stereoisomer" means isomers that result from the presence of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can give rise to racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. Particular individual molecules can also exist as geometric isomers (cis / trans).

[0099] In the present application, pharmaceutically acceptable salts include both acid and base addition salts. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. A review of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). "Pharmaceutically acceptable acid addition salt" means a salt formed by combination of an acid with the free base of the compound of the present application that retains the biological effectiveness of the free base and does not impart undesired toxicological effects to the compound. "Pharmaceutically acceptable base addition salt" means a salt formed by combination of an inorganic or organic base with the free acid of the compound of the present application that retains the biological effectiveness of the free acid and does not impart undesired toxicological effects to the compound.

[0100] In the present application, unless otherwise indicated, "ester" means an ester derived by acylation of a compound described herein, including physiologically hydrolysable esters (which can be hydrolyzed under physiological conditions to release the compound of the present application in free acid or alcohol form). The compounds of the present application can also be esters themselves.

[0101] The compounds of the present application can exist in solvate (preferably hydrate) form, wherein the compound of the present application contains a polar solvent, particularly, for example, water, methanol or ethanol, as a structural element of the crystal lattice of said compound. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric amounts.

[0102] Not all nitrogen-containing heterocycles are capable of forming nitroxides because nitrogen requires an available lone pair of electrons to oxidize to an oxide. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitroxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitroxides. Synthetic methods for preparing nitroxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of the heterocycle or tertiary amine with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0103] In the present application, "metabolite" refers to a substance formed in vivo upon administration of a compound of the present application. Metabolic products of the compounds can be identified by techniques known to those skilled in the art, and their activity can be characterized by methods known in the art. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like of the administered compound. Accordingly, the present application includes metabolites of compounds of the present application, made by a process comprising contacting a compound of the present application with a mammal sufficient to yield a metabolic product thereof.

[0104] In the present application, "prodrug" refers to certain derivatives of compounds of the present application that, when administered into or onto the body, are converted to compounds of the present application having the desired activity, for example, by hydrolytic cleavage. Such prodrugs are typically designed to improve the delivery of the active compound to the desired location within the body. For example, prodrugs can be designed to increase the half-life of the active compound, to improve its solubility, or to improve its transport across the blood-brain barrier.

[0105] In the present application, "pharmaceutical composition" refers to a preparation of a compound of the present application with a medium that is generally accepted in the art for the delivery of a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to the body, to facilitate absorption of the active ingredient, and to thereby render the active ingredient biologically active.

[0106] In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any intragastrically acceptable adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surface-active, wetting, dispersing, suspending, stabilizing agent, isotonic agent, solvent, or emulsor that is approved by a regulatory agency of the Federal or a state government of the relevant art for use in humans or animals.

[0107] The terms "pharmaceutical combination," "pharmaceutical combinations," "combination," "co-administration," "co-administering," and the like as used herein refer to the association of more than one active ingredient in the treatment of a disease, which includes fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one compound described herein and at least one co-agent are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that at least one compound described herein and at least one co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time periods. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.

[0108] In the present invention, "treatment" means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, unless otherwise indicated.

[0109] The above-mentioned preferred conditions can be combined in any way, without departing from the scope of the present invention, to provide various preferred embodiments of the present invention. BRIEF DESCRIPTION OF DRAWINGS

[0110] Figure 1 is a graph showing the results of measuring the inflammatory factor IL-6 in a TNFα-induced SIRS model of mice after administration of compound 1.

[0111] Figure 2 is a graph showing the results of measuring the inflammatory factor IL-6 in a TNFα-induced SIRS model of mice after administration of compound 51.

[0112] Figure 3 is a graph showing the body weight changes of EAE mice after administration of compound 51.

[0113] Figure 4 is a graph showing the clinical score statistics of EAE mice after administration of compound 51.

[0114] Figure 5 is a graph showing the changes in spinal cord myelin sheath of EAE mice after administration of compound 51.

[0115] Figure 6 is a graph showing the body weight changes of CPZ-induced multiple sclerosis disease model mice after administration of compound 51.

[0116] Figure 7 is a graph showing the changes in whole brain histopathology of CPZ-induced multiple sclerosis disease model mice after administration of compound 51. DETAILED DESCRIPTION

[0117] The schemes of the present application will be explained below with reference to examples. Those skilled in the art will understand that the examples below are only for illustration of the present application and should not be considered as limiting the scope of the present application. If no specific technique or condition is mentioned in the examples, the technique or condition described in the literature in the art or according to the product manual is used.

[0118] The reagents and raw materials used in the examples of the present application are commercially available.

[0119] Table 1. Abbreviations used in the present application and their meanings

[0120] The structure of the compounds described in the present application is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR determination is performed using a Bruker AVANCE-400 nuclear magnetic instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), the internal standard is tetramethylsilane (TMS), and the chemical shift is given in 10 -6 (ppm) as a unit.

[0121] The MS determination is performed using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).

[0122] The HPLC determination is performed using an Agilent 1200 DAD high-pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5ym column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18, 150X 4.5mm, 5ym column).

[0123] The thin layer chromatography silica gel plate uses a Qingdao Marine GF254 silica gel plate. The silica gel plate used in the thin layer chromatography (TLC) has a specification of 0.15mm-0.2mm, and the silica gel plate used in the thin layer chromatography separation and purification of the product has a specification of 0.4mm-0.5mm.

[0124] The column chromatography generally uses Qingdao Marine 100-200 and 200-300 mesh silica gel as the carrier.

[0125] In the following examples, if no special instruction is given, the reactions are all carried out under an argon or nitrogen atmosphere. The argon or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L. The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L. The hydrogenation reaction is usually carried out by vacuuming and filling hydrogen repeatedly for 3 times.

[0126] Example 1: (S)-5-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0127] First step: Compound 1a (50 g, 257 mmol) was added into 500 mL DCM, then diphenylphosphoryl hydroxylamine (108 g, 464 mmol) was added portionwise, and then stirred at 25 °C overnight. After TLC monitoring the reaction was complete, concentrated by rotary evaporation to give compound 1b, which was used directly in the next step without purification.

[0128] Second step: 1b (54 g, 257 mmol), K2CO3 (71 g, 514 mmol) were added into 500 mL DMF, then ethyl propiolate (30 g, 308 mmol) was added dropwise. Stirred at 25 °C overnight. After TLC monitoring the reaction was complete, 500 mL ethyl acetate and 1.5 L water were added, and then the two layers were separated in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, and then the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The obtained crude product was purified by column chromatography to give compound 1c (7.5 g, yellow solid). LC-MS: ESI [M+H] + = 306.3.

[0129] Third step: Compound 1c (7.5 g, 24.6 mmol) was added into 80 mL dioxane, then 4 mol / L hydrochloric acid dioxane solution (61.5 mL) was added, and then stirred at room temperature overnight. After TLC monitoring the reaction was complete, filtered, the filter cake was washed with dioxane, and then dried to give compound 1d (4.5 g, yellow solid). LC-MS: ESI [M+H] + = 206.2.

[0130] Fourth step: Compound 1d (4.5 g, 22 mmol) and cuprous bromide (6.3 g, 44 mmol) were added into 100 mL acetonitrile, then tert-butyl nitrite (4.5 g, 44 mmol) was added dropwise, and then stirred at 70 °C for 2 hours. After TLC monitoring the reaction was complete, the temperature was lowered to room temperature, filtered, the filter cake was washed with ethyl acetate, and then the filtrate was concentrated by rotary evaporation and then purified by column chromatography to give compound 1e (4.1 g, brown solid). LC-MS: ESI [M+H] + = 269.1.

[0131] Fifth step: Compound 1e (4.1 g, 15.2 mmol) was added to 50 mL of methanol, 10 mL of tetrahydrofuran and 10 mL of water, then lithium hydroxide monohydrate (3.2 g, 76 mmol) was added portionwise, and the mixture was stirred at 50 °C overnight. After TLC monitoring of the reaction completion, the mixture was concentrated by rotary evaporation, and the pH was adjusted to 4 with 1 mol / L aqueous hydrochloric acid solution. The mixture was filtered, and the filter cake was washed with water. After drying, compound 1f (3.1 g, gray solid) was obtained. LC-MS: ESI [M+H] + = 214.0.

[0132] Sixth step: Compound 1f (1.0 g, 4.2 mmol), (S)-1-(3-fluorophenyl)ethylamine (0.7 g, 5.04 mmol), HATU (1.9 g, 5.04 mmol) and DIPEA (1.1 g, 8.4 mmol) were added to 10 mL of DMF, and the mixture was stirred at 70 °C for 3 hours. After TLC monitoring of the reaction completion, 30 mL of ethyl acetate and 30 mL of water were added, and the mixture was separated into layers in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated. The obtained crude product was purified by column chromatography to obtain compound 1g (1.0 g, yellow solid). LC-MS: ESI [M+H] + = 362.2.

[0133] Seventh step: Compound 1h (1.0 g, 4.5 mmol), trimethylsilyl acetylene (0.9 g, 9.0 mmol), TEA (2.8 g, 27 mmol), bis(triphenylphosphine)palladium dichloride (160 mg, 0.23 mmol) and CuI (43 mg, 0.23 mmol) were added to 25 mL of acetonitrile, and the mixture was stirred at 25 °C overnight after replacing N2. After TLC monitoring of the reaction completion, the mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was rotary evaporated to obtain compound 1i, which was directly used in the next step without purification. LC-MS: ESI [M+H] + = 192.3.

[0134] Eighth step: Compound 1i (0.86 g, 4.5 mmol) and K2CO3 (6.2 g, 45 mmol) were added to 20 mL of methanol, and the mixture was stirred at 25 °C for 3 hours. After TLC monitoring of the reaction completion, the mixture was filtered, the filter cake was washed with methanol, and the filtrate was rotary evaporated. The obtained crude product was purified by column chromatography to obtain compound 1j (210 mg, yellow solid). LC-MS: ESI [M+H] + = 120.1;

[0135] Ninth step: Take compound 1g (100 mg, 0.27 mmol), compound 1j (33 mg, 0.27 mmol), Pd(dppf)Cl2(30 mg, 0.041 mmol), CuI (5 mg, 0.027 mmol) and TEA (55 mg, 0.54 mmol) into 5 mL DMF, replace N2, then warm to 100 °C and stir for 3 hours. After TLC monitoring reaction is completed, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, and the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 1 (34 mg, light yellow solid). LC-MS: ESI [M+H] + = 401.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (dd, J = 7.2, 1.0 Hz, 1H), 8.72 (s, 1H), 8.62 (d, J = 7.9 Hz, 1H), 8.49 (s, 2H), 8.27 (dd, J = 2.0, 1.0 Hz, 1H), 7.38 (td, J = 8.1, 6.3 Hz, 1H), 7.29 - 7.18 (m, 4H), 7.07 (dd, J = 7.2, 1.9 Hz, 2H), 5.18 - 2.22 (m, 1H), 1.49 (d, J = 7.0 Hz, 3H).

[0136] Example 2: (S)-N-(1-(3-fluorophenyl)ethyl)-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0137] Ninth step: Take compound 1g (100 mg, 0.27 mmol), compound 1j (33 mg, 0.27 mmol), Pd(dppf)Cl2(30 mg, 0.041 mmol), CuI (5 mg, 0.027 mmol) and TEA (55 mg, 0.54 mmol) into 5 mL DMF, replace N2, then warm to 100 °C and stir for 3 hours. After TLC monitoring reaction is completed, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, and the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 1 (34 mg, light yellow solid). LC-MS: ESI [M+H] + = 401.4; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (dd, J = 7.2, 1.0 Hz, 1H), 8.72 (s, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.22 (dd, J = 2.0, 1.0 Hz, 1H), 8.15 (s, 1H), 7.76 (d, J = 0.7 Hz, 1H), 7.38 (td, J = 8.2, 6.4 Hz, 1H), 7.29 - 7.17 (m, 2H), 7.09 - 7.00 (m, 2H), 5.18-5.22 (m, 1H), 3.87 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H).

[0138] Example 3: (S)-5-((2-(cyclopropanecarboxamide)pyrimidin-5-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0139] Compound 1 (25 mg, 0.06 mmol), cyclopropylcarbonyl chloride (8 mg, 0.075 mmol) and TEA (13 mg, 0.125 mmol) were added to 5 mL of dichloromethane, warmed to 25 °C and stirred overnight. After TLC monitoring the reaction was complete, concentrated by rotary evaporation and purified by flash column to give compound 3 (3 mg, yellowish solid) LC-MS: ESI [M+H] + = 469.5; 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.90 (s, 2H), 8.84 (dd, J = 7.2, 0.9 Hz, 1H), 8.75 (s, 1H), 8.67 (d, J = 7.9 Hz, 1H), 8.37 (dd, J = 2.0, 1.0 Hz, 1H), 7.38 (td, J = 8.2, 6.4 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.14 (dd, J = 7.2, 2.0 Hz, 1H), 7.06 (ddd, J = 10.0, 8.0, 2.5 Hz, 1H), 5.18-5.22 (m, 1H), 2.14-2.20 (m, 1H), 1.50 (d, J = 7.1 Hz, 3H), 0.93 - 0.79 (m, 4H).

[0140] Example 4: (S)-3-((2-amino pyrimidin-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)-7- methylpyrrolo[1,2-b]pyridazine-5-carboxamide

[0141] First step: Add compound 4a (15 g, 108 mmol) into 150 mL DMF, cool down to 0 °C, add NaH (60%, 5.6 g, 140 mmol) portionwise, stir for 30 min, then add diphenylphosphoryl hydroxylamine (37.8 g, 161 mmol) portionwise, warm up to 25 °C and stir overnight. After TLC monitoring, quench the reaction with a small amount of water, add 500 mL ethyl acetate and 500 mL water, separate the layers in a separatory funnel. Extract the aqueous phase with ethyl acetate three times, combine the organic phases, wash with water, saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. The crude product is used directly in the next step.

[0142] Second step: Add compound 4b (16.6 g, 108 mmol), 2-bromomalonaldehyde (32.5 g, 216 mmol), and H3PO4 (16.6 g) into 100 mL 1,4-dioxane, warm up to 45 °C and stir overnight. After TLC monitoring, adjust the pH to 7 with saturated aqueous sodium bicarbonate solution, add 500 mL ethyl acetate and 500 mL water, separate the layers in a separatory funnel. Extract the aqueous phase with ethyl acetate three times, combine the organic phases, wash with water, saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. Purify the crude product by column chromatography to obtain compound 4c (11 g, yellow solid). LC-MS: ESI [M+H] = 283.1. +

[0143] Third step: Add compound 4c (6.0 g, 22.3 mmol) into 50 mL methanol, 10 mL tetrahydrofuran, and 10 mL water, then add lithium hydroxide monohydrate (4.7 g, 111.5 mmol) portionwise, warm up to 50 °C and stir overnight. After TLC monitoring, concentrate under vacuum, adjust the pH to 4 with 1 mol / L aqueous hydrochloric acid solution, filter, wash the filter cake with water, and dry to obtain compound 4d (5.1 g, yellow solid). LC-MS: ESI [M+H] = 255.0. +

[0144] Fourth step: Add compound 4d (0.2 g, 0.78 mmol), (S)-1-(3-fluorophenyl)ethylamine (131 mg, 0.94 mmol), HATU (357 mg, 0.94 mmol), and DIPEA (201 mg, 1.56 mmol) into 5 mL DMF, warm up to 70 °C and stir for 3 h. After TLC monitoring, add 30 mL ethyl acetate and 30 mL water, separate the layers in a separatory funnel. Extract the aqueous phase with ethyl acetate three times, combine the organic phases, wash with water, saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. Purify the crude product by column chromatography to obtain compound 4e (164 mg, yellow solid). LC-MS: ESI [M+H] = 283.1. + ​​= 376.2.

[0145] Step 5: Take compound 4e (164 mg, 0.43 mmol), compound 1j (52 mg, 0.43 mmol), Pd(dppf)Cl2(47 mg, 0.065 mmol), CuI (8 mg, 0.043 mmol) and TEA (88 mg, 0.86 mmol) into 5 mL DMF, after replaced with N2, warm up to 100 °C and stir for 3 hours. TLC monitor the reaction is complete, add 30 mL ethyl acetate and 30 mL water, separate the layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 4 (40 mg, yellow solid). LC-MS: ESI [M+H] + = 415.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.3 Hz, 1H), 8.45 (d, J = 8.1 Hz, 1H), 8.40 (s, 2H), 8.35 (d, J = 2.3 Hz, 1H), 7.42 (s, 1H), 7.30 (td, J = 8.0, 6.1 Hz, 1H), 7.15 (td, J = 7.2, 6.3, 4.2 Hz, 4H), 6.97 (ddd, J = 10.1, 8.0, 2.6 Hz, 1H), 5.11 - 5.15 (m, 1H), 2.46 (s, 3H), 1.41 (d, J = 7.1 Hz, 3H).

[0146] Example 5: (S)-(3-((2-aminopyrimidin-5-yl)ethynyl)-7-methylpyrrolo[l,2-b]pyridazin-5-yl)(2-(4-fluorophenyl)pyrrolidin-l-yl)methanone

[0147] Step 1: Take compound 4d (410 mg, 1.6 mmol), compound 5a (317 mg, 1.92 mmol), HATU (730 mg, 1.92 mmol) and DIPEA (495 mg, 3.84 mmol) into 5 mL DMF, warm up to 70 °C and stir for 3 hours. TLC monitor the reaction is complete, add 30 mL ethyl acetate and 30 mL water, separate the layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 5b (370 mg, yellow solid). LC-MS: ESI [M+H] + = 402.3.

[0148] Second Step: Take compound 5b (185 mg, 0.46 mmol), compound 1j (55 mg, 0.46 mmol), Pd(dppf)Cl2(50 mg, 0.069 mmol), CuI (9 mg, 0.046 mmol) and TEA (93 mg, 0.92 mmol) into 5 mL DMF, replace N2, then warm to 100 °C and stir for 3 hours. After TLC monitoring reaction is completed, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, and the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 5 (63 mg, yellow solid). LC-MS: ESI [M+H] + = 441.5; 1 H NMR (400 MHz, DMSO-d6) δ 8.44 - 8.30 (m, 4H), 7.33 - 7.18 (m, 3H), 7.14 (s, 2H), 7.06 (t, J = 8.7 Hz, 2H), 5.16 (s, 1H), 3.90 - 3.98 (m, 2H), 2.48 (s, 3H), 2.27 (dq, J = 12.0, 7.3 Hz, 2H), 1.95 - 1.74 (m, 2H).

[0149] Example 6: (S)-(3-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-7-methylpyrrolo[1,2-b]pyridazin-5-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0150] Take compound 5b (185 mg, 0.46 mmol), compound 6a (65 mg, 0.46 mmol), Pd(dppf)Cl2(50 mg, 0.069 mmol), CuI (9 mg, 0.046 mmol) and TEA (93 mg, 0.92 mmol) into 5 mL DMF, replace N2, then warm to 100 °C and stir for 3 hours. After TLC monitoring reaction is completed, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, and the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 6 (28 mg, light yellow solid). LC-MS: ESI [M+H] + = 464.5; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 7.86 (t, J = 58.8 Hz, 1H), 7.32 (q, J = 9.3, 6.4 Hz, 3H), 7.13 (t, J = 8.6 Hz, 2H), 5.34 (m, 1H), 4.02 (m, 2H), 2.56 (s, 3H), 2.35 (dt, J = 12.1, 7.2 Hz, 2H), 2.06 - 1.82 (m, 2H).

[0151] Example 7: (3-((2-aminopyrimidin-5-yl)ethynyl)pyrrolo[1,2-a]pyrimidin-6-yl)(5-(4- fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone

[0152] Compound 11b (100 mg, 0.26 mmol), compound 1j (31 mg, 0.26 mmol), Pd(dppf)Cl2(28 mg, 0.039 mmol), Cul (5 mg, 0.026 mmol) and TEA (53 mg, 0.52 mmol) were added into 5 mL DMF, after replaced with N2, warmed to 100 °C and stirred for 3 hours. TLC monitoring reaction was completed, added 30 mL ethyl acetate and 30 mL water, separated into two layers in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was purified by column chromatography to obtain compound 7 (28 mg, light yellow solid). LC-MS: ESI [M+H] + = 426.4; 1 H NMR (400 MHz, DMSO-d6) δ 9.93 - 9.84 (m, 1H), 8.47 (s, 2H), 8.42 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 4.6 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.24 - 7.11 (m, 4H), 6.77 (d, J = 4.6 Hz, 1H), 5.59 (dd, J = 11.7, 5.0 Hz, 1H), 3.50-3.58 (m, 1H), 2.73-2.31 (m, 1H).

[0153] Example 8: (S)-(5-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyrazolo[1,5-a]pyridin-3- yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0154] To compound 12a (115 mg, 0.3 mmol), compound 6a (43 mg, 0.3 mmol), Pd(dppf)Cl2(33 mg, 0.045 mmol), CuI (6 mg, 0.03 mmol) and TEA (61 mg, 0.6 mmol) were added into 5 mL DMF, after replaced with N2, warmed to 100 °C and stirred for 3 hours. TLC monitoring reaction was complete, added 30 mL ethyl acetate and 30 mL water, separated in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was purified by column chromatography to obtain compound 8 (12 mg, yellow solid). LC-MS: ESI [M+H] + = 450.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.90 - 8.55 (m, 3H), 8.28 (s, 1H), 8.13 (s, 1H), 7.86 (t, J = 58.8 Hz, 2H), 7.30 (dd, J = 8.5, 5.5 Hz, 2H), 7.20 - 7.03 (m, 3H), 5.40 (m, 1H), 4.25 - 3.68 (m, 2H), 2.34 (s, 2H), 1.86 (m, 3H).

[0155] Example 9: (3-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-7-methylpyrrolo[1,2-b]pyridazin-5-yl)(3-(4-fluorophenyl)isoxazolidin-2-yl)methanone

[0156] First step: compound 9a (1.0 g, 10.0 mmol), cyclo(isopropylidene)malonate (1.44 g, 10.0 mmol), tert-butyl N-hydroxy carbamate (112 mg, 1.0 mmol), triethylenediamine (1.33 g, 10.0 mmol) were added into 20 mL EA, stirred at room temperature for 16 hours. LC-MS monitoring reaction was complete, added 30 mL water, separated in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain compound 9b (2.8 g, oil).

[0157] Second step: Take compound 9b (2.8 g, 10.0 mmol), add 50 mL THF, and add lithium borohydride (650 mg, 30.0 mmol) portionwise while stirring. After the addition is complete, stir at room temperature for 1 hour. After LC-MS monitoring shows that the reaction is complete, add 80 mL water, and separate the layers in a separatory funnel. Extract the aqueous phase with ethyl acetate three times, wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 9c (2.7 g, oil).

[0158] Third step: Take compound 9c (2.7 g, 9.4 mmol), and add triphenylphosphine (3.7 g, 14.2 mmol) to 60 mL THF. Stir while adding DIAD (2.87 g, 14.2 mmol) dropwise at 0 °C. After the addition is complete, stir at 0 °C for 1 hour. After LC-MS monitoring shows that the reaction is complete, add 80 mL water, and separate the layers in a separatory funnel. Extract the aqueous phase with ethyl acetate three times, wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 9d (10.5 g, oil).

[0159] Fourth step: Take compound 9d (10.5 g, 9.4 mmol), add 100 mL 4N HCl / dioxane, and stir at room temperature for 3 hours. After LC-MS monitoring shows that the reaction is complete, rotary evaporate the reaction liquid, add 50 mL 1N HCl / H2O and 50 mL ethyl acetate to extract twice, separate the layers in a separatory funnel. Add 50 mL saturated aqueous sodium bicarbonate solution to the aqueous phase, extract twice with 50 mL ethyl acetate, wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and rotary evaporate. Column chromatography gives compound 9e (1.0 g, yellow oil). LC-MS: ESI [M+H] + = 168.1; 1H NMR (400 MHz, Chloroform-d) δ 7.32-7.24 (m, 2H), 6.99-6.92 (m, 2H), 4.40 (s, 1H), 3.98 (m, 2H), 2.55-3.03 (m, 1H), 2.15-2.21 (m, 1H).

[0160] Fifth step: Take compound 4d (150 mg, 0.59 mmol), compound 9e (118 mg, 0.71 mmol), HATU (270 mg, 0.71 mmol) and DIPEA (153 mg, 1.18 mmol) into 5 mL DMF, warm up to 70 °C and stir for 3 hours. After TLC monitoring reaction is completed, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, and the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 9f (80 mg, yellow solid). LC-MS: ESI [M+H] + = 404.2.

[0161] Sixth step: Take compound 9f (80 mg, 0.2 mmol), compound 6a (28 mg, 0.2 mmol), Pd(dppf)Cl2(21 mg, 0.03 mmol), CuI (4 mg, 0.02 mmol) and TEA (40 mg, 0.4 mmol) into 5 mL DMF, replace N2, warm up to 100 °C and stir for 3 hours. After TLC monitoring reaction is completed, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, and the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 9 (5 mg, light yellow solid). LC-MS: ESI [M+H] + = 466.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 7.86 (t, J = 58.8 Hz, 1H), 7.46 - 7.39 (m, 3H), 7.24 - 7.15 (m, 2H), 5.62 (dd, J = 8.6, 6.2 Hz, 1H), 4.34 (td, J = 7.8, 2.9 Hz, 1H), 3.85 (ddd, J = 9.3, 8.0, 6.6 Hz, 1H), 2.87 - 2.93 (m, 1H), 2.55 (s, 3H), 2.29 - 2.21 (m, 1H).

[0162] Example 10: (3-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyrrolo[1,2-a]pyrimidin-6-yl)(3-(4-fluorophenyl)isoxazolidin-2-yl)methanone

[0163] First step: Compound 10a (10 g, 35 mmol), compound 10b (5.9 g, 38.5 mmol), Pd(PPh3)2Cl2 (1.2 g, 1.75 mmol), XPhos Pd G2 (0.7 g, 0.875 mmol) and Cs2CO3 (28.5 g, 87.5 mmol) were added into 200 mL of dioxane and 20 mL of water, and the mixture was stirred at 100 °C overnight under N2. After TLC detection showed that the reaction was complete, 300 mL of ethyl acetate and 300 mL of water were added, and the mixture was separated into layers in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was purified by column chromatography to obtain compound 10c (5.1 g, white solid). LC-MS: ESI [M+H] + = 185.0.

[0164] Second step: NaOAc (6.6 g, 81 mmol) and NIS (21.3 g, 94.5 mmol) were added into 500 mL of acetonitrile, and then compound 10d (7.1 g, 54 mmol) was slowly added dropwise, followed by the addition of compound 10c (5.0 g, 27 mmol) dissolved in 50 mL of acetonitrile. The mixture was stirred at 100 °C overnight. After TLC detection showed that the reaction was complete, saturated aqueous sodium sulfite was added to quench the reaction, and 200 mL of ethyl acetate and 200 mL of water were added to separate the mixture into layers in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was purified by column chromatography to obtain compound 10e (2.0 g, yellow solid). LC-MS: ESI [M+H] + = 269.1.

[0165] Third step: Compound 10e (1.0 g, 3.7 mmol) was added into 20 mL of methanol, 4 mL of tetrahydrofuran and 4 mL of water, and then lithium hydroxide monohydrate (0.47 g, 11.1 mmol) was added portionwise. The mixture was stirred at 50 °C overnight. After TLC detection showed that the reaction was complete, the mixture was concentrated by rotary evaporation, and the pH was adjusted to 4 with 1 mol / L aqueous hydrochloric acid solution. The mixture was filtered, and the filter cake was washed with water and dried to obtain compound 10f (0.8 g, gray solid). LC-MS: ESI [M+H] + = 241.0.

[0166] Fourth Step: Take compound 10f (0.3 g, 1.25 mmol), compound 9e (0.25 g, 1.5 mmol), HATU (570 mg, 1.5 mmol) and DIPEA (323 mg, 2.5 mmol) into 5 mL DMF, warm up to 70 °C and stir for 3 hours. TLC monitor the reaction is complete, add 30 mL ethyl acetate and 30 mL water, separate the layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, and the combined organic phases are washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The resulting crude product is purified by column chromatography to obtain compound 10g (440 mg, yellow solid). LC-MS: ESI [M+H] + = 390.2.

[0167] Fifth Step: Take compound 10g (100 mg, 0.26 mmol), compound 6a (37 mg, 0.26 mmol), Pd(dppf)Cl2(29 mg, 0.039 mmol), CuI (5 mg, 0.026 mmol) and TEA (53 mg, 0.52 mmol) into 5 mL DMF, replace N2, warm up to 100 °C and stir for 3 hours. TLC monitor the reaction is complete, add 30 mL ethyl acetate and 30 mL water, separate the layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, and the combined organic phases are washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The resulting crude product is purified by column chromatography to obtain compound 10 (9 mg, light yellow solid). LC-MS: ESI [M+H] + = 452.4; 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (d, J = 2.1 Hz, 1H), 8.76 (s, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J = 4.6 Hz, 1H), 7.90 (t, J = 58.8 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.30 - 7.20 (m, 2H), 6.83 (d, J = 4.6 Hz, 1H), 5.65 (dd, J = 8.5, 6.4 Hz, 1H), 4.42 (td, J = 7.7, 2.9 Hz, 1H), 3.98 - 4.04 (m, 1H), 2.92 - 2.98 (m, 1H), 2.29 - 2.35 (m, 1H).

[0168] Example 11: (3-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)pyrrolo[1,2-a]pyrimidin-6-yl)(5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazin-1-yl)methanone

[0169] First Step: Take compound 10f (0.3 g, 1.25 mmol), compound 11a (0.32 g, 1.5 mmol), HATU (570 mg, 1.5 mmol) and DIPEA (323 mg, 2.5 mmol) into 5 mL DMF, warm up to 70 °C and stir for 3 hours. TLC monitor the reaction is complete, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 11b (320 mg, yellow solid). LC-MS: ESI [M+H] + = 387.2.

[0170] Second Step: Take compound 11b (100 mg, 0.26 mmol), compound 6a (37 mg, 0.26 mmol), Pd(dppf)Cl2(29 mg, 0.039 mmol), CuI (5 mg, 0.026 mmol) and TEA (53 mg, 0.52 mmol) into 5 mL DMF, replace N2, warm up to 100 °C and stir for 3 hours. TLC monitor the reaction is complete, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 11 (28 mg, light yellow solid). LC-MS: ESI [M+H] + = 449.4; 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (d, J = 2.1 Hz, 1H), 8.71 (s, 1H), 8.43 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 4.6 Hz, 1H), 8.11 (s, 1H), 7.85 (t, J = 58.9 Hz, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.21 - 7.12 (m, 2H), 6.78 (d, J = 4.6 Hz, 1H), 5.59 (dd, J = 11.7, 5.0 Hz, 1H), 3.54 (ddd, J = 19.0, 11.8, 1.6 Hz, 1H), 2.77 (ddd, J = 19.0, 5.0, 1.8 Hz, 1H).

[0171] Example 12: (S)-(5-((2-aminopyrimidin-5-yl)ethynyl)pyrazolo[l,5-a]pyridin-3-yl)(2-(4- fluorophenyl)pyrrolidin-l-yl)methanone

[0172] First Step: To compound 1f (200 mg, 0.87 mmol), compound 5a (165 mg, 1.0 mmol), HATU (0.38 g, 1.0 mmol) and DIPEA (224 mg, 1.74 mmol) were added in 5 mL DMF and stirred at 50 °C overnight. After TLC monitoring the reaction was complete, 30 mL ethyl acetate and 30 mL water were added and the layers were separated in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 12a (230 mg, yellow solid). LC-MS: ESI [M+H]=388.2. +

[0173] Second Step: To compound 12a (115 mg, 0.3 mmol), compound 1j (36 mg, 0.3 mmol), Pd(dppf)Cl2(33 mg, 0.045 mmol), CuI (6 mg, 0.03 mmol) and TEA (61 mg, 0.6 mmol) were added in 5 mL DMF and stirred at 100 °C for 3 hours after N2 replacement. After TLC monitoring the reaction was complete, 30 mL ethyl acetate and 30 mL water were added and the layers were separated in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 12 (20 mg, yellowish solid). LC-MS: ESI [M+H]=426.5; + 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.60 (s, 1H), 8.49 (s, 2H), 8.25 (s, 1H), 7.37 - 7.21 (m, 4H), 7.20 - 6.99 (m, 3H), 5.36-5.42 (m, 1H), 4.01-4.10 (m, 2H), 2.34 (s, 1H), 1.95 (s, 3H).

[0174] Example 13: (R)-3-((2-Aminopyrimidin-5-yl)ethynyl)-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyrrolo[1,2-a]pyrimidine-6-carboxamide

[0175] ​​First Step: Take compound 10f (0.3 g, 1.25 mmol), compound 13a (0.29 g, 1.5 mmol), HATU (0.57 g, 1.5 mmol) and DIPEA (0.32 g, 2.5 mmol) into 5 mL DMF, warm up to 70 °C and stir for 3 hours. TLC monitor the reaction is complete, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 13b (0.43 g, light yellow solid). LC-MS: ESI [M+H] + = 416.2.

[0176] Second Step: Take compound 13b (100 mg, 0.24 mmol), compound 1j (29 mg, 0.24 mmol), Pd(dppf)Cl2(26 mg, 0.036 mmol), CuI (5 mg, 0.024 mmol) and TEA (49 mg, 0.48 mmol) into 5 mL DMF, replace N2, warm up to 100 °C and stir for 3 hours. TLC monitor the reaction is complete, add 30 mL ethyl acetate and 30 mL water, separate into two layers in a separatory funnel. The aqueous phase is extracted with ethyl acetate three times, the combined organic phase is washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product is purified by column chromatography to obtain compound 13 (30 mg, white solid). LC-MS: ESI [M+H] + = 455.4; 1 H NMR (400 MHz, DMSO-d6) δ 9.92 - 9.81 (m, 1H), 9.31 (d, J = 9.6 Hz, 1H), 8.49 (s, 2H), 8.43 (d, J = 2.1 Hz, 1H), 8.18 (d, J = 4.6 Hz, 1H), 7.77 (dd, J = 8.6, 5.4 Hz, 2H), 7.31 (t, J = 8.8 Hz, 2H), 7.22 (s, 2H), 6.77 (d, J = 4.6 Hz, 1H), 6.11 - 6.19 (m, 1H).

[0177] Example 14: (3-((2-aminopyrimidin-5-yl)ethynyl)pyrrolo[1,2-a]pyrimidin-6-yl)(3-(4- fluorophenyl)isoxazolidin-2-yl)methanone

[0178] To compound 10g (100 mg, 0.26 mmol), compound 1j (31 mg, 0.26 mmol), Pd(dppf)Cl2(28 mg, 0.039 mmol), CuI (5 mg, 0.026 mmol) and TEA (53 mg, 0.52 mmol) were added into 5 mL DMF, after replaced with N2, warmed to 100 °C for 3 h. TLC monitored the reaction was complete, added 30 mL ethyl acetate and 30 mL water, separated in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was purified by column chromatography to give compound 14 (12 mg, yellow solid). LC-MS: ESI [M+H] + = 429.3; 1 H NMR (400 MHz, DMSO-d6) δ 9.98 - 9.75 (m, 1H), 8.52 - 8.43 (m, 3H), 7.95 (d, J = 4.6 Hz, 1H), 7.52 - 7.34 (m, 2H), 7.29 - 7.10 (m, 4H), 6.78 (d, J = 4.6 Hz, 1H), 5.61 (dd, J = 8.5, 6.5 Hz, 1H), 4.38 (td, J = 7.7, 2.9 Hz, 1H), 3.92 - 4.01 (m, 1H), 2.89 - 2.95 (m, 1H), 2.24 - 2.31 (m, 1H).

[0179] Example 15: (S)-3-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)pyrrolo[1,2-a]pyrimidine-6-carboxamide

[0180] First step: To compound 10f (1.0 g, 4.2 mmol), 15a (0.7 g, 5.04 mmol), HATU (1.9 g, 5.04 mmol) and DIPEA (1.1 g, 8.4 mmol) were added into 10 mL DMF, warmed to 70 °C for 3 h. TLC monitored the reaction was complete, added 30 mL ethyl acetate and 30 mL water, separated in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was purified by column chromatography to give compound 15b (0.9 g, yellow solid). LC-MS: ESI [M+H] + = 362.2.

[0181] Second step: take compound 15b (100 mg, 0.28 mmol), compound 1j (33 mg, 0.28 mmol), Pd(dppf)Cl2(30 mg, 0.041 mmol), CuI (5 mg, 0.028 mmol) and TEA (56 mg, 0.55 mmol) into 5 mL of DMF, replace N2, and then warm to 100 °C for 3 hours of stirring. After TLC monitoring, the reaction was complete, 30 mL of ethyl acetate and 30 mL of water were added, and the layers were separated in a separatory funnel. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The obtained crude product was purified by column chromatography to obtain compound 15 (25 mg, light pink solid). LC-MS: ESI [M+H] + = 401.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (d, J = 1.9 Hz, 1H), 8.79 (d, J = 7.9 Hz, 1H), 8.48 (s, 2H), 8.37 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 4.5 Hz, 1H), 7.39 (dd, J = 14.3, 8.0 Hz, 1H), 7.27 - 7.19 (m, 4H), 7.07 (dd, J = 11.7, 5.0 Hz, 1H), 6.74 (d, J = 4.4 Hz, 1H), 5.18 - 5.22 (m, 1H), 1.51 (d, J = 7.1 Hz, 3H).

[0182] Example 16: (3-((2-aminopyrimidin-5-yl)ethynyl)-7-methylpyrrolo[1,2-b]pyridazin-5-yl)(3-(4- fluorophenyl)isoxazolidin-2-yl)methanone

[0183] Compound 9f (75 mg, 0.186 mmol), 1j (22 mg, 0.186 mmol), Pd(dppf)Cl2(0.014 g, 0.019 mmol), copper iodide (5.30 mg, 0.028 mmol), triethylamine (0.037 g, 0.371 mmol) were weighed into 3.0 ml of DMF, replaced with nitrogen three times, warmed to 100 °C for 16 h of stirring, and LC-MS monitoring. After the reaction was complete, rotary evaporation was performed, and the obtained crude product was purified by column chromatography and then prepared to obtain compound 16 (3 mg, white solid). LC-MS: ESI [M+H] + = 443.5; 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.3 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.49 (s, 2H), 7.48 - 7.41 (m, 3H), 7.22 (dd, J = 11.9, 3.0 Hz, 4H), 5.63 (dd, J = 8.7, 6.3 Hz, 1H), 4.35 (td, J = 7.8, 2.9 Hz, 1H), 3.86 (m, 1H), 2.90 (m, 1H), 2.55 (s, 3H), 2.26 (m, 1H).

[0184] Example 17: (S)-5-((1H-pyrrolo[2,3-b]pyridine-5-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0185] First step: Take compound 17a (0.50 g, 2.049 mmol), trimethylsilylethynyl (0.603 g, 6.147 mmol), triethylamine (1.24 g, 12.29 mmol), Pd(PPh3)2Cl2 (72.0 mg, 0.102 mmol), cuprous iodide (19.5 mg, 0.102 mmol) into acetonitrile 10 ml, stir at 25 °C for 16 h, monitor by LC-MS, after the reaction is completed, the reaction solution is rotary dried, the obtained crude product is directly used for the next step. LC-MS: ESI [M+H] + = 215.3.

[0186] Second step: Add methanol 15 ml into the crude product of the previous step, add potassium carbonate (2.77 mg, 20.06 mmol), stir at 25 °C for 1 h, monitor by LC-MS, after the reaction is completed, filter, rotary dry the filtrate, the obtained crude product is purified by column chromatography to obtain compound 17c (187 mg). LC-MS: ESI [M+H] + = 143.2.

[0187] Third step: Take compound 1g (100 mg, 0.276 mmol), 17c (40 mg, 0.276 mmol), Pd(dppf)Cl2 (0.021 g, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol), add DMF 2.0 ml, replace with nitrogen for three times, heat to 100 °C, stir for 16 h, monitor by LC-MS, after the reaction is completed, rotary dry, the obtained crude product is purified by column chromatography to obtain compound 17 (28 mg, white solid). LC-MS: ESI [M+H] + = 424.5; 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.82 (dd, J = 7.2, 1.0 Hz, 1H), 8.74 (s, 1H), 8.65 (d, J = 7.9 Hz, 1H), 8.46 (dd, J = 8.6, 2.0 Hz, 1H), 8.37 - 8.31 (m, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 3.4, 2.0 Hz, 1H), 7.39 (td, J = 8.1, 6.3 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.15 (dd, J = 7.2, 1.9 Hz, 1H), 7.07 (m, 1H), 6.53 (dd, J = 3.5, 1.3 Hz, 1H), 5.22 (m, 1H), 1.51 (d, J = 7.1 Hz, 3H).

[0188] Example 18: (3-((2-aminopyrimidin-5-yl)ethynyl)-7-methylpyrrolo[1,2-b]pyridazin-5-yl)(3-(4- fluorophenyl)isoxazolidin-2-yl)methanone

[0189] First step: Compound 18a (0.50 g, 2.336 mmol), trimethylsilylacetylene (0.458 g, 4.671 mmol), triethylamine (1.42 g, 14.01 mmol), Pd(PPh3)2Cl2(82.0 mg, 0.117 mmol), cuprous iodide (22.3 mg, 0.117 mmol) were weighed into acetonitrile 10 ml, stirred at 25 °C for 16 h, LC-MS monitoring, after the reaction was completed, the reaction liquid was rotary dried, and the obtained crude product was continuously transferred to the next step. LC-MS: ESI [M+H] + = 232.4.

[0190] Second step: methanol 15 ml was added to the crude product of the previous step, potassium carbonate (2.56 g, 18.58 mmol) was added, and stirred at 25 °C for 1 h, LC-MS monitoring, after the reaction was completed, filtered, the filtrate was rotary dried, and the obtained crude product was subjected to column chromatography to obtain compound 18c (105 mg). LC-MS: ESI [M+H] + = 160.2.

[0191] Third Step: Take compound 1g (100 mg, 0.276 mmol), 18c (44 mg, 0.276 mmol), Pd(dppf)Cl2(21 mg, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol), add DMF 2.0 ml, replace with nitrogen three times, warm to 100 °C, stir for 16 h, monitor by LC-MS, after the reaction is completed, spin dry, the obtained crude product is purified by column chromatography to obtain compound 18 (20 mg, white solid). LC-MS: ESI [M+H] + = 441.5; 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 7.2 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.76 (s, 1H), 8.68 (d, J = 7.9 Hz, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.50 (d, J = 6.0 Hz, 1H), 7.39 (td, J = 8.0, 6.1 Hz, 1H), 7.30 - 7.15 (m, 3H), 7.07 (td, J = 8.7, 8.1, 2.7 Hz, 1H), 5.22 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H).

[0192] Example 19: (S)-5-((5-aminopyrazin-2-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0193] First Step: Take compound 19a (0.50 g, 2.874 mmol), trimethylsilylethynyl (0.565 g, 5.747 mmol), triethylamine (1.75 g, 17.24 mmol), Pd(PPh3)2Cl2(100.8 mg, 0.144 mmol), cuprous iodide (27.3 mg, 0.144 mmol), add acetonitrile 10 ml, stir at 25 °C for 16 h, monitor by LC-MS, after the reaction is completed, spin dry the reaction solution, the obtained crude product is directly used in the next step. LC-MS: ESI [M+H] + = 192.1.

[0194] Second Step: Add methanol 20 ml to the crude product of the previous step, add potassium carbonate (3.97 g, 28.6 mmol), stir at 25 °C for 1 h, monitor by LC-MS, after the reaction is completed, filter, spin dry the filtrate, the obtained crude product is purified by column chromatography to obtain compound 19c (80 mg). LC-MS: ESI [M+H] += 120.1.

[0195] Third step: Take compound 1g (120 mg, 0.336 mmol), 19c (40 mg, 0.336 mmol), Pd(dppf)Cl2(28 mg, 0.039 mmol), cuprous iodide (9.6 mg, 0.050 mmol), triethylamine (68.0 mg, 0.672 mmol), add DMF 2.0 ml, replace with nitrogen three times, warm to 100 °C, stir for 16 h, monitor by LC-MS, dry after the reaction is complete, and the obtained crude product is purified by column chromatography to give compound 19 (13 mg, white solid). LC-MS: ESI [M+H] + = 401.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 7.2 Hz, 1H), 8.74 (s, 1H), 8.64 (d, J = 7.9 Hz, 1H), 8.31 - 8.27 (m, 1H), 8.24 (d, J = 1.4 Hz, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.39 (td, J = 8.1, 6.3 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.10 (dd, J = 7.2, 2.0 Hz, 1H), 7.06 (d, J = 3.4 Hz, 3H), 5.22 (m, 1H), 1.50 (d, J = 7.1 Hz, 3H).

[0196] Example 20: (S)-5-((3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)ethynyl)-N-(l-(3- fluorophenyl)ethyl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0197] First step: Take compound 20a (0.50 g, 2.325 mmol), trimethylsilylethynyl (0.685 g, 6.975 mmol), triethylamine (1.42 g, 13.95 mmol), Pd(PPh3)2Cl2(82.0 mg, 0.117 mmol), cuprous iodide (22.3 mg, 0.117 mmol) into dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, dry the reaction liquid after the reaction is complete, and the obtained crude product is directly used in the next step. LC-MS: ESI [M+H] + = 233.4.

[0198] Second Step: To the crude product of previous step, add methanol 15 ml, add potassium carbonate (2.37 g, 17.21 mmol) and stir at 25 °C for 1 h, monitor by LC-MS, after the reaction is completed, filter, spin dry the filtrate, the obtained crude product is purified by column chromatography to give compound 20c (220 mg). LC-MS: ESI [M+H] + = 161.2.

[0199] Third Step: Take compound 1g (100 mg, 0.276 mmol), 20c (44 mg, 0.276 mmol), Pd(dppf)Cl2(21 mg, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol), add DMF 2.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 16 h, monitor by LC-MS, after the reaction is completed, spin dry, the obtained crude product is purified by column chromatography to give compound 20 (8 mg, white solid). LC-MS: ESI [M+H] + = 442.5; 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 7.1 Hz, 1H), 8.50 (s, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.03 - 7.99 (m, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.16 (td, J = 8.1, 6.3 Hz, 2H), 7.06 - 6.97 (m, 2H), 6.91 (d, J = 1.8 Hz, 1H), 6.84 (m, 2H), 4.99 (m, 1H), 3.91 (m, 2H), 3.23 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H).

[0200] Example 21: (S)-5-((3,3-dimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)-N-(l- (3-fluorophenyl)ethyl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0201] First Step: Take compound 21a (1.00 g, 4.148 mmol), trimethylsilylethynyl (1.22 g, 12.44 mmol), triethylamine (2.58 g, 24.88 mmol), Pd(PPh3)2Cl2(145.0 mg, 0.207 mmol), cuprous iodide (99.5 mg, 0.207 mmol), add dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, after the reaction is completed, spin dry the reaction solution, the obtained crude product is directly used for next step. LC-MS: ESI [M+H] += 259.4.

[0202] Second Step: To the crude product of previous step, methanol 20 ml was added, potassium carbonate (5.34 g, 38.70 mmol) was added and stirred at 25 °C for 1 h, LC-MS monitoring, after the reaction was completed, filtered, the filtrate was rotary evaporated, the obtained crude product was purified by column chromatography to give compound 21c (530 mg). LC-MS: ESI [M+H] + = 187.2.

[0203] Third Step: Compound 1g (100 mg, 0.276 mmol), 21c (40 mg, 0.276 mmol), Pd(dppf)Cl2(21 mg, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol) were weighed, DMF 2.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 16 h, LC-MS monitoring, after the reaction was completed, rotary evaporated, the obtained crude product was purified by column chromatography to give compound 21 (22 mg, white solid). LC-MS: ESI [M+H] + = 468.5; 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.91 (dd, J = 7.2, 1.0 Hz, 1H), 8.83 (s, 1H), 8.74 (d, J = 7.9 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.42 (dd, J = 1.9, 1.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.47 (td, J = 8.2, 6.4 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.23 - 7.10 (m, 2H), 5.30 (m, 1H), 1.59 (d, J = 7.1 Hz, 3H), 1.40 (s, 6H).

[0204] Example 22: (S)-N-(1-(3-fluorophenyl)ethyl)-5-((2-(1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-5-yl)ethynyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0205] First step: Take compound 22a (2.19 g, 12.35 mmol), 22b (1.00 g, 10.29 mmol), DIEA (3.99 g, 30.89 mmol) into DMSO 10 ml, stir at 120 °C for 16 h, monitor by LC-MS, after the reaction is completed, add water, extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, the obtained crude product is column chromatographed to obtain compound 22c (2.40 g). LC-MS: ESI [M+H] + = 255.1.

[0206] Second step: Take compound 22c (0.50 g, 1.968 mmol), trimethylsilylethynyl (0.579 g, 5.903 mmol), triethylamine (1.19 g, 11.80 mmol), Pd (PPh3)2Cl2 (69.0 mg, 0.098 mmol), cuprous iodide (19.0 mg, 0.098 mmol) into dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, after the reaction is completed, dry the reaction liquid, the obtained crude product is directly used in the next step. LC-MS: ESI [M+H] + = 272.4.

[0207] Third step: Add methanol 15 ml to the crude product of the previous step, add potassium carbonate (2.54 g, 18.42 mmol) and stir at 25 °C for 1 h, monitor by LC-MS, after the reaction is completed, filter, dry the filtrate, the obtained crude product is column chromatographed to obtain compound 22e (326 mg). LC-MS: ESI [M+H] + = 200.2.

[0208] Fourth step: Take compound 1g (100 mg, 0.276 mmol), 22e (55 mg, 0.276 mmol), Pd (dppf)Cl2 (0.021 g, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol) into DMF 2.0 ml, replace with nitrogen for three times, heat to 100 °C and stir for 16 h, monitor by LC-MS, after the reaction is completed, dry, the obtained crude product is column chromatographed and then prepared and purified to obtain compound 22 (39 mg, white solid). LC-MS: ESI [M+H] + = 481.5; 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.81 (dd, J = 7.2, 1.0 Hz, 1H), 8.74 (s, 1H), 8.70 - 8.62 (m, 3H), 8.31 (dd, J = 2.0, 1.0 Hz, 1H), 7.93 (d, J = 0.7 Hz, 1H), 7.51 (d, J = 0.8 Hz, 1H), 7.39 (td, J = 8.1, 6.3 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.13 - 7.02 (m, 2H), 5.21 (m, 1H), 3.83 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H).

[0209] Example 23: (S)-5-((2-aminothiazol-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0210] First step: Compound 23a (0.50 g, 1.791 mmol), trimethylsilylethynyl (0.527 g, 5.373 mmol), triethylamine (1.08 g, 10.74 mmol), Pd(PPh3)2Cl2(62.8 mg, 0.090 mmol), cuprous iodide (17.6 mg, 0.090 mmol) were added into dioxane 10 ml, stirred at 100 °C for 16 h, LC-MS monitoring, after the reaction was completed, the reaction liquid was rotary dried, the obtained crude product was continuously transferred to the next step. LC-MS: ESI [M+H] + = 241.5.

[0211] Second step: methanol 20 ml was added to the crude product of the previous step, potassium carbonate (1.86 g, 13.49 mmol) was added, stirred at 25 °C for 1 h, LC-MS monitoring, after the reaction was completed, filtered, the filtrate was rotary dried, the obtained crude product was purified by column chromatography to obtain compound 23c (100 mg). LC-MS: ESI [M+H] + = 169.3; 1 H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.43 (s, 1H), 4.35 (s, 1H), 1.27 (s, 9H).

[0212] Third step: Take compound 1g (150 mg, 0.414 mmol), 22c (93 mg, 0.414 mmol), Pd(dppf)Cl2(0.030 g, 0.041 mmol), cuprous iodide (11.8 mg, 0.062 mmol), triethylamine (84.0 mg, 0.828 mmol), add DMF 2.0 ml, replace with nitrogen three times, heat to 100°C and stir for 16 h, monitor by LC-MS, add water after the reaction is complete, extract with ethyl acetate, dry the organic phase, and the obtained crude product is directly connected to the next step.

[0213] Fourth step: Add 20 ml of 4N hydrochloric acid ethyl acetate solution to the crude product of the third step, stir at 25°C for 3 h, monitor by LC-MS, add water after the reaction is complete, extract, adjust the pH of the aqueous layer to 7-8 with 10% sodium hydroxide solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, and the obtained crude product is prepared by column chromatography to obtain compound 23 (10 mg, white solid). LC-MS: ESI [M+H] + = 406.5; 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (dd, J = 7.2, 1.0 Hz, 1H), 8.64 (s, 1H), 8.54 (d, J = 7.9 Hz, 1H), 8.11 (dd, J = 2.0, 1.0 Hz, 1H), 7.57 (s, 2H), 7.36-7.27 (m, 2H), 7.20-7.11 (m, 2H), 6.98 (m, 2H), 5.13 (m, 1H), 1.42 (d, J = 7.0 Hz, 3H).

[0214] Example 24: (3-(3-fluorophenyl)isoxazolidin-2-yl)(3-((3-hydroxyoxetan-3-yl)ethynyl)pyrrolo[1,2-a]pyrimidin-6-yl)methanone

[0215] First step: Take compound 10f (0.063 g, 0.261 mmol), 24a (0.044 g, 0.261 mmol), HATU (0.119 g, 0.314 mmol), DIEA (0.67 g, 0.520 mmol), add DMF 1.0 ml, stir at 50°C for 16 h, monitor by LC-MS, add water after the reaction is complete, extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, and the obtained crude product is obtained by column chromatography to obtain compound 24b (0.068 g). LC-MS: ESI [M+H] + = 390.2.

[0216] Second step: Take compound 24b (0.068 g, 0.174 mmol), 24c (0.034 g, 0.349 mmol), Pd(dppf)Cl2(0.013 g, 0.017 mmol), cuprous iodide (5.0 mg, 0.026 mmol), triethylamine (53.0 mg, 0.523 mmol), add DMF 2.0 ml, replace with nitrogen for three times, stir at 100 °C for 16 h, monitor by LC-MS, dry after the reaction is completed, and the obtained crude product is purified by column chromatography to obtain compound 24 (24 mg, white solid). LC-MS: ESI [M+H] + = 408.5; 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (dd, J = 2.2, 0.7 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 4.6 Hz, 1H), 7.47 (m, 1H), 7.32-7.23 (m, 2H), 7.20-7.13 (m, 1H), 6.83 (dd, J = 4.5, 0.7 Hz, 1H), 6.77 (s, 1H), 5.67 (dd, J = 8.7, 6.4 Hz, 1H), 4.84 (d, J = 6.4 Hz, 2H), 4.65 (d, J = 6.4 Hz, 2H), 4.42 (m, 1H), 4.00 (m, 1H), 2.98 (m, 1H), 2.32 (m, 1H).

[0217] Example 25: (S)-3-((3,3-dimethyl-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5- yl)ethynyl)-N-(l-(3-fluorophenyl)ethyl)pyrrolo[l,2-a]pyrimidine-6-carboxamide

[0218] Take compound 15b (100 mg, 0.276 mmol), 21c (51 mg, 0.276 mmol), Pd(dppf)Cl2(0.021 g, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol), add DMF 2.0 ml, replace with nitrogen for three times, stir at 100 °C for 16 h, monitor by LC-MS, dry after the reaction is completed, and the obtained crude product is purified by column chromatography to obtain compound 25 (14 mg, white solid). LC-MS: ESI [M+H] + = 468.5; 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.96 (d, J = 2.1 Hz, 1H), 8.80 (d, J = 7.9 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 4.5 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.38 (m, 1H), 7.30 - 7.19 (m, 2H), 7.06 (m, 1H), 6.75 (d, J = 4.5 Hz, 1H), 5.21 (m, 1H), 1.51 (d, J = 7.1 Hz, 3H), 1.31 (s, 6H).

[0219] Example 26: (S)-N-(l-(3-fluorophenyl)ethyl)-3-((2-(l-methyl-lH-pyrazol-4- yl)amino)pyrimidin-5-yl)ethynyl)pyrrolo[l,2-a]pyrimidine-6-carboxamide

[0220] Compound 15b (100 mg, 0.276 mmol), 22e (55 mg, 0.276 mmol), Pd(dppf)Cl2(0.021 g, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol) were weighed out, DMF 2.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C, stirred for 16 h, monitored by LC-MS, after the reaction was completed, rotary evaporation was performed, the obtained crude product was purified by column chromatography to give compound 26 (39 mg, white solid). LC-MS: ESI [M+H] + = 481.5; 1 H NMR (400 MHz, DMSO-d6) δ 9.98 - 9.88 (m, 2H), 8.79 (d, J = 7.9 Hz, 1H), 8.64 (s, 2H), 8.39 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 4.5 Hz, 1H), 7.92 (s, 1H), 7.50 (d, J = 0.7 Hz, 1H), 7.38 (m, 1H), 7.28 - 7.18 (m, 2H), 7.11 - 7.00 (m, 1H), 6.74 (dd, J = 4.5, 0.8 Hz, 1H), 5.21 (m, 1H), 3.82 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H).

[0221] Example 27: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(l-(3-fluorophenyl)ethyl)- 2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazin-l-formamide

[0222] First Step: Compound 27a (0.5 g, 2.325 mmol) was weighed into dichloromethane 10 ml, under stirring, temperature was lowered to 0 °C, triphosgene (0.23 g, 0.76 mmol) was added in portions, stirred for 30 min, triethylamine (1.20 g, 9.30 mmol) was added dropwise, stirred for 30 min, (S)-1-(3-fluorophenyl)ethylamine (0.32 g, 2.325 mmol) was added, then stirred at 25 °C overnight. LC-MS monitoring, after the reaction was completed, water was added for extraction, the organic phase was rotary evaporated, the obtained crude product was purified by column chromatography to obtain compound 27b (275 mg, white solid). LC-MS: ESI [M+H] + = 380.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.37 (td, J = 7.8, 6.0 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.11 - 7.01 (m, 1H), 4.90 (p, J = 7.1 Hz, 1H), 4.35 (td, J = 4.4, 1.2 Hz, 2H), 3.89 - 3.75 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H).

[0223] Second Step: Compound 27b (70 mg, 0.184 mmol), 1j (21 mg, 0.184 mmol), Pd(dppf)Cl2(0.014 g, 0.018 mmol), cuprous iodide (5.3 mg, 0.028 mmol), triethylamine (37.2 mg, 0.368 mmol) were weighed into DMF 2.0 ml, replaced with nitrogen for three times, temperature was raised to 100 °C, stirred for 16 h, LC-MS monitoring, after the reaction was completed, rotary evaporation, the obtained crude product was purified by column chromatography and then prepared to obtain compound 27 (6 mg, white solid). LC-MS: ESI [M+H] + = 419.5; 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.37 (td, J = 7.8, 6.0 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.11 - 7.01 (m, 1H), 4.90 (p, J = 7.1 Hz, 1H), 4.35 (td, J = 4.4, 1.2 Hz, 2H), 3.89 - 3.75 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H).

[0224] Example 28: (S)-N-(1-(3-fluorophenyl)ethyl)-5-((2-(1-(2-hydroxyethyl)-1H- pyrazol-4-yl)amino)pyrimidin-5-yl)ethynyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0225] First step: Take compound 22a (1.67 g, 9.43 mmol), 28a (1.00 g, 7.86 mmol), DIEA (3.05 g, 23.59 mmol) into DMSO 10 ml, stir at 120 °C for 16 h, monitor by LC-MS, after the reaction is completed, add water, extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase, the obtained crude product is column chromatographed to obtain compound 28b (1.50 g). LC-MS: ESI [M+H] + = 285.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.51 (s, 2H), 7.89 (d, J = 0.8 Hz, 1H), 7.50 (d, J = 0.8 Hz, 1H), 4.90 (t, J = 5.3 Hz, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.71 (m, 2H).

[0226] Second step: Take compound 28b (1.00 g, 3.520 mmol), trimethylsilylethynyl (1.03 g, 10.55 mmol), triethylamine (2.13 g, 21.11 mmol), Pd(PPh3)2Cl2 (123.5 mg, 0.176 mmol), cuprous iodide (33.5 mg, 0.176 mmol) into dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, after the reaction is completed, dry the reaction liquid, the obtained crude product is directly used in the next step. LC-MS: ESI [M+H] + = 302.4.

[0227] Third step: Add methanol 30 ml to the crude product of the previous step, add potassium carbonate (4.58 g, 33.17 mmol) and stir at 25 °C for 1 h, monitor by LC-MS, after the reaction is completed, filter, dry the filtrate, the obtained crude product is column chromatographed to obtain compound 28d (680 mg). LC-MS: ESI [M+H] + = 230.2.

[0228] Fourth step: Take compound 1g (158 mg, 0.436 mmol), 28d (100 mg, 0.436 mmol), Pd(dppf)Cl2(0.032 g, 0.044 mmol), cuprous iodide (12.5 mg, 0.065 mmol), triethylamine (88.0 mg, 0.872 mmol), add DMF 3.0 ml, replace with nitrogen three times, warm to 100°C and stir for 16h, monitor by LC-MS, dry after the reaction is complete, and the obtained crude product is purified by column chromatography to obtain compound 28 (24 mg, white solid). LC-MS: ESI [M+H] + = 511.5; 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.80 (dd, J = 7.2, 1.0 Hz, 1H), 8.73 (s, 1H), 8.71-8.58 (m, 3H), 8.30 (dd, J = 2.0, 1.0 Hz, 1H), 7.96 (d, J = 0.7 Hz, 1H), 7.54 (d, J = 0.7 Hz, 1H), 7.38 (m, 1H), 7.28-7.17 (m, 2H), 7.13-7.00 (m, 2H), 5.21 (m, 1H), 4.88 (t, J = 5.3 Hz, 1H), 4.11 (t, J = 5.6 Hz, 2H), 3.71 (m, 2H), 1.50 (d, J = 7.1 Hz, 3H).

[0229] Example 29: (S)-N-(1-(3-fluorophenyl)ethyl)-5-((1-methyl-2'-oxo-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-5'-yl)ethynyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0230] First step: Take compound 29a (1.00 g, 2.616 mmol) and add 4N hydrochloric acid in dioxane 30 ml, stir at 25°C for 4h, monitor by LC-MS, dry the reaction solution after the reaction is complete, and the obtained crude product compound 29b is directly used in the next step. LC-MS: ESI [M+H] + = 283.1.

[0231] Second step: Take compound 29b (0.80 g, 2.511 mmol) and add dichloromethane 30 ml, drop triethylamine (0.254 mg, 2.511 mmol), after adding drop acetic acid (0.015 mg, 0.251 mmol), add paraformaldehyde (0.151 mg, 5.022 mmol), stir at 25 ℃ for 1 h, add sodium borohydride (1.064 g, 5.022 mmol) in batches, stir at 25 ℃ for 48 h, monitor by LC-MS, after the reaction is completed, the reaction solution is rotary dried, and the obtained crude product is subjected to column chromatography to obtain compound 29c (168 mg). LC-MS: ESI [M+H] + = 297.2.

[0232] Third step: Take compound 29c (0.168 g, 0.567 mmol), trimethylsilylethynyl (0.167 g, 1.702 mmol), triethylamine (0.35 g, 3.40 mmol), Pd (PPh3) 2Cl2 (19.1 mg, 0.028 mmol), cuprous iodide (5.4 mg, 0.028 mmol) and add dioxane 3.0 ml, stir at 100 ℃ for 16 h, monitor by LC-MS, after the reaction is completed, the reaction solution is rotary dried, and the obtained crude product is directly used in the next step. LC-MS: ESI [M+H] + = 314.5.

[0233] Fourth step: Add methanol 15 ml to the crude product of the previous step, add potassium carbonate (0.75 g, 5.10 mmol) and stir at 25 ℃ for 1 h, monitor by LC-MS, after the reaction is completed, filter, rotary dry the filtrate, and the obtained crude product is subjected to column chromatography to obtain compound 29e (289 mg). LC-MS: ESI [M+H] + = 242.3.

[0234] Fifth step: Take compound 1g (100 mg, 0.276 mmol), 29e (66 mg, 0.276 mmol), Pd (dppf) Cl2 (0.021 g, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol), add DMF 2.0 ml, replace with nitrogen for three times, heat to 100 ℃ and stir for 16 h, monitor by LC-MS, after the reaction is completed, rotary dry, and the obtained crude product is subjected to column chromatography and then preparative purification to obtain compound 29 (12 mg, white solid). LC-MS: ESI [M+H] + = 553.6; 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.82 (d, J = 7.2 Hz, 1H), 8.76 (s, 1H), 8.69 (d, J = 7.9 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 8.36 (t, J = 1.4 Hz, 1H), 7.38 (td, J = 8.1, 6.2 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.13 (dd, J = 7.2, 2.0 Hz, 1H), 7.06 (m, 1H), 5.19 (m, 1H), 3.20. (s, 2H), 2.79 (s, 2H), 2.51 (s, 3H), 2.08 (s, 2H), 2.00 (dd, J = 16.1, 8.3 Hz, 2H), 1.50 (d, J = 7.1 Hz, 3H).

[0235] Example 30: (S)-5-((2-(cyclopropylamino)pyrimidin-5-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0236] First step: Compound 30a (0.50 g, 2.336 mmol), trimethylsilylacetylene (0.688 g, 7.007 mmol), triethylamine (1.41 g, 14.01 mmol), Pd(PPh3)2Cl2(82.0 mg, 0.117 mmol), cuprous iodide (22.3 mg, 0.117 mmol) were added into dioxane 5.0 ml, stirred at 100 °C for 16 h, LC-MS monitoring, after the reaction was completed, the reaction liquid was rotary dried, the obtained crude product was continuously transferred to the next step. LC-MS: ESI [M+H] + = 232.4.

[0237] Second step: methanol 15 ml was added to the crude product of the previous step, potassium carbonate (2.68 g, 19.45 mmol) was added, stirred at 25 °C for 1 h, LC-MS monitoring, after the reaction was completed, filtered, the filtrate was rotary dried, the obtained crude product was purified by column chromatography to obtain compound 30c (289 mg). LC-MS: ESI [M+H] + = 160.2.

[0238] Third Step: Take compound 1g (100 mg, 0.276 mmol), 30c (53 mg, 0.276 mmol), Pd(dppf)Cl2(0.021 g, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol), add DMF 2.0 ml, replace with nitrogen three times, warm to 100 °C and stir for 16 h, monitor by LC-MS, dry the reaction solution after the reaction is completed, and the obtained crude product is purified by column chromatography to obtain compound 30 (11 mg, white solid). LC-MS: ESI [M+H] + = 441.5; 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (dd, J = 7.2, 1.0 Hz, 1H), 8.65 (s, 1H), 8.56 (d, J = 7.9 Hz, 1H), 8.49 (s, 2H), 8.21 (dd, J = 2.0, 1.0 Hz, 1H), 7.91 (d, J = 3.9 Hz, 1H), 7.31 (m, 1H), 7.19 - 7.11 (m, 2H), 7.04 - 6.93 (m, 2H), 5.13 (m, 1H), 2.70 (m, 1H), 1.43 (d, J = 7.1 Hz, 3H), 0.64 (m, 2H), 0.49 - 0.38 (m, 2H).

[0239] Example 31: (S)-N-(1-(3-fluorophenyl)ethyl)-5-((2'-oxo-1',2'-dihydrospiro[cyclobutane-1,3'- pyrrolo[2,3-b]pyridin]-5'-yl)ethynyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0240] First Step: Take compound 31a (0.50 g, 1.976 mmol), trimethylsilylethynyl (0.582 g, 5.927 mmol), triethylamine (1.20 g, 11.85 mmol), Pd(PPh3)2Cl2(69.3 mg, 0.099 mmol), cuprous iodide (18.5 mg, 0.099 mmol) and add dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, dry the reaction solution after the reaction is completed, and the obtained crude product is directly used in the next step. LC-MS: ESI [M+H] + = 271.4.

[0241] Second Step: To the crude product of previous step, methanol 20 ml was added, potassium carbonate (2.04 g, 14.79 mmol) was added and stirred at 25 °C for 1 h, LC-MS monitoring, after the reaction was completed, filtered, the filtrate was rotary evaporated, the obtained crude product was purified by column chromatography to give compound 31c (290 mg). LC-MS: ESI [M+H] + = 199.2.

[0242] Third Step: Compound 1g (100 mg, 0.276 mmol), 31c (55 mg, 0.276 mmol), Pd(dppf)Cl2(0.021 g, 0.028 mmol), cuprous iodide (7.9 mg, 0.041 mmol), triethylamine (56.0 mg, 0.552 mmol) were weighed, DMF 2.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 16 h, LC-MS monitoring, after the reaction was completed, rotary evaporated, the obtained crude product was purified by column chromatography to give compound 31 (6 mg, white solid). LC-MS: ESI [M+H] + = 480.5; 1 H NMR (400 MHz, DMSO-d6) d 11.18 (s, 1H), 8.82 (dd, J = 7.2, 0.9 Hz, 1H), 8.74 (s, 1H), 8.65 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 1.9 Hz, 2H), 8.20 (d, J = 1.9 Hz, 1H), 7.38 (m, 1H), 7.28 - 7.18 (m, 2H), 7.12 (dd, J = 7.2, 2.0 Hz, 1H), 7.06 (m, 1H), 5.21 (m, 1H), 2.48 - 2.41 (m, 2H), 2.41 - 2.31 (m, 2H), 2.31 - 2.11 (m, 2H), 1.50 (d, J = 7.1 Hz, 3H).

[0243] Example 32: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)-3,4- dihydro-1,5-naphthyridine-1 (2H)-carboxamide

[0244] First Step: Take compound 32a (1.00 g, 4.693 mmol) into dichloromethane 10 ml, cool down to 0 ℃ under stirring, add triphosgene (0.46 g, 1.549 mmol) in batches, stir for 30 min, add DIEA (2.43 g, 18.77 mmol) dropwise, stir for 30 min, then add (S)-1-(3-fluorophenyl)ethylamine (0.65 g, 4.693 mmol), and then stir overnight at 25 ℃. After the reaction is completed, add water for extraction, dry the organic phase, and purify the obtained crude product by column chromatography to obtain compound 32b (1.42 g, white solid). LC-MS: ESI [M+H] + = 379.3; 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.37 (td, J = 8.1, 6.2 Hz, 1H), 7.24-7.17 (m, 2H), 7.09-7.01 (m, 1H), 4.92 (m, 1H), 3.78-3.61 (m, 2H), 2.81 (t, J = 6.4 Hz, 2H), 1.94 (m, 2H), 1.44 (d, J = 7.1 Hz, 3H).

[0245] Second Step: Take compound 32b (100 mg, 0.263 mmol), 1j (37 mg, 0.316 mmol), Pd(dppf)Cl2(0.019 g, 0.026 mmol), cuprous iodide (7.5 mg, 0.039 mmol), triethylamine (66.5 mg, 0.658 mmol), add DMF 2.0 ml, replace with nitrogen for three times, warm up to 100 ℃ and stir for 16 h. After the reaction is completed, dry, and purify the obtained crude product by column chromatography to obtain compound 32 (10 mg, white solid) by preparative purification. LC-MS: ESI [M+H] + = 417.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 2H), 8.18 (d, J = 1.9 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.37 (td, J = 8.1, 6.2 Hz, 1H), 7.22 (d, J = 1.7 Hz, 1H), 7.21-7.18 (m, 1H), 7.16 (s, 2H), 7.07-7.01 (m, 1H), 4.91 (m, 1H), 3.80-3.61 (m, 2H), 2.86 (t, J = 6.5 Hz, 2H), 1.95 (m, 2H), 1.44 (d, J = 7.1 Hz, 3H).

[0246] Example 33: (S)-6-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)- 2,3-dihydro-4H-benzo[6][1,4]oxazin-4-carboxamide

[0247] First Step: Take compound 33a (2.24 g, 10.464 mmol) into dichloromethane 10 ml, cool down to 0 °C, add triphosgene (1.02 g, 3.453 mmol) in batches, stir for 30 min, add DIEA (5.41 g, 41.85 mmol) dropwise, stir for 30 min, add (S)-1-(3-fluorophenyl) ethanamine (1.46 g, 10.46 mmol), then stir overnight at 25 °C. LC-MS monitoring, after the reaction is completed, add water to extract, dry the organic phase, and the obtained crude product is purified by column chromatography to obtain compound 33b (2.16 g, white solid). LC-MS: ESI [M+H] + = 380.2; 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.38 (td, J = 8.1, 6.2 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.09 - 7.00 (m, 2H), 6.81 (d, J = 8.6 Hz, 1H), 4.90 (m, 1H), 4.26 - 4.14 (m, 2H), 3.79 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H).

[0248] Second Step: Take compound 33b (100 mg, 0.263 mmol), 1j (37 mg, 0.316 mmol), Pd(dppf)Cl2(0.019 g, 0.026 mmol), cuprous iodide (7.5 mg, 0.039 mmol), triethylamine (66.5 mg, 0.658 mmol), add DMF 2.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 16 h, LC-MS monitoring, dry after the reaction is completed, and the obtained crude product is purified by column chromatography and then prepared to obtain compound 33 (3 mg, white solid). LC-MS: ESI [M+H] + = 418.4; 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 2H), 7.78 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.37 (td, J = 7.8, 6.0 Hz, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.20 (d, J = 2.9 Hz, 1H), 7.07 (s, 2H), 7.04 (dd, J = 8.4, 2.1 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.90 (m, 1H), 4.29 - 4.18 (m, 2H), 3.81 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H).

[0249] Example 34: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide

[0250] Compound 27b (100 mg, 0.263 mmol), 6a (56 mg, 0.395 mmol), Pd(dppf)Cl2(0.019 g, 0.026 mmol), cuprous iodide (7.5 mg, 0.039 mmol), triethylamine (66.5 mg, 0.658 mmol) were weighed out, DMF 2.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C, stirred for 16 h, monitored by LC-MS, after the reaction was completed, rotary evaporation was performed, the obtained crude product was purified by column chromatography to give compound 34 (15 mg, white solid). LC-MS: ESI [M+H] + = 442.4; 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.05 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.37 (td, J = 7.7, 5.9 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.08 - 7.01 (m, 1H), 4.90 (m, 1H), 4.38 (t, J = 4.5 Hz, 2H), 3.85 (td, J = 4.3, 1.8 Hz, 2H), 1.43 (d, J = 7.1 Hz, 3H).

[0251] Example 35: (S)-5-((2-Aminopyrimidin-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)-1- methyl-1H-indole-3-carboxamide

[0252] First step: Take compound 35a (1.00 g, 3.93 mmol), methyl iodide (4.92 g, 4.92 mmol), cesium carbonate (1.80 g, 5.54 mmol) into DMF 15 ml, warm up to 80 ℃ and stir for 3 h. Monitor by LC-MS. After the reaction is completed, add water, filter to obtain compound 35b (0.96 g, white solid). LC-MS: ESI [M+H] + = 268.0.

[0253] Second step: Take compound 35b (0.96 g, 3.58 mmol), lithium hydroxide (0.45 g, 18.60 mmol) into methanol 15 ml, water 1.5 ml, warm up to 50 ℃ and stir for 3 h. Monitor by LC-MS. After the reaction is completed, adjust the pH of the solution to 4-5 with 1N aqueous hydrochloric acid solution to obtain compound 35c (0.74 g, white solid). LC-MS: ESI [M+H] + = 255.1.

[0254] Third step: Take compound 35c (0.50 g, 1.96 mmol), (S)-1-(3-fluorophenyl) ethylamine (0.325 g, 2.36 mmol), HATU (0.50 g, 3.92 mmol), DIEA (0.506 g, 3.92 mmol) into DMF 5.0 ml, warm up to 50 ℃ and stir for 16 h. Monitor by LC-MS. After the reaction is completed, add water, extract with ethyl acetate, dry the organic phase, and purify the obtained crude product by column chromatography to obtain compound 35d (400 mg). LC-MS: ESI [M+H] + = 423.3.

[0255] Fourth step: Take compound 35d (100 mg, 0.266 mmol), 1j (39 mg, 0.320 mmol), Pd(dppf)Cl2 (0.020 g, 0.027 mmol), cuprous iodide (7.8 mg, 0.040 mmol), triethylamine (67.4 mg, 0.666 mmol) into DMF 2.0 ml, replace with nitrogen three times, warm up to 100 ℃ and stir for 16 h. Monitor by LC-MS. After the reaction is completed, dry, and purify the obtained crude product by column chromatography to obtain compound 35 (2 mg, white solid). LC-MS: ESI [M+H] + = 414.4; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 3H), 8.30 - 8.22 (m, 2H), 7.54 (d, J = 8.6 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.27 - 7.19 (m, 2H), 7.09 - 7.00 (m, 3H), 5.19 (m, 1H), 3.86 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H).

[0256] Example 36: (S)-5-((6-amino-5-(trifluoromethoxy)pyridin-3-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0257] First step: Take compound 36a (1.00 g, 3.891 mmol), trimethylsilylethynyl (1.15 g, 11.67 mmol), triethylamine (2.36 g, 23.34 mmol), Pd(PPh3)2Cl2 (140.0 mg, 0.195 mmol), cuprous iodide (40.0 mg, 0.195 mmol) into dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, after the reaction is completed, the reaction solution is rotary dried, and the obtained crude product is directly used in the next step. LC-MS: ESI [M+H] + = 275.4.

[0258] Second step: Add methanol 20 ml into the crude product of the previous step, and add potassium carbonate (4.03 g, 29.16 mmol) and stir at 25 °C for 1 h, monitor by LC-MS, after the reaction is completed, filter, and the filtrate is rotary dried. The obtained crude product is purified by column chromatography to obtain compound 36c (480 mg). LC-MS: ESI [M+H] + = 203.1.

[0259] Third step: Take compound 1g (150 mg, 0.414 mmol), 36c (101 mg, 0.497 mmol), Pd(dppf)Cl2 (0.031 g, 0.041 mmol), cuprous iodide (11.8 mg, 0.062 mmol), triethylamine (104.8 mg, 1.035 mmol), add DMF 3.0 ml, replace with nitrogen for three times, and stir at 100 °C for 16 h. Monitor by LC-MS, after the reaction is completed, rotary dry, and the obtained crude product is purified by column chromatography to obtain compound 36 (45 mg, white solid). LC-MS: ESI [M+H] + = 484.4; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (dd, J = 7.1, 0.9 Hz, 1H), 8.72 (s, 1H), 8.62 (d, J = 7.9 Hz, 1H), 8.28 (dd, J = 1.8, 0.9 Hz, 1H), 8.22 (d, J = 1.9 Hz, 1H), 7.76 (t, J = 1.7 Hz, 1H), 7.38 (td, J = 8.2, 6.4 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.13 - 7.01 (m, 4H), 5.20 (m, 1H), 1.49 (d, J = 7.0 Hz, 3H).

[0260] Example 37: (S)-5-((6-amino-5-methoxypyridin-3-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0261] First step: Take compound 37a (1.00 g, 4.925 mmol), trimethylsilylethynyl (1.45 g, 14.77 mmol), triethylamine (2.99 g, 29.55 mmol), Pd(PPh3)2Cl2 (170.0 mg, 0.246 mmol), cuprous iodide (50.0 mg, 0.246 mmol) into dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, after the reaction is completed, spin dry the reaction solution, the obtained crude product is directly used for the next step. LC-MS: ESI [M+H] + = 221.4.

[0262] Second step: Add methanol 20 ml into the crude product of the previous step, add potassium carbonate (6.27 g, 45.38 mmol), stir at 25 °C for 1 h, monitor by LC-MS, after the reaction is completed, filter, spin dry the filtrate, the obtained crude product is purified by column chromatography to obtain compound 37c (650 mg). LC-MS: ESI [M+H] + = 149.2.

[0263] Third step: Take compound 1g (0.150 g, 0.414 mmol), 37c (0.074 g, 0.497 mmol), Pd(dppf)Cl2 (0.031 g, 0.041 mmol), cuprous iodide (11.8 mg, 0.062 mmol), triethylamine (104.8 mg, 1.035 mmol), add DMF 3.0 ml, replace with nitrogen for three times, heat to 100 °C, stir for 16 h, monitor by LC-MS, after the reaction is completed, spin dry, the obtained crude product is purified by column chromatography to obtain compound 37 (30 mg, white solid). LC-MS: ESI [M+H] + = 430.5;1 H NMR (400 MHz, DMSO-d6) δ 8.77 (dd, J = 7.2, 1.0 Hz, 1H), 8.71 (s, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.25 (dd, J = 1.9, 1.0 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.38 (td, J = 8.1, 6.3 Hz, 1H), 7.22 (m, 3H), 7.09 - 7.02 (m, 2H), 6.35 (s, 2H), 5.28 - 5.11 (m, 1H), 3.82 (s, 3H), 1.49 (d, J = 7.1 Hz, 3H).

[0264] Example 38: (5-((2-aminopyrimidin-5-yl)ethynyl)pyrazolo[1,5-a]pyridin-3-yl)(3-(3- fluorophenyl)isoxazolidin-2-yl)methanone

[0265] First step: Take compound 1f (0.200 g, 0.830 mmol), 24a (0.138 g, 0.830 mmol), HATU (0.378 g, 0.996 mmol), DIEA (0.22 g, 1.659 mmol) into DMF 2.0 ml, stir at 50 °C for 16 h, monitor by LC-MS, after the reaction is completed, add water, extract with ethyl acetate, wash the organic phase with saturated brine, rotary evaporate the organic phase, the obtained crude product is column chromatographed to obtain compound 38a (0.200 g). LC-MS: ESI [M+H] + = 391.2.

[0266] Second step: Take compound 38a (100 mg, 0.256 mmol), 1j (36 mg, 0.308 mmol), Pd(dppf)Cl2(0.019 g, 0.026 mmol), cuprous iodide (7.3 mg, 0.038 mmol), triethylamine (53.0 mg, 0.523 mmol), into DMF 2.0 ml, replace with nitrogen for three times, warm to 100 °C and stir for 16 h, monitor by LC-MS, after the reaction is completed, rotary evaporate, the obtained crude product is column chromatographed to obtain compound 38 (23 mg, white solid) by preparative purification. LC-MS: ESI [M+H] + = 429.4; 1H NMR (400 MHz, DMSO-d6) δ 8.87 (dd, J = 7.1, 1.0 Hz, 1H), 8.67 (s, 1H), 8.50 (s, 2H), 8.32 (dd, J = 2.0, 0.9 Hz, 1H), 7.43 (m, 1H), 7.27 (s, 2H), 7.26 - 7.19 (m, 2H), 7.19 - 7.09 (m, 2H), 5.62 (dd, J = 8.7, 6.3 Hz, 1H), 4.38 (td, J = 7.8, 2.9 Hz, 1H), 3.91 (m, 1H), 2.94 (m, 1H), 2.37 - 2.22 (m, 1H).

[0267] Example 39: (S)-5-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0268] First step: Take compound 1f (0.20 g, 0.83 mmol), 39a (0.177 g, 0.83 mmol), HATU (0.378 g, 0.996 mmol), DIEA (0.43 g, 3.31 mmol) into DMF 2.0 ml, stir at 50 °C for 16 h, monitor by LC-MS, after the reaction is completed, add water, extract with ethyl acetate, wash the organic phase with saturated brine, rotary evaporate the organic phase, the obtained crude product is column chromatographed to obtain compound 39b (0.28 g). LC-MS: ESI [M+H] + = 363.2.

[0269] Second step: Take compound 39b (150 mg, 0.413 mmol), 1j (55 mg, 0.454 mmol), Pd(dppf)Cl2(0.030 g, 0.041 mmol), cuprous iodide (11.9 mg, 0.062 mmol), triethylamine (105 mg, 1.033 mmol), into DMF 2.0 ml, replace with nitrogen for three times, warm to 100 °C, stir for 16 h, monitor by LC-MS, after the reaction is completed, rotary evaporate, the obtained crude product is column chromatographed to obtain compound 39 (50 mg, white solid) by preparative purification. LC-MS: ESI [M+H] + = 402.1; 1H NMR (400 MHz, DMSO-d6) δ 8.81-8.77 (m, 1H), 8.76 (s, 1H), 8.67 (d, J = 7.7 Hz, 1H), 8.52 (d, J = 3.0 Hz, 1H), 8.49 (s, 2H), 8.30-8.22 (m, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.50 (dd, J = 8.8, 4.5 Hz, 1H), 7.26 (s, 2H), 7.07 (dd, J = 7.2, 1.9 Hz, 1H), 5.32-5.18 (m, 1H), 1.52 (d, J = 7.1 Hz, 3H).

[0270] Example 40: (S)-5-((6-amino-5-(difluoromethyl)pyridin-3-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0271] First Step: Take compound 40a (1.50 g, 7.462 mmol) add dichloromethane 20 ml, drop DAST (12.20 g, 74.62 mmol) under stirring, at 25 °C for 16 h, monitor by LC-MS, after completion of reaction, take reaction mixture in water, extract organic phase, dry the organic phase, get crude product, purify by column chromatography to get compound 40b (940 mg). LC-MS: ESI [M+H] + = 223.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.81-8.77 (m, 1H), 8.76 (s, 1H), 8.67 (d, J = 7.7 Hz, 1H), 8.52 (d, J = 3.0 Hz, 1H), 8.49 (s, 2H), 8.30-8.22 (m, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.50 (dd, J = 8.8, 4.5 Hz, 1H), 7.26 (s, 2H), 7.07 (dd, J = 7.2, 1.9 Hz, 1H), 5.32-5.18 (m, 1H), 1.52 (d, J = 7.1 Hz, 3H).

[0272] Second Step: Take compound 40b (0.90 g, 4.036 mmol), trimethylsilylethynyl (1.19 g, 12.10 mmol), triethylamine (2.45 g, 24.21 mmol), Pd(PPh3)2Cl2 (141.0 mg, 0.202 mmol), cuprous iodide (40.0 mg, 0.202 mmol) in dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, after completion of reaction, dry the reaction mixture, take crude product for next step. LC-MS: ESI [M+H] + = 241.1.

[0273] Third step: add methanol 20 ml to the crude product of the previous step, add potassium carbonate (4.60 g, 33.28 mmol) and stir at 25 °C for 1 h, monitor by LC-MS, filter after the reaction is complete, and dry the filtrate by evaporation. The resulting crude product is purified by column chromatography to obtain compound 40d (400 mg). LC-MS: ESI [M+H] + = 169.1.

[0274] Third step: weigh compound 1g (150 mg, 0.414 mmol), 40d (91 mg, 0.538 mmol), Pd(dppf)Cl2(0.031 g, 0.041 mmol), cuprous iodide (11.8 mg, 0.062 mmol), triethylamine (125.8 mg, 1.242 mmol), add DMF 3.0 ml, replace with nitrogen three times, warm to 100 °C and stir for 16 h, monitor by LC-MS, dry by evaporation after the reaction is complete, and purify the resulting crude product by column chromatography to obtain compound 40 (64 mg, white solid). LC-MS: ESI [M+H] + = 450.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 7.2 Hz, 1H), 8.72 (s, 1H), 8.62 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.27 (t, J = 1.3 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.38 (td, J = 8.0, 6.2 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.16 - 6.99 (m, 3H), 6.87 (d, J = 2.6 Hz, 2H), 5.28 - 5.13 (m, 1H), 1.49 (d, J = 7.0 Hz, 3H).

[0275] Example 41: (S)-5-((2-amino-5-methylthiazol-4-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0276] First step: weigh compound 41a (1.00 g, 5.180 mmol), trimethylsilylethynyl (1.53 g, 15.54 mmol), triethylamine (3.15 g, 31.07 mmol), Pd(PPh3)2Cl2(182.0 mg, 0.259 mmol), cuprous iodide (49.0 mg, 0.259 mmol), add dioxane 10 ml, stir at 100 °C for 16 h, monitor by LC-MS, dry the reaction solution by evaporation after the reaction is complete, and transfer the resulting crude product to the next step. LC-MS: ESI [M+H] + = 211.1.

[0277] Second Step: To the crude of previous step, add methanol 20 ml, add potassium carbonate (4.59 g, 33.27 mmol) and stir at 25 °C for 1 h, monitor by LC-MS, after the reaction is completed, filter, spin dry the filtrate, the obtained crude compound 41c (100 mg) is obtained by column chromatography. LC-MS: ESI [M+H] + = 139.0.

[0278] Third Step: Take compound 1g (200 mg, 0.552 mmol), 41c (99 mg, 0.718 mmol), Pd(dppf)Cl2(0.041 g, 0.055 mmol), cuprous iodide (15.7 mg, 0.083 mmol), triethylamine (167.8 mg, 1.657 mmol), add DMF 3.0 ml, replace with nitrogen three times, heat to 100 °C and stir for 16 h, monitor by LC-MS, after the reaction is completed, spin dry, the obtained crude compound 41 (18 mg, white solid) is obtained by column chromatography and preparative purification. LC-MS: ESI [M+H] + = 420.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 7.2 Hz, 1H), 8.73 (s, 1H), 8.63 (d, J = 7.9 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 7.38 (td, J = 8.0, 6.2 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.10 - 7.00 (m, 2H), 6.96 (s, 2H), 5.29 - 5.11 (m, 1H), 2.37 (s, 3H), 1.49 (d, J = 7.0 Hz, 3H).

[0279] Example 42: (S)-1-(3-fluorophenyl)ethyl 7-((2-aminopyrimidin-5-yl)ethynyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxylate

[0280] First Step: Take compound 27a (0.5 g, 2.325 mmol) and add dichloromethane 10 ml, stir and cool to 0 °C, add triphosgene (0.23 g, 0.76 mmol) in batches, stir for 30 min, add triethylamine (1.20 g, 9.30 mmol) dropwise, stir for 30 min, add compound 42a (0.32 g, 2.325 mmol), then stir at 25 °C overnight. Monitor by LC-MS, after the reaction is completed, add water to extract, spin dry the organic phase, the obtained crude compound 42b (42 mg, white solid) is obtained by column chromatography and purification. LC-MS: ESI [M+H]+ = 381.0.

[0281] Second Step: Take compound 42b (150 mg, 0.393 mmol), 1j (70 mg, 0.590 mmol), Pd(dppf)Cl2(0.029 g, 0.039 mmol), copper iodide (11.3 mg, 0.059 mmol), triethylamine (120.2 mg, 1.180 mmol), add DMF 3.0 ml, replace with nitrogen three times, warm up to 100 °C, stir for 16 h, monitor by LC-MS, after the reaction is completed, spin dry, the obtained crude product is purified by column chromatography to obtain compound 42 (24 mg, white solid). LC-MS: ESI [M+H] + = 420.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.6 Hz, 3H), 8.03 (d, J = 2.1 Hz, 1H), 7.48-7.38 (m, 1H), 7.35-7.24 (m, 2H), 7.20-7.10 (m, 3H), 5.85 (m, 1H), 4.43 (t, J = 4.6 Hz, 2H), 3.98 (t, J = 4.6 Hz, 2H), 1.57 (d, J = 6.6 Hz, 3H).

[0282] Example 43: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(5-fluoropyridin-2-yl)ethyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine-1-carboxamide

[0283] First Step: Take compound 43a (0.80 g, 3.462 mmol) and add dichloromethane 10 ml, stir and cool to 0 °C, add triphosgene (0.34 g, 1.142 mmol) in batches, stir for 30 min, add DIEA (1.80 g, 13.84 mmol) dropwise, stir for 30 min, add 39a (0.50 g, 3.462 mmol), then stir at 25 °C overnight. Monitor by LC-MS, after the reaction is completed, add water to extract, spin dry the organic phase, the obtained crude product is purified by column chromatography to obtain compound 43b (1.13 g, white solid). LC-MS: ESI [M+H] + = 396.0.

[0284] Second Step: Take compound 43b (0.250 g, 0.631 mmol), 1j (0.112 g, 0.946 mmol), Pd(dppf)Cl2(0.046 g, 0.063 mmol), copper iodide (18.3 mg, 0.095 mmol), triethylamine (191.2 mg, 1.893 mmol), add DMF 3.0 ml, replace with nitrogen three times, warm to 100 °C and stir for 16 h. Monitor by LC-MS, after the reaction is completed, spin dry, and the obtained crude product is purified by column chromatography to obtain compound 43 (33 mg, white solid). LC-MS: ESI [M+H] + = 435.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 0.6 Hz, 2H), 8.22 (dd, J = 2.0, 0.7 Hz, 1H), 7.62 (dd, J = 2.0, 0.7 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.37 (td, J = 8.0, 6.1 Hz, 1H), 7.22 - 7.13 (m, 3H), 7.04 (td, J = 8.6, 2.6 Hz, 1H), 4.96 - 4.83 (m, 1H), 4.01 - 3.91 (m, 1H), 3.91 - 3.79 (m, 1H), 3.28 - 3.21 (m, 2H), 1.41 (d, J = 7.0 Hz, 3H).

[0285] Example 44: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0286] First Step: Take compound 27a (0.50 g, 2.325 mmol) and add dichloromethane 10 ml, and stir while cooling to 0 °C. Add triphosgene (0.23 g, 0.76 mmol) in batches, stir for 30 min, add DIEA (1.80 g, 13.95 mmol) dropwise, stir for 30 min, add 39a (0.50 g, 2.325 mmol), and then stir at 25 °C overnight. Monitor by LC-MS, add water after the reaction is complete, extract the organic phase, spin dry, and the obtained crude product is purified by column chromatography to obtain compound 44a (600 mg, white solid). LC-MS: ESI [M+H] + = 381.0.

[0287] Second Step: Take compound 44a (200 mg, 0.525 mmol), 1j (93 mg, 0.787 mmol), Pd(dppf)Cl2(0.038 g, 0.052 mmol), copper iodide (15.3 mg, 0.079 mmol), triethylamine (159.2 mg, 1.574 mmol), add DMF 3.0 ml, replace with nitrogen three times, stir at 100 °C for 16 h, monitor by LC-MS, dry after the reaction is completed, and the obtained crude product is purified by column chromatography to obtain compound 44 (33 mg, white solid). LC-MS: ESI [M+H] + = 420.5; 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 0.7 Hz, 2H), 8.24 (dd, J = 2.1, 0.7 Hz, 1H), 7.93 (dd, J = 2.1, 0.7 Hz, 1H), 7.70 (td, J = 8.7, 2.9 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.7, 4.5 Hz, 1H), 7.13 (s, 2H), 5.00 - 4.89 (m, 1H), 4.38 (t, J = 4.6 Hz, 2H), 3.94 - 3.77 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

[0288] Example 45: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxamide

[0289] Take compound 32b (150 mg, 0.397 mmol), 6a (85 mg, 0.595 mmol), Pd(dppf)Cl2(0.029 g, 0.040 mmol), copper iodide (11.5 mg, 0.059 mmol), triethylamine (100.5 mg, 0.998 mmol), add DMF 2.0 ml, replace with nitrogen three times, stir at 100 °C for 16 h, monitor by LC-MS, dry after the reaction is completed, and the obtained crude product is purified by column chromatography to obtain compound 45 (30 mg, white solid). LC-MS: ESI [M+H] + = 440.1; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.08 (s, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.84 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.37 (td, J = 8.1, 6.2 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.04 (td, J = 8.8, 8.3, 2.2 Hz, 1H), 4.97 - 4.86 (m, 1H), 3.80 - 3.63 (m, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.02 - 1.86 (m, 2H), 1.44 (d, J = 7.0 Hz, 3H).

[0290] Example 46: (7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-3,4-dihydro-1,5- naphthyridin-1(2H)-yl)(3-(3-fluorophenyl)isoxazolidin-2-yl)methanone

[0291] First step: Take compound 32a (0.5 g, 2.325 mmol) into dichloromethane 10 ml, under stirring, cooling to 0 °C, add triphosgene (0.23 g, 0.76 mmol) in batches, stir for 30 min, add triethylamine (1.20 g, 9.30 mmol) dropwise, stir for 30 min, add 24a (0.39 g, 2.325 mmol), then stir at 25 °C overnight. LC-MS monitoring, after the reaction is completed, add water to extract, the organic phase is dried, and the obtained crude product is purified by column chromatography to obtain compound 46a (500 mg, white solid). LC-MS: ESI [M+H] + = 406.1.

[0292] Second step: Take compound 46a (200 mg, 0.490 mmol), 6a (83 mg, 0.588 mmol), Pd(dppf)Cl2(0.036 g, 0.049 mmol), cuprous iodide (14.3 mg, 0.073 mmol), triethylamine (149.2 mg, 1.474 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm to 100 °C, stir for 16 h, LC-MS monitoring, after the reaction is completed, dry, and the obtained crude product is purified by column chromatography to obtain compound 46 (68 mg, white solid). LC-MS: ESI [M+H] + = 468.2; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.09 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 58.8 Hz, 1H), 7.40 (td, J = 7.9, 6.1 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.09 (td, J = 8.6, 2.6 Hz, 1H), 5.43 (dd, J = 8.7, 5.2 Hz, 1H), 4.16 (td, J = 7.9, 3.5 Hz, 1H), 4.00 - 3.82 (m, 2H), 3.64 (m, 1H), 2.94 - 2.82 (m, 3H), 2.24 - 2.12 (m, 1H), 2.04 - 1.95 (m, 1H), 1.95 - 1.83 (m, 1H).

[0293] Example 47: (7-((2-aminopyrimidin-5-yl)ethynyl)-3,4-dihydro-l,5-naphthyridin-l(2H)- yl)(3-(3-fluorophenyl)isoxazolidin-2-yl)methanone

[0294] Compound 46a (200 mg, 0.490 mmol), 1j (87 mg, 0.735 mmol), Pd(dppf)Cl2(0.036 g, 0.049 mmol), cuprous iodide (14.3 mg, 0.073 mmol), triethylamine (149.2 mg, 1.474 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C, stirred for 16 h, LC-MS monitoring, after the reaction was completed, rotary evaporation, the obtained crude product was purified by column chromatography to give compound 47 (39 mg, white solid). LC-MS: ESI [M+H] + = 445.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H), 8.25 (d, J = 1.8 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.40 (td, J = 7.9, 6.1 Hz, 1H), 7.23 - 7.14 (m, 4H), 7.09 (td, J = 8.6, 2.7 Hz, 1H), 5.43 (dd, J = 8.7, 5.2 Hz, 1H), 4.16 (td, J = 7.9, 3.5 Hz, 1H), 3.98 - 3.81 (m, 2H), 3.63 (m, 1H), 2.96 - 2.81 (m, 3H), 2.26 - 2.11 (m, 1H), 2.06 - 1.95 (m, 1H), 1.94 - 1.84 (m, 1H).

[0295] Example 48: (7-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)(3-(3-fluorophenyl)isoxazolidin-2-yl)methanone

[0296] First Step: Take compound 27a (0.5 g, 2.325 mmol) into dichloromethane 10 ml, cool down to 0 °C under stirring, add triphosgene (0.23 g, 0.76 mmol) in batches, stir for 30 min, add triethylamine (1.20 g, 9.30 mmol) dropwise, stir for 30 min, add 24a (0.39 g, 2.325 mmol), then stir at 25 °C overnight. LC-MS monitoring, after the reaction is completed, add water to extract, dry the organic phase, and the obtained crude product is purified by column chromatography to obtain compound 48a (500 mg, white solid). LC-MS: ESI [M+H] + = 408.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 2.3 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.41 (td, J = 8.2, 6.3 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.14 - 7.07 (m, 1H), 5.49 (dd, J = 8.6, 5.4 Hz, 1H), 4.47 - 4.40 (m, 1H), 4.36 - 4.25 (m, 1H), 4.24 - 4.15 (m, 1H), 4.06 - 4.00 (m, 1H), 4.00 - 3.92 (m, 1H), 3.78 - 3.69 (m, 1H), 2.95 - 2.84 (m, 1H), 2.29 - 2.15 (m, 1H).

[0297] Second Step: Take compound 48a (200 mg, 0.490 mmol), 6a (83 mg, 0.588 mmol), Pd(dppf)Cl2(0.036 g, 0.049 mmol), cuprous iodide (14.3 mg, 0.073 mmol), triethylamine (149.2 mg, 1.474 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm up to 100 °C and stir for 16 h, LC-MS monitoring, after the reaction is completed, dry, and the obtained crude product is purified by column chromatography and then prepared to obtain compound 48 (23 mg, white solid). LC-MS: ESI [M+H] + = 470.2; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.10-8.04 (m, 2H), 8.02 (d, J = 2.1 Hz, 1H), 7.84 (m, 1H), 7.41 (td, J = 8.0, 6.1 Hz, 1H), 7.28-7.17 (m, 2H), 7.14-7.07 (m, 1H), 5.49 (dd, J = 8.6, 5.3 Hz, 1H), 4.47 (m, 1H), 4.38-4.27 (m, 1H), 4.18 (td, J = 7.9, 3.5 Hz, 1H), 4.05 (m, 1H), 4.01-3.91 (m, 1H), 3.76 (m, 1H), 2.96-2.82 (m, 1H), 2.29-2.15 (m, 1H).

[0298] Example 49: (7-((2-aminopyrimidin-5-yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1 -yl)(3-(3-fluorophenyl)isoxazolidin-2-yl)methanone

[0299] Compound 48a (0.200 g, 0.490 mmol), 1j (0.087 g, 0.735 mmol), Pd(dppf)Cl2(0.036 g, 0.049 mmol), cuprous iodide (14.3 mg, 0.073 mmol), triethylamine (149.2 mg, 1.474 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C, stirred for 16 h, monitored by LC-MS, after the reaction was completed, rotary evaporation was carried out, and the obtained crude product was purified by column chromatography to give compound 49 (50 mg, white solid). LC-MS: ESI [M+H] + = 447.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 2H), 8.05 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.40 (td, J = 8.0, 6.0 Hz, 1H), 7.27-7.19 (m, 2H), 7.16 (s, 2H), 7.10 (td, J = 8.6, 2.6 Hz, 1H), 5.50 (dd, J = 8.6, 5.3 Hz, 1H), 4.52-4.41 (m, 1H), 4.38-4.27 (m, 1H), 4.25-4.13 (m, 1H), 4.12-4.00 (m, 1H), 3.96 (m, 1H), 3.80-3.69 (m, 1H), 2.97-2.77 (m, 1H), 2.30-2.14 (m, 1H).

[0300] Example 50: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-3,4-dihydro-1,5-naphthyridine-1 (2H)-carboxamide

[0301] First step: Take compound 32a (0.50 g, 2.347 mmol) into dichloromethane 10 ml, under stirring, cool down to 0 °C, add triphosgene (0.23 g, 0.774 mmol) in batches, stir for 30 min, add DIEA (1.80 g, 13.95 mmol) dropwise, stir for 30 min, add 39a (0.50 g, 2.347 mmol), then stir at 25 °C overnight. LC-MS monitoring, after the reaction is completed, add water to extract, dry the organic phase, the obtained crude product is purified by column chromatography to obtain compound 50a (800 mg, white solid). LC-MS: ESI [M+H] + = 379.0.

[0302] Second step: Take compound 50a (200 mg, 0.525 mmol), 1j (93 mg, 0.787 mmol), Pd(dppf)Cl2(0.038 g, 0.052 mmol), cuprous iodide (15.3 mg, 0.079 mmol), triethylamine (159.2 mg, 1.574 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 16 h, LC-MS monitoring, after the reaction is completed, dry, the obtained crude product is purified by column chromatography and then prepared to obtain compound 50 (32 mg, white solid). LC-MS: ESI [M+H] + = 418.2; 1 H NMR (400 MHz, DMSO-d6) d 8.50 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 0.7 Hz, 2H), 8.19 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.70 (td, J = 8.8, 2.9 Hz, 1H), 7.50 (dd, J = 8.7, 4.5 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.16 (s, 2H), 5.02 - 4.90 (m, 1H), 3.81 - 3.63 (m, 2H), 2.86 (t, J = 6.5 Hz, 2H), 2.01 - 1.89 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

[0303] Example 51: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0304] Compound 44a (200 mg, 0.525 mmol), 6a (90 mg, 0.630 mmol), Pd(dppf)Cl2(0.039 g, 0.052 mmol), Copper(I)iodide (15.3 mg, 0.079 mmol), triethylamine (159.2 mg, 1.587 mmol) were weighed out and added to DMF 3.0 ml, replaced with nitrogen for three times, warmed to 100 °C and stirred for 16 h, monitored by LC-MS, after the reaction was completed, rotary evaporation, the obtained crude product was purified by column chromatography to give compound 51 (30 mg). LC-MS: ESI [M+H] + = 443.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.27 (dd, J = 2.1, 0.8 Hz, 1H), 8.06 (s, 1H), 7.95 (dd, J = 2.1, 0.7 Hz, 1H), 7.83 (s, 1H), 7.74 - 7.66 (m, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.8, 4.5 Hz, 1H), 5.01 - 4.87 (m, 1H), 4.39 (t, J = 4.6 Hz, 2H), 3.96 - 3.77 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

[0305] Example 52: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxamide

[0306] Compound 50a (150 mg, 0.396 mmol), 6a (84 mg, 0.593 mmol), Pd(dppf)Cl2(0.029 g, 0.040 mmol), Copper(I)iodide (11.3 mg, 0.059 mmol), triethylamine (119.2 mg, 1.187 mmol) were weighed out and added to DMF 3.0 ml, replaced with nitrogen for three times, warmed to 100 °C and stirred for 16 h, monitored by LC-MS, after the reaction was completed, rotary evaporation, the obtained crude product was purified by column chromatography to give compound 52 (30 mg, white solid). LC-MS: ESI [M+H] += 441.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 8.09-8.04 (m, 2H), 7.84 (s, 1H), 7.74-7.66 (m, 1H), 7.54-7.43 (m, 2H), 5.02-4.90 (m, 1H), 3.82-3.66 (m, 2H), 2.87 (t, J = 6.5 Hz, 2H), 2.01-1.90 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

[0307] Example 53: (5-((2-aminopyrimidin-5-yl)ethynyl)pyrazolo[1,5-a]pyridin-3-yl)(3-(5- fluoropyridin-2-yl)isoxazolidin-2-yl)methanone

[0308] First step: Take compound 53a (3.0 g, 23.98 mmol), triethylenediamine (0.27 g, 2.39 mmol), propylene glycol (isopropylidene) (3.46 g, 23.98 mmol), 53b (3.15 g, 23.98 mmol), add 40 ml of ethyl acetate, stir at 25°C for 16 h, monitor by LC-MS, after the reaction is complete, add saturated brine to wash, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 53c (6.00 g).

[0309] Second step: Take compound 53c (6.00 g, 21.25 mmol), add THF 200 ml, add lithium borohydride (1.39 g, 63.76 mmol) in batches with stirring, stir for 2 h after addition, monitor by LC-MS, add water after the reaction is complete, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 53d (5.50 g).

[0310] Third step: Take compound 53d (5.50 g, 19.21 mmol), triphenylphosphine (7.56 g, 28.81 mmol), add THF 50 ml, cool to 0°C, add DIAD (5.83 g, 28.81 mmol) dropwise, stir for 1 h after addition, monitor by LC-MS, add saturated brine to wash after the reaction is complete, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate, and the obtained compound 53e crude product is directly used in the next step reaction.

[0311] Fourth step: Take compound 53e (5.50 g, 20.50 mmol), add 40 ml of 4M hydrochloric acid ethyl acetate solution, stir at 25°C for 2h, monitor by LC-MS, after the reaction is completed, add 1N hydrochloric acid aqueous solution to extract, wash the aqueous phase with ethyl acetate twice, adjust the pH of the water layer to 7-8 with saturated sodium bicarbonate solution, then add ethyl acetate to extract, wash the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and rotary evaporate to obtain compound 53f (350 mg). LC-MS: ESI [M+H] + = 169.1.

[0312] Fifth step: Take compound 53f (0.25 g, 0.83 mmol), 1f (0.177 g, 1.037 mmol), HATU (0.473 g, 1.245 mmol), DIEA (0.268 g, 2.074 mmol) and add DMF 2.0 ml, stir at 50°C for 16h, monitor by LC-MS, after the reaction is completed, add water, extract with ethyl acetate, wash the organic phase with saturated brine, rotary evaporate the organic phase, and obtain compound 53g (0.295 g) after column chromatography of the crude product. LC-MS: ESI [M+H] + = 391.0.

[0313] Sixth step: Take compound 53g (250 mg, 0.525 mmol), 1j (91 mg, 0.767 mmol), Pd(dppf)Cl2 (0.038 g, 0.052 mmol), cuprous iodide (15.3 mg, 0.079 mmol), triethylamine (159.2 mg, 1.534 mmol), and add DMF 3.0 ml, replace with nitrogen three times, warm to 100°C and stir for 16h, monitor by LC-MS, after the reaction is completed, rotary evaporate, and obtain compound 53 (32 mg, white solid) after column chromatography and preparative purification of the crude product. LC-MS: ESI [M+H] + = 417.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (dd, J = 7.1, 1.0 Hz, 1H), 8.66 (s, 1H), 8.57 (d, J = 2.9 Hz, 1H), 8.51 (s, 2H), 8.33 (dd, J = 1.9, 1.0 Hz, 1H), 7.75 (td, J = 8.8, 2.9 Hz, 1H), 7.56 (dd, J = 8.7, 4.5 Hz, 1H), 7.27 (s, 2H), 7.17 (dd, J = 7.1, 1.9 Hz, 1H), 5.66 (dd, J = 8.8, 6.0 Hz, 1H), 4.40 (td, 1H), 4.01 - 3.87 (m, 1H), 2.91 - 2.79 (m, 1H), 2.61 - 2.52 (m, 1H).

[0314] Example 54: (S)-7-((6-aminopyridin-3-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0315] Compound 67a (31.00 mg, 0.26 mmol), compound 44a (100 mg, 0.26 mmol), copper iodide (5.01 mg, 0.026 mmol), Pd(dppf)Cl2(19.24 mg, 0.026 mmol) and triethylamine (0.18 mL, 1.32 mmol) were weighed into DMF (5 mL), replaced with N2, warmed to 100 °C and stirred overnight. The mixture was concentrated by rotary evaporation and purified by column chromatography to give compound 54 (5 mg, white solid). LC-MS: ESI [M+H] + = 419.4. 1 H NMR (400 MHz, DMSO) δ 8.50 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.69 (td, J = 8.8, 2.9 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.55 - 7.46 (m, 2H), 6.46 - 6.38 (m, 3H), 4.95 (m, 1H), 4.36 (d, J = 13.0 Hz, 2H), 3.93 - 3.77 (m, 2H), 1.46 (d, J = 7.1 Hz, 3H).

[0316] Example 55: (S)-5-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(4-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0317] First step: Compound 1f (1 g, 4.15 mmol), compound 55a (0.58 g, 4.15 mmol), HATU (1.89 g, 4.98 mmol) and DIEA (1.45 mL, 8.30 mmol) were weighed into DMF (10 mL), warmed to 70 °C and stirred for 3 hours. TLC was used to monitor the reaction. The mixture was extracted with H2O and EA. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated by rotary evaporation and purified by column chromatography (0-30% PE / EA) to give compound 55b (0.9 g, white solid). LC-MS: ESI [M+H] + = 362.2.

[0318] Second Step: Take compound 1j (49.34 mg, 0.41 mmol), 55b (100 mg, 0.28 mmol), Pd(PPh3)4 (31.90 mg, 0.028 mmol), CuI (5.26 mg, 0.028 mmol) and DIEA (178.42 mg, 1.38 mmol) into DMF (5 mL), replace N2, warm up to 100 °C and stir overnight, monitor by TLC, extract with EA and H2O for three times, dry the organic phase with anhydrous sodium sulfate, concentrate by rotary evaporation, purify by column chromatography (0-7% DCM / MeOH) to get 55 (10 mg, yellow solid). LC-MS: ESI [M+H] + = 401.4; 1 H NMR (400 MHz, DMSO) δ 8.78 (dd, J = 7.2, 0.9 Hz, 1H), 8.71 (s, 1H), 8.60 (d, J = 7.8 Hz, 1H), 8.49 (s, 2H), 8.27 (d, J = 1.0 Hz, 1H), 7.43 (s, 2H), 7.26 (s, 2H), 7.16 (d, J = 8.9 Hz, 2H), 7.06 (dd, J = 7.2, 1.9 Hz, 1H), 5.19 (m, 1H), 1.48 (d, J = 7.1 Hz, 3H).

[0319] Example 56: (S)-3-((1H-pyrrolo[2,3-b]pyridine-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)pyrrolo[1,2-a]pyrimidine-6-carboxamide

[0320] First Step: Take 56a (2 g, 10.15 mmol), trimethylsilyl acetylene (1.99 g, 20.30 mmol), triethylamine (8.47 mL, 60.91 mmol), PdCl2(PPh3)2 (0.36 g, 0.51 mmol) and cuprous iodide (0.10 g, 0.51 mmol) into acetonitrile (50 mL), replace N2, warm up to 60 °C and stir overnight, monitor by LC-MS, filter, wash the filter residue with EA, concentrate the filtrate by rotary evaporation, purify by column chromatography (0-15% PE / EA) to get compound 56b (1.97 g, yellow solid). LC-MS: ESI [M+H] + = 215.3; 1 H NMR (400 MHz, CDCl3) δ 10.45 (d, J = 16.6 Hz, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.38 - 7.35 (m, 1H), 6.49 (dd, J = 3.5, 1.9 Hz, 1H), 0.28 (s, 9H).

[0321] Second Step: Take compound 56b (1.9 g, 8.86 mmol) and potassium carbonate (12.25 g, 88.64 mmol), add methanol (40 mL), stir at room temperature for 3 h, monitor by LC-MS, filter, wash the filter cake with methanol, concentrate by rotary evaporation, purify by column chromatography (0-5% DCM / MeOH) to get compound 56c (0.9 g, light yellow solid). LC-MS: ESI [M+H] + = 143.2.

[0322] Third Step: Take compound 56c (47.10 mg, 0.33 mmol), compound 15b (100 mg, 0.28 mmol), CuI (5.26 mg, 0.028 mmol), tetrakis triphenylphosphine palladium (15.95 mg, 0.014 mmol), and DIEA (71.37 mg, 0.55 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, about 1 / 3 of reaction, continue to react for 5 h, monitor by LCMS, add water and EA to extract three times, combine the organic phase, concentrate by rotary evaporation, purify by column chromatography (0-7% DCM / MeOH) to get compound 56 (10 mg, yellow solid). LC-MS: ESI [M+H] + = 424.5; 1 H NMR (400 MHz, DMSO) δ 11.96 (s, 1H), 9.97 (d, J = 1.8 Hz, 1H), 8.80 (d, J = 7.9 Hz, 1H), 8.44 (d, J = 2.1 Hz, 2H), 8.23 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 4.5 Hz, 1H), 7.63 - 7.53 (m, 1H), 7.38 (dd, J = 14.2, 7.9 Hz, 1H), 7.25 (t, J = 8.4 Hz, 2H), 7.07 (dd, J = 11.9, 5.2 Hz, 1H), 6.74 (d, J = 4.4 Hz, 1H), 6.51 (d, J = 1.7 Hz, 1H), 5.22 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H).

[0323] Example 57: (S)-N-(1-(3-fluorophenyl)ethyl)-5-(pyrazolo[1,5-a]pyrimidine-6-ylethynyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0324] First Step: Take 57a (1 g, 5.05 mmol), trimethylsilyl acetylene (0.99 g, 10.10 mmol), triethylamine (3.06 g, 30.30 mmol), PdCl2(PPh3)2 (0.35 g, 0.51 mmol) and cuprous iodide (0.10 g, 0.51 mmol), add 1,4-dioxane (20 mL), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, filter, wash the residue with EA, concentrate the filtrate by rotary evaporation, purify by column chromatography (0-15% PE / EA) to give compound 57b (1.0 g, yellow solid). LC-MS: ESI [M+H] + = 216.3.

[0325] Second Step: Take compound 57b (1.0 g, 4.64 mmol), add DCM (20 mL), add tetrabutylammonium fluoride (1.46 g, 5.57 mmol) in portions, stir at room temperature for 2 h, monitor by LC-MS, concentrate by rotary evaporation, purify by column chromatography (0-5% DCM / MeOH) to give compound 57c (0.25 g, yellow solid). LC-MS: ESI [M+H] + = 144.2.

[0326] Third Step: Take compound 57c (47.43 mg, 0.33 mmol), compound 1g (100 mg, 0.28 mmol), CuI (5.26 mg, 0.028 mmol), tetrakis(triphenylphosphine)palladium (31.90 mg, 0.028 mmol) and DIEA (178.42 mg, 1.38 mmol), add DMF (5 mL), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, extract with water and EA for three times, concentrate the combined organic phase by rotary evaporation, purify by column chromatography (0-7% DCM / MeOH) to give compound 57 (10 mg, yellow solid). LC-MS: ESI [M+H] + = 425.4; 1 H NMR (400 MHz, DMSO) δ 9.60 (dd, J = 2.0, 0.7 Hz, 1H), 8.85 (dt, J = 7.4, 3.7 Hz, 1H), 8.76 (s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 7.9 Hz, 1H), 8.41 (d, J = 0.9 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.24 (s, 2H), 7.15 (dt, J = 5.8, 2.9 Hz, 1H), 7.10 - 7.01 (m, 1H), 6.87 - 6.83 (m, 1H), 5.27 - 5.16 (m, 1H), 1.50 (d, J = 7.1 Hz, 3H).

[0327] Example 58: (S)-N-(l-(3-fluorophenyl)ethyl)-5-(imidazo[l,2-b]pyridazin-3- ylethynyl)pyrazolo[l,5-a]pyridine-3-carboxamide

[0328] First Step: Take compound 58a (1 g, 5.05 mmol), trimethylsilyl acetylene (0.99 g, 10.10 mmol), triethylamine (3.06 g, 30.30 mmol), PdCl2(PPh3)2(0.35 g, 0.51 mmol) and cuprous iodide (0.10 g, 0.51 mmol), add 1,4-dioxane (20 mL), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, filter, wash the residue with EA, concentrate the filtrate by rotary evaporation, purify by column chromatography (0-15% PE / EA) to get compound 58b (1.0 g, yellow solid). LC-MS: ESI [M+H] + = 216.3.

[0329] Second Step: Take compound 58b (1.0 g, 4.64 mmol), add DCM (20 mL), add tetrabutylammonium fluoride (1.46 g, 5.57 mmol) in portions, stir at room temperature for 2 h, monitor by LCMS, concentrate by rotary evaporation, purify by column chromatography (0-5% DCM / MeOH) to get compound 58c (0.5 g, light yellow solid). LC-MS: ESI [M+H] + = 144.1.

[0330] Third Step: Take compound 58c (59.28 mg, 0.41 mmol), compound 1g (100 mg, 0.28 mmol), CuI (5.26 mg, 0.028 mmol), tetrakis(triphenylphosphine)palladium (31.90 mg, 0.028 mmol) and DIEA (178.42 mg, 1.38 mmol), add DMF (5 mL), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, extract with water and EA for three times, concentrate the combined organic phase by rotary evaporation, purify by column chromatography (0-7% DCM / MeOH) to get compound 58 (10 mg, yellow solid). LC-MS: ESI [M+H] + = 425.4; 1H NMR (400 MHz, DMSO) δ 8.92 (d, J = 7.2 Hz, 1H), 8.85 (s, 1H), 8.77 (d, J = 7.9 Hz, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 7.47 (d, J = 6.1 Hz, 1H), 7.33 (t, J = 9.1 Hz, 2H), 7.26 (dd, J = 7.2, 1.8 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 5.30 (s, 1H), 1.59 (d, J = 7.1 Hz, 3H).

[0331] Example 59: (S)-5-((3H-imidazo[4,5-b]pyridin-6-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0332] First Step: Take compound 59a (2 g, 10.15 mmol), trimethylsilyl acetylene (1.99 g, 20.30 mmol), triethylamine (8.47 mL, 60.91 mmol), PdCl2(PPh3)2 (0.36 g, 0.51 mmol) and cuprous iodide (0.10 g, 0.51 mmol), add acetonitrile (50 mL), replace N2, warm up to 60 °C and stir overnight, monitor by LCMS, filter, wash the residue with EA, concentrate the filtrate by rotary evaporation, purify by column chromatography (0-15% PE / EA) to get compound 59b (1.58 g, yellow solid). LC-MS: ESI [M+H]= 216.3. +

[0333] Second Step: Take compound 59b (1.0 g, 4.64 mmol), add DCM (20 mL), add tetrabutylammonium fluoride (1.82 g, 6.96 mmol) in portions, stir at room temperature for 2 h, monitor by LCMS, concentrate by rotary evaporation, purify by column chromatography (0-5% DCM / MeOH) to get compound 59c (0.45 g, light yellow solid). LC-MS: ESI [M+H]= 144.2. +

[0334] ​​Step 3: Compound 59c (47.43 mg, 0.33 mmol), compound 1g (100 mg, 0.28 mmol), CuI (5.26 mg, 0.028 mmol), Pd(PPh3)4(15.95 mg, 0.014 mmol), and DIEA (71.37 mg, 0.55 mmol) were weighed into DMF (5 mL), and the mixture was stirred at 100 °C overnight under N2. The reaction was monitored by LCMS. The reaction mixture was diluted with water and extracted with EA three times. The organic phase was combined and concentrated by rotary evaporation. Compound 59 (10 mg, yellow solid) was obtained by column chromatography (0-7% DCM / MeOH). LC-MS: ESI [M+H]=425.4; + 1 H NMR (400 MHz, DMSO) δ 8.84 (dd, J = 7.2, 0.8 Hz, 1H), 8.76 (s, 1H), 8.74 (dd, J = 4.5, 1.5 Hz, 1H), 8.67 (d, J = 7.9 Hz, 1H), 8.37 (dd, J = 1.8, 0.8 Hz, 1H), 8.30 - 8.25 (m, 2H), 7.45 - 7.34 (m, 2H), 7.29 - 7.20 (m, 2H), 7.16 (dd, J = 7.2, 1.9 Hz, 1H), 7.10 - 7.02 (m, 1H), 5.22 (m, 1H), 1.50 (d, J = 7.1 Hz, 3H).

[0335] Example 60: (S)-5-((2-amino-4-methylpyrimidin-5-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0336] Step 1: Compound 60a (1 g, 5.32 mmol), trimethylsilyl acetylene (1.04 g, 10.64 mmol), triethylamine (2.69 g, 26.60 mmol), PdCl2(PPh3)2(0.37 g, 0.53 mmol), and CuI (0.10 g, 0.53 mmol) were weighed into 1,4-dioxane (20 mL), and the mixture was stirred at 100 °C overnight under N2. The reaction was monitored by LCMS. The reaction mixture was filtered, and the residue was washed with EA. The filtrate was concentrated by rotary evaporation. Compound 60b (0.6 g, yellow solid) was obtained by column chromatography (0-15% PE / EA). LC-MS: ESI [M+H]=206.3. +

[0337] ​​Second Step: Take compound 60b (0.6 g, 2.92 mmol), add methanol (20 mL), add potassium carbonate (4.04 g, 29.22 mmol), stir at room temperature for 2 h, monitor by LCMS, filter, rinse the filter residue with methanol, concentrate the filtrate by rotary evaporation, purify by column chromatography (0-5% DCM / MeOH) to obtain compound 60c (330 mg, white solid). LC-MS: ESI [M+H] + = 134.2.

[0338] Third Step: Take compound 60c (36.76 mg, 0.28 mmol), compound 1g (100 mg, 0.28 mmol), CuI (5.26 mg, 0.028 mmol), PdCl2(PPh3)2 (19.38 mg, 0.028 mmol), and triethylamine (139.69 mg, 1.38 mmol), add DMF (5 mL), replace N2, warm to 100 °C, stir overnight, monitor by LCMS, extract with water and EA three times, combine the organic phase, concentrate by rotary evaporation, purify by column chromatography (0-7% DCM / MeOH) to obtain compound 60 (22 mg, light yellow solid). LC-MS: ESI [M+H] + = 415.4; 1 H NMR (400 MHz, DMSO) δ 8.79 (dd, J = 7.2, 0.8 Hz, 1H), 8.73 (s, 1H), 8.63 (d, J = 7.9 Hz, 1H), 8.38 (s, 1H), 8.24 (d, J = 1.0 Hz, 1H), 7.38 (dd, J = 14.1, 8.1 Hz, 1H), 7.23 (t, J = 9.5 Hz, 2H), 7.14 (s, 2H), 7.06 (ddd, J = 18.5, 7.6, 2.3 Hz, 2H), 5.25 - 5.14 (m, 1H), 2.44 (s, 3H), 1.49 (d, J = 7.1 Hz, 3H).

[0339] Example 61: (S)-5-((6-amino-5-(trifluoromethyl)pyridin-3-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0340] First Step: Take compound 61a (0.5 g, 2.07 mmol), trimethylsilyl acetylene (0.41 g, 4.15 mmol), triethylamine (1.05 g, 10.37 mmol), PdCl2(PPh3)2(0.15 g, 0.21 mmol) and cuprous iodide (0.04 g, 0.21 mmol), add 1,4-dioxane (20 mL), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, filter, wash the residue with EA, concentrate the filtrate by rotary evaporation, purify by column chromatography (0-15% PE / EA) to get compound 61b (0.5 g, yellowish solid). LC-MS: ESI [M+H]=259.3. +

[0341] Second Step: Take compound 61b (57.06 mg, 0.22 mmol), compound 1g (80 mg, 0.22 mmol), CuI (4.21 mg, 0.022 mmol), PdCl2(PPh3)2(16.16 mg, 0.022 mmol) and cesium carbonate (215.89 mg, 0.66 mmol), add DMF (3 mL), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, extract with water and EA for three times, concentrate by rotary evaporation, purify by column chromatography (0-7% DCM / MeOH) to get compound 61 (15 mg, yellowish solid). LC-MS: ESI [M+H]=468.4. + 1 H NMR (400 MHz, DMSO) δ 8.80 (d, J = 7.2 Hz, 1H), 8.74 (s, 1H), 8.65 (d, J = 7.8 Hz, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.43 - 7.33 (m, 1H), 7.23 (dd, J = 14.1, 4.6 Hz, 2H), 7.13 - 7.02 (m, 4H), 5.33 - 5.09 (m, 1H), 1.50 (d, J = 7.1 Hz, 3H).

[0342] Example 62: (S)-5-((6-amino-5-(difluoromethoxy)pyridin-3-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0343] ​​First Step: Take compound 62a (10 g, 45.66 mmol), add dioxane (100 mL), replace N2, cool to 0 °C, add sodium hydride (60%) (18.27 g, 456.64 mmol) in batches, react for 0.5 h, add water (41.27 mL, 2283.21 mmol) dropwise, react for 0.5 h, add bromodifluoromethyl phosphonic acid diethyl ester (24.39 g, 91.33 mmol) dropwise, warm to room temperature and react for 0.5 h, monitor by TLC, extract with EA for 3 times, wash the organic phase with saturated aqueous ammonium chloride solution twice, dry the organic phase with anhydrous sodium sulfate, concentrate by rotary evaporation, purify by column chromatography (0-5% PE / EA) to obtain compound 62b (4.2 g, yellowish liquid). LC-MS: ESI [M+H] + = 269.0; 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 1.9 Hz, 1H), 8.04 (dt, J = 1.9, 1.0 Hz, 1H), 6.68 (t, J = 71.3 Hz, 1H).

[0344] Second Step: Take compound 62b (4.2 g, 15.61 mmol), add methanol (50 mL), cool to 0 °C, add zinc powder (10.21 g, 156.13 mmol) and ammonium chloride (8.35 g, 156.13 mmol) in batches, stir at 0 °C for 10 min, slowly add water (1 mL) dropwise, warm to room temperature and stir for 10 min, monitor by TLC, filter with diatomite, concentrate by rotary evaporation, purify by column chromatography to obtain compound 62c (2.2 g, pink solid). LC-MS: ESI [M+H] + = 229.0.

[0345] Third Step: Take compound 62c (0.5 g, 2.09 mmol), trimethylsilyl acetylene (0.59 mL, 4.18 mmol), triethylamine (1.45 mL, 10.46 mmol), cuprous iodide (0.04 g, 0.21 mmol) and PdCl2(PPh3)2 (0.15 g, 0.21 mmol), add dioxane (20 mL), replace N2, warm to 100 °C and stir overnight, monitor by LCMS, concentrate by rotary evaporation, purify by column chromatography (0-15% PE / EA) to obtain compound 62d (0.51 g, brown solid). LC-MS: ESI [M+H] + = 257.3.

[0346] Fourth Step: Take compound 62d (53.08 mg, 0.21 mmol), compound 1g (50 mg, 0.14 mmol), cesium carbonate (134.93 mg, 0.41 mmol), copper iodide (2.63 mg, 0.014 mmol) and Pd(dppf)Cl2(10.10 mg, 0.014 mmol), add DMF (2 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, spin concentrate, purify by column chromatography to get compound 62 (25 mg, white solid). LC-MS: ESI [M+H] + = 466.4. 1 H NMR (400 MHz, DMSO) δ 8.79 (d, J = 7.1 Hz, 1H), 8.72 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.24 (t, J = 9.6 Hz, 2H), 7.20 (t, J = 72.8 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.75 (s, 2H), 5.21 (t, J = 7.3 Hz, 1H), 1.50 (d, J = 7.1 Hz, 3H).

[0347] Example 63: (S)-5-((6-amino-5-methylpyridin-3-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0348] First Step: Take compound 63a (1 g, 4.27 mmol), trimethylsilylacetylene (1.21 mL, 8.55 mmol), copper iodide (0.08 g, 0.43 mmol), triethylamine (2.97 mL, 21.36 mmol) and PdCl2(PPh3)2(0.30 g, 0.43 mmol), add dioxane (20 mL), replace N2, warm up to 100 °C, stir overnight, monitor by LCMS, spin concentrate, purify by column chromatography (0-15% PE / EA) to get compound 63b (0.68 g, white solid). LC-MS: ESI [M+H] + = 205.4.

[0349] Second Step: Take compound 63b (45.14 mg, 0.22 mmol), compound 1g (80 mg, 0.22 mmol), cesium carbonate (215.89 mg, 0.66 mmol), copper iodide (4.21 mg, 0.022 mmol) and PdCl2(PPh3)2 (15.50 mg, 0.022 mmol), add DMF (2 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, spin concentrate, purify by column chromatography to get compound 63 (15 mg, yellowish solid). LC-MS: ESI [M+H] + = 414.5; 1 H NMR (400 MHz, DMSO) δ 8.65 - 8.59 (m, 1H), 8.57 (s, 1H), 8.48 (d, J = 7.9 Hz, 1H), 8.08 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.32 (s, 1H), 7.28 - 7.19 (m, 1H), 7.09 (t, J = 9.4 Hz, 2H), 6.94 - 6.87 (m, 2H), 6.19 (s, 2H), 5.06 (m, 1H), 1.91 (s, 3H), 1.35 (d, J = 7.1 Hz, 3H).

[0350] Example 64: (S)-7-((6-aminopyridin-3-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0351] Take compound 67a (31.07 mg, 0.26 mmol), compound 27b (100 mg, 0.26 mmol), copper iodide (5.01 mg, 0.026 mmol), Pd(dppf)Cl2 (19.24 mg, 0.026 mmol) and triethylamine (0.18 mL, 1.32 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir overnight, spin concentrate, purify by column chromatography to get compound 64 (8 mg, pink solid). LC-MS: ESI [M+H] + = 418.4; 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 7.91 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.49 (dd, J = 8.5, 2.2 Hz, 1H), 7.37 (dd, J = 14.3, 7.5 Hz, 1H), 7.22 (s, 2H), 7.05 (dd, J = 9.2, 7.1 Hz, 1H), 6.41 (s, 3H), 4.91 (m, 1H), 4.36 (s, 2H), 3.91 - 3.76 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H).

[0352] Example 65: (S)-5-((6-amino-5-fluoropyridin-3-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0353] First Step: Take compound 65a (1 g, 5.24 mmol), trimethylsilylacetylene (1.48 mL, 10.47 mmol), cuprous iodide (0.10 g, 0.52 mmol), PdCl2(PPh3)2(0.37 g, 0.524 mmol) and triethylamine (3.64 mL, 26.18 mmol), add dioxane (20 mL), replace N2, warm up to 100 °C, stir overnight, monitor by LCMS, rotary evaporation to concentrate, purify by column chromatography (0-15% PE / EA) to get compound 65b (0.9 g, yellow solid). LC-MS: ESI [M+H]=209.3. +

[0354] Second Step: Take compound 65b (63.26 mg, 0.30 mmol), compound 1g (100 mg, 0.28 mmol), cesium carbonate (269.87 mg, 0.83 mmol), cuprous iodide (5.26 mg, 0.028 mmol) and PdCl2(PPh3)2(19.38 mg, 0.028 mmol), add DMF (2 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, rotary evaporation to concentrate, purify by column chromatography to get compound 65 (14 mg, yellow solid). LC-MS: ESI [M+H]=418.4. + 1 ​​H NMR (400 MHz, DMSO) δ 8.79 (d, J = 7.2 Hz, 1H), 8.73 (s, 1H), 8.64 (d, J = 7.9 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.62 (dd, J = 11.8, 1.5 Hz, 1H), 7.37 (s, 1H), 7.25 (d, J = 7.2 Hz, 2H), 7.07 (dd, J = 7.3, 1.7 Hz, 2H), 6.86 (s, 2H), 5.21 (s, 1H), 1.50 (d, J = 7.1 Hz, 3H).

[0355] Example 66: (S)-6-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0356] First Step: Take compound 66a (1 g, 5.02 mmol), add DCM (20 mL), cool to 0 °C, drop in triphosgene (0.60 g, 2.01 mmol) dissolved in DCM, stir for 20 min, drop in DIEA (3.50 mL, 20.10 mmol), stir for 20 min, drop in compound (S)-1-(3- fluorophenyl)ethylamine (0.70 g, 5.02 mmol), stir overnight at room temperature, monitor by TLC, add water and DCM to extract, rotary evaporate the organic phase, then purify by column chromatography to obtain compound 66b (1.12 g, light yellow solid). LC-MS: ESI [M+H] = 364.2. +

[0357] Second Step: Take compound 1j (32.71 mg, 0.28 mmol), compound 66b (100 mg, 0.28 mmol), cuprous iodide (5.23 mg, 0.028 mmol), Pd(dppf)Cl2(20.09 mg, 0.028 mmol) and triethylamine (0.19 mL, 1.37 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, rotary evaporate to concentrate, purify by column chromatography to obtain compound 66 (20 mg, white solid). LC-MS: ESI [M+H] = 403.4. + 1 ​​H NMR (400 MHz, DMSO) δ 8.43 (s, 2H), 8.08 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 1.4 Hz, 1H), 7.36 (dd, J = 14.4, 7.5 Hz, 1H), 7.25 - 7.19 (m, 3H), 7.16 (s, 2H), 7.04 (dd, J = 9.1, 6.9 Hz, 1H), 4.95 (m, 1H), 4.17 - 3.98 (m, 2H), 3.25 (s, 2H), 1.45 (d, J = 7.1 Hz, 3H).

[0358] Example 67: (S)-5-((6-aminopyridin-3-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0359] Compound 67a (32.62 mg, 0.28 mmol), compound 1g (100 mg, 0.28 mmol), cuprous iodide (5.23 mg, 0.028 mmol), Pd(dppf)Cl2(20.09 mg, 0.028 mmol) and triethylamine (0.19 mL, 1.37 mmol) were weighed into DMF (5 mL), replaced with N2, warmed to 100 °C and stirred overnight. The mixture was concentrated by rotary evaporation and purified by column chromatography to give compound 67 (15 mg, pink solid). LC-MS: ESI [M+H] + = 400.4; 1 H NMR (400 MHz, DMSO) δ 8.76 (d, J = 7.2 Hz, 1H), 8.71 (s, 1H), 8.61 (d, J = 7.9 Hz, 1H), 8.25 - 8.21 (m, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.6, 2.3 Hz, 1H), 7.38 (dd, J = 14.0, 8.0 Hz, 1H), 7.23 (t, J = 9.4 Hz, 2H), 7.05 (qd, J = 6.3, 3.6 Hz, 2H), 6.54 (s, 2H), 6.47 (d, J = 8.6 Hz, 1H), 5.20 (m, 1H), 1.49 (d, J = 7.1 Hz, 3H).

[0360] Example 68: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(4-fluorophenyl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0361] First Step: Take compound 27a (0.5 g, 2.33 mmol), add DCM (20 mL), cool to 0 °C, add triphosgene (0.30 g, 0.93 mmol) dissolved in DCM dropwise, stir for 20 min, add DIEA (0.12 g, 9.32 mmol) dropwise, stir for 20 min, add compound 55a (0.32 g, 2.33 mmol) dropwise, warm to room temperature and stir overnight, monitor by TLC, add water and extract with DCM, rotary evaporate the organic phase and purify by column chromatography to give compound 68a (0.6 g, light yellow solid). LC-MS: ESI [M+H] = 380.2. +

[0362] Second Step: Take compound 1j (31.33 mg, 0.26 mmol), compound 68a (100 mg, 0.26 mmol), cuprous iodide (5.01 mg, 0.026 mmol), Pd(dppf)Cl2(19.24 mg, 0.026 mmol) and triethylamine (0.18 mL, 1.32 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, concentrate by rotary evaporation and purify by column chromatography to give compound 68 (10 mg, white solid). LC-MS: ESI [M+H] = 419.4. + 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 2H), 8.22 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.41 (s, 2H), 7.13 (m 4H), 4.89 (m, 1H), 4.36 (s, 2H), 3.88 - 3.76 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H).

[0363] Example 69: (S)-6-((2-Aminopyrimidin-5-yl)ethynyl)-N-(1-(5-fluoropyridin-2-yl)ethyl)- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0364] ​​First Step: Take compound 66a (0.5 g, 2.51 mmol), add DCM (20 mL), cool to 0 °C, add triphosgene (0.30 g, 1.00 mmol) dissolved in DCM dropwise, stir for 20 min, add DIEA (0.13 g, 10.05 mmol) dropwise, stir for 20 min, add compound 39a (0.5 g, 2.51 mmol) dropwise, warm to room temperature and stir overnight, monitor by TLC, add water and extract with DCM, rotary evaporate the organic phase and purify by column chromatography to give compound 69a (0.7 g, light yellow solid). LC-MS: ESI [M+H] + = 365.2.

[0365] Second Step: Take compound 1j (32.62 mg, 0.28 mmol), compound 69a (100 mg, 0.28 mmol), copper iodide (5.23 mg, 0.028 mmol), Pd(dppf)Cl2(20.09 mg, 0.028 mmol) and triethylamine (0.19 mL, 1.37 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, concentrate by rotary evaporation and purify by column chromatography to give compound 69 (25 mg, white solid). LC-MS: ESI [M+H] + = 404.4; 1 H NMR (400 MHz, DMSO) δ 8.50 (d, J = 2.8 Hz, 1H), 8.43 (s, 2H), 8.08 (s, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.69 (td, J = 8.8, 2.9 Hz, 1H), 7.52 (dd, J = 8.7, 4.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.16 (s, 2H), 4.99 (m, 1H), 4.09 (d, J = 9.8 Hz, 2H), 3.26 (d, J = 8.7 Hz, 2H), 1.48 (d, J = 7.1 Hz, 3H).

[0366] Example 70: (S)-6'-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3-fluorophenyl)ethyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-1'(2'H)-carboxamide

[0367] First Step: Take sodium hydride (60%) (3.38, 84.50 mmol), add DMF (20 mL), replace N2, cool to 0 °C, add compound 70a (3 g, 14.08 mmol) dissolved in DMF (20 mL), 0 °C stirring for 15 min, dropwise addition of 1,2-dibromoethane (3.66 mL, 42.25 mmol), warm to room temperature and stir overnight, LCMS monitoring, quench with water, extract with EA three times, dry the organic phase with anhydrous sodium sulfate, rotary evaporation to concentrate, column chromatography to purify to obtain compound 70b (1.0 g, white solid). LC-MS: ESI [M+H] + = 239.1.

[0368] Second Step: Take compound 70b (1 g, 4.18 mmol), add THF (20 mL), cool to 0 °C, add lithium aluminum hydride (0.63 g, 16.73 mmol) in batches, warm to room temperature and stir overnight, LCMS monitoring, quench with water, extract with DCM, rotary evaporation to concentrate the combined organic phase, column chromatography to purify (0-10% DCM / MeOH) to obtain compound 70c (0.2 g, white solid). LC-MS: ESI [M+H] + = 225.1; 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 1.7 Hz, 1H), 6.84 (d, J = 1.8 Hz, 1H), 3.91 (s, 1H), 3.72 (s, 2H), 1.30 (m, 2H), 0.96 (m, 2H).

[0369] Third Step: Take compound 70c (200 mg, 0.89 mmol), add DCM (10 mL), cool to 0 °C, dropwise addition of triphosgene (105.46 mg, 0.36 mmol) dissolved in DCM, stir for 20 min, dropwise addition of DIEA (0.62 mL, 3.55 mmol), stir for 20 min, dropwise addition of compound (S)-1-(3-fluorophenyl)ethylamine (123.66 mg, 0.89 mmol), warm to room temperature and stir overnight, TLC monitoring, extract with water and DCM, rotary evaporation of the organic phase, column chromatography to purify to obtain compound 70d (0.24 g, white solid). LC-MS: ESI [M+H] + = 390.3.

[0370] Fourth Step: Take compound 1j (36.63 mg, 0.31 mmol), compound 70d (120 mg, 0.31 mmol), cuprous iodide (5.86 mg, 0.031 mmol), triethylamine (0.17 mL, 1.23 mmol) and Pd(dppf)Cl2(22.50 mg, 0.031 mmol), add DMF (5 mL), replace with N2, warm to 100 °C and stir overnight. Monitor by LCMS, rotary evaporation to concentrate, and purify by column chromatography to obtain compound 70 (20 mg, yellow solid). LC-MS: ESI [M+H] + = 429.5; 1 H NMR (400 MHz, DMSO) δ 8.42 (s, 2H), 8.02 (d, J = 1.4 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.36 (d, J = 6.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 3H), 7.04 (s, 1H), 4.94 (s, 1H), 4.16 (d, J = 15.5 Hz, 2H), 1.44 (d, J = 7.1 Hz, 3H), 1.24 (m, 2H), 1.17 (m, 2H).

[0371] Example 71: (S)-5-((6-aminopyridin-3-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0372] Take compound 39b (250 mg, 0.688 mmol), compound 67a (122 mg, 1.033 mmol), Pd(dppf)Cl2(0.049 g, 0.069 mmol), cuprous iodide (19.9 mg, 0.103 mmol), triethylamine (209 mg, 2.065 mmol), add DMF 2.0 ml, replace with nitrogen three times, warm to 100 °C and stir for 16 h. Monitor by LC-MS, rotary evaporation to concentrate after the reaction is completed, and purify by column chromatography to obtain compound 71 (100 mg, white solid). LC-MS: ESI [M+H] + = 401.1; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 7.2 Hz, 1H), 8.74 (s, 1H), 8.65 (d, J = 7.7 Hz, 1H), 8.52 (d, J = 2.9 Hz, 1H), 8.24 - 8.21 (m, 1H), 8.18 (d, J = 2.3 Hz, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.56 (dd, J = 8.6, 2.3 Hz, 1H), 7.50 (dd, J = 8.7, 4.5 Hz, 1H), 7.06 (dd, J = 7.2, 1.9 Hz, 1H), 6.54 (s, 2H), 6.47 (d, J = 8.6 Hz, 1H), 5.33 - 5.14 (m, 1H), 1.52 (d, J = 7.1 Hz, 3H).

[0373] Example 72: (S)-6-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(3- fluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0374] First Step: Take compound 72a (2.70 g, 11.06 mmol), trimethylsilylethynyl (3.26 g, 33.19 mmol), triethylamine (6.72 g, 66.39 mmol), Pd(PPh3)2Cl2(390.0 mg, 0.553 mmol), cuprous iodide (110.0 mg, 0.553 mmol) into dioxane 30 ml, stir at 100 °C for 16 h, monitor by LC-MS, after reaction is completed, spin dry, the obtained crude product is purified by column chromatography to obtain compound 72c. LC-MS: ESI [M+H] + = 215.1.

[0375] Second Step: Take compound 66b (500 mg, 1.373 mmol), 72c (588 mg, 2.749 mmol), Pd(dppf)Cl2(0.100 g, 0.137 mmol), cuprous iodide (39.5 mg, 0.206 mmol), triethylamine (347.5 mg, 3.432 mmol), add DMF 5.0 ml, replace with nitrogen for three times, heat to 100 °C and stir for 16 h, monitor by LC-MS, after reaction is completed, spin dry, the obtained crude product is purified by column chromatography to obtain compound 72 (42 mg, white solid). LC-MS: ESI [M+H] + = 426.2; 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.09 (d, J = 1.9 Hz, 1H), 8.07 (s, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.83 (t, J = 58.9 Hz, 1H), 7.41 - 7.31 (m, 1H), 7.27 - 7.18 (m, 3H), 7.04 (td, J = 9.0, 2.4 Hz, 1H), 5.01 - 4.88 (m, 1H), 4.18 - 3.97 (m, 2H), 3.25 (t, J = 8.7 Hz, 2H), 1.45 (d, J = 7.1 Hz, 3H).

[0376] Example 73: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3,5-difluorophenyl)ethyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0377] First Step: Compound 27a (0.30 g, 1.395 mmol) was weighed into dichloromethane 10 ml, under stirring, temperature was lowered to 0 °C, triphosgene (0.17 g, 0.558 mmol) was added in portions, stirred for 30 min, DIEA (0.72 g, 5.58 mmol) was added dropwise, stirred for 30 min, 73a (0.22 g, 1.395 mmol) was added, then stirred at 25 °C overnight. LC-MS monitoring, after the reaction was completed, water was added for extraction, the organic phase was rotary evaporated, the obtained crude product was purified by column chromatography to obtain compound 73b (0.39 g, white solid). LC-MS: ESI [M+H] + = 398.0.

[0378] Second Step: Compound 73b (150 mg, 0.377 mmol), 1j (67 mg, 0.565 mmol), Pd(dppf)Cl2(0.027 g, 0.038 mmol), cuprous iodide (10.7 mg, 0.057 mmol), triethylamine (114.5 mg, 1.130 mmol) were weighed into DMF 3.0 ml, replaced with nitrogen for three times, temperature was raised to 100 °C, stirred for 16 h, LC-MS monitoring, the reaction solution was rotary evaporated, the obtained crude product was purified by column chromatography and then prepared to obtain compound 73 (27 mg, white solid). LC-MS: ESI [M+H] + = 437.2; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 2H), 8.25 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.15 - 7.03 (m, 5H), 4.96 - 4.83 (m, 1H), 4.38 (t, J = 4.6 Hz, 2H), 3.96 - 3.74 (m, 2H), 1.42 (d, J = 7.2 Hz, 3H).

[0379] Example 74: (S)-N-(l-(5-fluoropyridin-2-yl)ethyl)-7-((l-methyl-lH-pyrazol-4- yl)ethynyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-formamide

[0380] Compound 44a (100 mg, 0.262 mmol), 74a (42 mg, 0.395 mmol), Pd(dppf)Cl2(0.019 g, 0.026 mmol), cuprous iodide (7.5 mg, 0.039 mmol), triethylamine (79.2 mg, 0.787 mmol) were weighed, DMF 2.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C, stirred for 16 h, LC-MS monitoring, after the reaction was completed, the reaction solution was rotary dried, and the obtained crude product was purified by column chromatography to give compound 74 (33 mg, white solid). LC-MS: ESI [M+H] + = 407.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.25 - 8.20 (m, 1H), 8.06 (s, 1H), 7.92 - 7.88 (m, 1H), 7.73 - 7.66 (m, 2H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.7, 4.5 Hz, 1H), 5.00 - 4.90 (m, 1H), 4.37 (t, J = 4.6 Hz, 2H), 3.89 - 3.81 (m, 5H), 1.46 (d, J = 7.0 Hz, 3H).

[0381] Example 75: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(l-(4-fluorophenyl)ethyl)-3,4- dihydro-l,5-naphthyridine-l(2H)carboxamide

[0382] First Step: Take compound 32a (200 mg, 0.94 mmol), add DCM (10 mL), cool to 0 °C, add triphosgene (111.41 mg, 0.38 mmol) dissolved in DCM dropwise, stir for 20 min, add DIEA (0.65 mL, 3.75 mmol) dropwise, stir for 20 min, add compound 55a (0.13 mL, 0.94 mmol), warm to room temperature and stir overnight, monitor by TLC, add water and extract with DCM, evaporate the organic phase and purify by column chromatography to give compound 75a (300 mg, white solid). LC-MS: ESI [M+H]=378.3. +

[0383] Second Step: Take compound 1j (31.50 mg, 0.26 mmol), compound 75a (100 mg, 0.26 mmol), copper(I) iodide (5.04 mg, 0.026 mmol), triethylamine (0.15 mL, 1.06 mmol) and Pd(dppf)Cl2(19.34 mg, 0.026 mmol), add DMF (3 mL), replace N2, warm to 100 °C and stir overnight, monitor by LCMS, evaporate to dryness and purify by column chromatography to give compound 75 (22 mg, yellow solid). LC-MS: ESI [M+H]=417.5. + 1 H NMR (400 MHz, DMSO) δ 8.43 (s, 2H), 8.17 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 8.4, 6.1 Hz, 3H), 7.19 - 7.10 (m, 4H), 4.90 (t, J = 7.2 Hz, 1H), 3.76 - 3.63 (m, 2H), 2.85 (t, J = 6.4 Hz, 2H), 1.94 (dd, J = 12.2, 6.1 Hz, 2H), 1.43 (d, J = 7.0 Hz, 3H).

[0384] Example 76: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(pyridin-2-yl)ethyl)-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-formamide

[0385] ​​First Step: Take compound 27a (500 mg, 2.33 mmol), add DCM (15 mL), cool to 0 °C, add triphosgene (280 mg, 0.93 mmol) dissolved in DCM dropwise, stir for 20 min, add DIEA (1.62 mL, 9.30 mmol) dropwise, stir for 20, add compound 76a (280 mg, 2.33 mmol), warm to room temperature and stir overnight, monitor by TLC, add water and extract with DCM, rotary evaporate the organic phase and purify by column chromatography to obtain compound 76b (620 mg, white solid). LC-MS: ESI [M+H]=363.2. +

[0386] Second Step: Take compound 1j (49.20 mg, 0.41 mmol), compound 76b (150 mg, 0.41 mmol), copper(I) iodide (7.87 mg, 0.041 mmol), triethylamine (0.23 mL, 1.65 mmol) and Pd(dppf)Cl2(30.22 mg, 0.041 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, monitor by LCMS, rotary evaporate and purify by column chromatography to obtain compound 76 (10 mg, white solid). LC-MS: ESI [M+H]=402.4; + 1 H NMR (400 MHz, DMSO) δ 8.52 (d, J = 4.8 Hz, 1H), 8.41 (s, 2H), 8.26 (d, J = 1.9 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.26 (dd, J = 7.3, 4.9 Hz, 1H), 7.13 (s, 2H), 4.94 (m, 1H), 4.43 - 4.34 (m, 2H), 3.96 - 3.78 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

[0387] Example 77: (S)-7-((6-aminopyridazin-3-yl)ethynyl)-N-(1-(4-fluorophenyl)ethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0388] ​​First Step: Take compound 77a (1 g, 4.53 mmol), trimethylsilyl acetylene (1.28 mL, 9.05 mmol), copper(I) iodide (0.09 g, 0.45 mmol), Pd(PPh3)Cl2 (0.32 g, 0.45 mmol) and triethylamine (3.15 mL, 22.62 mmol), add acetonitrile (20 mL), replace N2, stir at room temperature overnight, monitor by LCMS, filter, wash the residue with methanol, concentrate the filtrate by rotary evaporation, and then proceed to the next step. LC-MS: ESI [M+H] + = 192.3.

[0389] Second Step: Take compound 77b (0.8 g, 4.18 mmol), add methanol (20 mL), add potassium carbonate (5.78 g, 41.82 mmol), stir at room temperature for 2 h, monitor by LCMS, filter, rinse the residue with methanol, concentrate the filtrate by rotary evaporation, and then purify by column chromatography to obtain compound 77c (250 mg, yellow solid). LC-MS: ESI [M+H] + = 120.1.

[0390] Third Step: Take compound 77c (31.25 mg, 0.26 mmol), compound 68a (100 mg, 0.26 mmol), copper(I) iodide (5.00 mg, 0.026 mmol), Pd(dppf)Cl2 (19.19 mg, 0.026 mmol) and triethylamine (0.15 mL, 1.05 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, monitor by LCMS, concentrate by rotary evaporation, and then purify by column chromatography to obtain compound 77 (6 mg, white solid). LC-MS: ESI [M+H] + = 420.4; 1 H NMR (400 MHz, DMSO) δ 8.51 (d, J = 2.9 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 7.70 (td, J = 8.8, 2.9 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.52 (dd, J = 8.7, 4.5 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 6.80 (s, 2H), 6.75 (d, J = 9.2 Hz, 1H), 4.96 (m, 1H), 4.38 (d, J = 13.9 Hz, 2H), 3.95 - 3.76 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

[0391] Example 78: (S)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0392] Example 78: (S)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide + = 427.1;1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H), 8.07 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.84 (s, 1H), 7.69 (td, J = 8.6, 2.9 Hz, 1H), 7.52 (dd, J = 8.8, 4.5 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 5.05 - 4.91 (m, 1H), 4.17 - 3.99 (m, 2H), 3.29 - 3.22 (m, 2H), 1.48 (d, J = 7.1 Hz, 3H).

[0393] Example 78: (S)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0394] First Step: Compound 27a (0.500 g, 2.325 mmol) was added to dichloromethane 20 ml, stirred and cooled to 0 °C, then triphosgene (0.280 g, 0.930 mmol) was added in batches, stirred for 30 min, DIEA (1.500 g, 11.625 mmol) was added dropwise, stirred for 30 min, then 79a (0.300 g, 2.325 mmol) was added, then stirred at 25 °C overnight. LC-MS monitoring, after the reaction was completed, water was added for extraction, the organic phase was rotary evaporated, the obtained crude product was purified by column chromatography to obtain compound 79b (0.53 g, white solid). LC-MS: ESI [M+H] + = 369.0.

[0395] Second Step: Take compound 79b (0.150 g, 0.406 mmol), 1j (0.072 g, 0.609 mmol), Pd(dppf)Cl2(0.030 g, 0.041 mmol), cuprous iodide (11.6 mg, 0.061 mmol), triethylamine (123.5 mg, 1.219 mmol), add DMF 3.0 ml, replace with nitrogen three times, warm to 100 °C, stir for 16 h, monitor by LC-MS, after the reaction is completed, spin dry, the obtained crude product is purified by column chromatography to obtain compound 79 (24 mg, white solid). LC-MS: ESI [M+H] + = 408.1; 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 2H), 8.26 (d, J = 2.9 Hz, 1H), 7.99 - 7.92 (m, 2H), 7.73 (d, J = 3.1 Hz, 1H), 7.62 (d, J = 3.2 Hz, 1H), 7.14 (s, 2H), 5.27 - 5.09 (m, 1H), 4.49 - 4.30 (m, 2H), 3.95 - 3.71 (m, 2H), 1.58 (d, J = 7.0 Hz, 3H).

[0396] Example 80: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(2,4-difluorophenyl)ethyl)- 3,4-dihydro-1,5-naphthyridine-1(2H)-carboxamide

[0397] First Step: Take compound 32a (0.300 g, 1.408 mmol) and add dichloromethane 10 ml, stir and cool to 0 °C, add triphosgene (0.170 g, 0.563 mmol) in batches, stir for 30 min, add DIEA (0.910 g, 7.04 mmol) dropwise, stir for 30 min, add 80a (0.220 g, 1.143 mmol), then stir at 25 °C overnight. Monitor by LC-MS, after the reaction is completed, add water to extract, spin dry the organic phase, the obtained crude product is purified by column chromatography to obtain compound 80b (0.44 g, white solid). LC-MS: ESI [M+H] + = 396.0.

[0398] Second Step: Take compound 80b (0.200 g, 0.505 mmol), 1j (0.090 g, 0.757 mmol), Pd(dppf)Cl2(0.036 g, 0.050 mmol), copper iodide (14.7 mg, 0.076 mmol), triethylamine (153.5 mg, 1.514 mmol), add DMF 3.0 ml, replace with nitrogen three times, warm to 100 °C and stir for 16 h. Monitor by LC-MS, after the reaction is completed, spin dry, and the obtained crude product is purified by column chromatography to obtain compound 80 (34 mg, white solid). LC-MS: ESI [M+H] + = 435.17; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 0.8 Hz, 2H), 8.18 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.22 - 7.13 (m, 3H), 7.11 - 7.04 (m, 1H), 5.18 - 5.06 (m, 1H), 3.81 - 3.61 (m, 2H), 2.86 (t, J = 6.5 Hz, 2H), 2.01 - 1.86 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H).

[0399] Example 81: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(2,4-difluorophenyl)ethyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0400] First Step: Take compound 27a (0.500 g, 2.325 mmol) and add dichloromethane 10 ml, and stir while cooling to 0 °C. Add triphosgene (0.280 g, 0.930 mmol) in batches, stir for 30 min, add DIEA (1.500 g, 11.625 mmol) dropwise, stir for 30 min, add 80a (0.370 g, 1.887 mmol), and then stir at 25 °C overnight. Monitor by LC-MS, add water after the reaction is completed, extract the organic phase, spin dry, and the obtained crude product is purified by column chromatography to obtain compound 81a (0.68 g, white solid). LC-MS: ESI [M+H] + = 398.0.

[0401] Second Step: Take compound 81a (0.200 g, 0.505 mmol), 1j (0.090 g, 0.757 mmol), Pd(dppf)Cl2(0.036 g, 0.050 mmol), cuprous iodide (14.7 mg, 0.076 mmol), triethylamine (153.5 mg, 1.514 mmol), add DMF 3.0 ml, replace with nitrogen three times, warm to 100 °C and stir for 16 h, monitor by LC-MS, spin dry after the reaction is completed, and the obtained crude product is purified by column chromatography to obtain compound 81 (34 mg, white solid). LC-MS: ESI [M+H] + = 437.2; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 0.9 Hz, 2H), 8.21 (dd, J = 2.1, 0.9 Hz, 1H), 7.93 (dd, J = 2.1, 0.9 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.56 - 7.46 (m, 1H), 7.23 - 7.15 (m, 1H), 7.13 (s, 2H), 7.11 - 7.04 (m, 1H), 5.17 - 5.03 (m, 1H), 4.44 - 4.30 (m, 2H), 3.93 - 3.76 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H).

[0402] Example 82: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(4- (trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- formamide

[0403] First Step: Take compound 27a (0.5 g, 2.33 mmol), add DCM (15 mL), cool to 0 °C, drop triphosgene (0.28 g, 0.930 mmol) dissolved in DCM, stir for 20 min, drop DIEA (1.62 mL, 9.30 mmol), stir for 20 min, add compound 82a (0.48 g, 1.97 mmol), warm to room temperature and stir overnight, monitor by TLC, add water and DCM to extract, spin dry the organic phase after rotary evaporation, and purify by column chromatography to obtain compound 82b (0.6 g, white solid). LC-MS: ESI [M+H] + = 446.2.

[0404] Second Step: Take compound 1j (40.05 mg, 0.34 mmol), compound 82b (150 mg, 0.34 mmol), copper(I)iodide (6.40 mg, 0.034 mmol), Pd(dppf)Cl2(24.60 mg, 0.034 mmol) and triethylamine (0.19 mL, 1.35 mmol), add DMF (5 mL), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, spin to concentrate, purify by column chromatography to obtain compound 82 (10 mg, yellow solid). LC-MS: ESI [M+H] + = 485.4. 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 2H), 8.23 (s, 1H), 7.93 (s, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.13 (s, 2H), 4.97 - 4.86 (m, 1H), 4.37 (s, 2H), 3.84 (d, J = 3.7 Hz, 2H), 1.44 (d, J = 7.0 Hz, 3H).

[0405] Example 83: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(5-chloropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-formamide

[0406] First Step: Take compound 27a (0.5 g, 2.33 mmol), add DCM (15 mL), cool down to 0 °C, drop in triphosgene (0.28 g, 0.93 mmol) dissolved in DCM, stir for 20 min, drop in DIEA (1.62 mL, 9.30 mmol), stir for 20 min, add compound 83a (0.36 g, 1.59 mmol), warm up to room temperature and stir overnight, monitor by TLC, add water and DCM to extract, spin to concentrate the organic phase, purify by column chromatography to obtain compound 83b (0.36 g, white solid). LC-MS: ESI [M+H] + = 397.7.

[0407] Second Step: Take compound 1j (44.94 mg, 0.38 mmol), compound 83b (150 mg, 0.38 mmol), copper(I) iodide (7.18 mg, 0.038 mmol), Pd(dppf)Cl2(27.60 mg, 0.038 mmol) and triethylamine (0.21 mL, 1.51 mmol), add DMF (5 mL), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, spin to concentrate, purify by column chromatography to obtain compound 83 (20 mg, white solid). LC-MS: ESI [M+H] + = 436.9. 1 H NMR (400 MHz, DMSO) δ 8.56 (d, J = 2.2 Hz, 1H), 8.41 (s, 2H), 8.24 (d, J = 1.8 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.89 (dd, J = 8.4, 2.4 Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.13 (s, 2H), 4.92 (t, J = 7.1 Hz, 1H), 4.38 (t, J = 4.3 Hz, 2H), 3.85 (qd, J = 13.5, 6.8 Hz, 2H), 1.45 (d, J = 7.1 Hz, 3H).

[0408] Example 84: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(4-cyanophenyl)ethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0409] First Step: Take compound 27a (0.5 g, 2.33 mmol), add DCM (15 mL), cool down to 0 °C, drop in triphosgene (0.28 g, 0.93 mmol) dissolved in DCM, stir for 20 min, drop in DIEA (1.62 mL, 9.30 mmol), stir for 20 min, add compound 84a (0.34 g, 2.33 mmol), warm up to room temperature and stir overnight, monitor by LCMS, add water and DCM to extract, spin to concentrate the organic phase, purify by column chromatography to obtain compound 84b (0.5 g, white solid). LC-MS: ESI [M+H] + = 387.2.

[0410] Second Step: Take compound 1j (92.29 mg, 0.78 mmol), compound 84b (150 mg, 0.39 mmol), copper(I)iodide (7.38 mg, 0.039 mmol), Pd(dppf)Cl2(28.34 mg, 0.039 mmol) and triethylamine (0.22 mL, 1.55 mmol), add DMF (5 mL), replace N2, warm up to 100 °C and stir overnight. Monitor by LCMS, spin to concentrate, and purify by column chromatography to obtain compound 84 (36 mg, white solid). LC-MS: ESI [M+H] + = 426.5; 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 2H), 8.23 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 1.1 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 7.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.13 (s, 2H), 4.99 - 4.87 (m, 1H), 4.43 - 4.33 (m, 2H), 3.86 (d, J = 4.0 Hz, 2H), 1.44 (d, J = 7.0 Hz, 3H).

[0411] Example 85: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(3,5- difluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1 -carboxamide

[0412] Take compound 73b (0.500 g, 1.256 mmol), 72c (0.807 g, 3.763 mmol), Pd(dppf)Cl2(0.091 g, 0.126 mmol), copper(I)iodide (35.3 mg, 0.188 mmol), triethylamine (635.2 mg, 6.278 mmol), add DMF 5.0 ml, replace N2for three times, warm up to 100 °C and stir for 2 h. Monitor by LC-MS, spin to concentrate after reaction, and purify by column chromatography to obtain compound 85 (41 mg, white solid). LC-MS: ESI [M+H] += 460.1; 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 0.6 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 0.6 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.83 (s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.15 - 7.02 (m, 3H), 4.96 - 4.83 (m, 1H), 4.39 (t, J = 4.7 Hz, 2H), 3.93 - 3.75 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H).

[0413] Example 86: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(2,4- difluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazine-1-carboxamide

[0414] Example 86: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(2,4- difluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazine-1-carboxamide

[0414] Example 86: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(2,4- difluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazine-1-carboxamide + = 460.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 0.6 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 0.6 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.56 - 7.45 (m, 1H), 7.23 - 7.14 (m, 1H), 7.11 - 7.03 (m, 1H), 5.16 - 5.03 (m, 1H), 4.38 (t, J = 4.5 Hz, 2H), 3.90 - 3.76 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H).

[0415] Example 86: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(2,4- difluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazine-1-carboxamide

[0416] First Step: Compound 27a (0.300 g, 1.395 mmol) was weighed into dichloromethane 10 ml, stirred and cooled to 0 °C, then triphosgene (0.170 g, 0.560 mmol) was added in portions, stirred for 30 min, DIEA (0.900 g, 6.975 mmol) was added dropwise, stirred for 30 min, 87a (0.300 g, 1.535 mmol) was added, then stirred at 25 °C overnight. LC-MS monitoring, after the reaction was completed, water was added for extraction, the organic phase was rotary evaporated, the obtained crude product was purified by column chromatography to obtain compound 87b (0.400 g, white solid). LC-MS: ESI [M+H] + = 398.0.

[0417] Second Step: Compound 87b (0.200 g, 0.505 mmol), 1j (0.120 g, 1.004 mmol), Pd(dppf)Cl2(0.036 g, 0.050 mmol), cuprous iodide (14.7 mg, 0.076 mmol), triethylamine (177.5 mg, 1.758 mmol) were weighed into DMF 3.0 ml, replaced with nitrogen for three times, stirred at 100 °C for 16 h, LC-MS monitoring, after the reaction was completed, rotary evaporation, the obtained crude product was purified by column chromatography and then prepared to obtain compound 87 (29 mg, white solid). LC-MS: ESI [M+H] + = 437.2; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 2H), 8.23 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.49 - 7.33 (m, 2H), 7.25 - 7.18 (m, 1H), 7.13 (s, 2H), 4.94 - 4.80 (m, 1H), 4.37 (t, J = 4.6 Hz, 2H), 3.90 - 3.77 (m, 2H), 1.42 (d, J = 7.1 Hz, 3H).

[0418] Example 88: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(4-chlorophenyl)ethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0419] First Step: Take compound 27a (0.5 g, 2.33 mmol), add DCM (15 mL), cool to 0 °C, add triphosgene (0.28 g, 0.93 mmol) dissolved in DCM dropwise, stir for 20 min, add DIEA (1.62 mL, 9.30 mmol) dropwise, stir for 20 min, add compound 88a (0.63 mL, 4.65 mmol), warm to room temperature and stir overnight, monitor by TLC, extract with water and DCM, rotary evaporate the organic phase and purify by column chromatography to obtain compound 88b (0.62 g, white solid). LC-MS: ESI [M+H] = 396.7. +

[0420] Second Step: Take compound 1j (90.10 mg, 0.76 mmol), compound 88b (150 mg, 0.38 mmol), copper(I) iodide (7.20 mg, 0.038 mmol), Pd(dppf)Cl2(27.67 mg, 0.038 mmol) and triethylamine (0.21 mL, 1.51 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, monitor by LCMS, rotary evaporate and purify by column chromatography to obtain compound 88 (36 mg, white solid). LC-MS: ESI [M+H] = 435.9. + 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 2H), 8.21 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 2.4 Hz, 4H), 7.13 (s, 2H), 4.87 (m, 1H), 4.37 (t, J = 4.4 Hz, 2H), 3.88 - 3.79 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H).

[0421] Example 89: (S)-6-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(4-fluorophenyl)ethyl)- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0422] ​​Step 1: Weigh compound 66a (0.3 g, 1.51 mmol), add DCM (15 mL), cool to 0 °C, add triphosgene dissolved in DCM (0.18 g, 0.60 mmol), stir for 20 min, add DIEA (1.05 mL, 6.03 mmol), stir for 20 min, add compound 55a (0.36 g, 1.59 mmol), heat to room temperature and stir overnight, monitor by TLC, extract with water and DCM, and purify by column chromatography after rotary evaporation of the organic phase to obtain compound 89a (0.3 g, yellow solid). LC-MS: ESI [M+H] + =364.2.

[0423] Step 2: Weigh out compound 1j (73.59 mg, 0.62 mmol), compound 89a (150 mg, 0.41 mmol), cuprous iodide (I) (7.84 mg, 0.041 mmol), Pd(dppf)Cl2 (30.13 mg, 0.041 mmol), and triethylamine (0.23 mL, 1.65 mmol). Add DMF (5 mL), replace with N2, heat to 100 °C, stir overnight, monitor with LC-MS, concentrate by rotary evaporation, and purify by column chromatography to obtain compound 89 (55 mg, pink solid). LC-MS: ESI [M+H] + =403.4; 1 H NMR (400MHz, DMSO) δ8.43(s,2H),8.07(d,J=1.7Hz,1H),7.99(d,J=1.8Hz,1H),7.43(dd,J=8.6,5.6Hz,2H) ,7.20–7.11(m,5H),4.88–5.00(m,1H),4.05(d,J=9.3Hz,2H),3.25(d,J=8.9Hz,2H),1.45(d,J=7.1Hz,3H).

[0424] Example 90: (S)-6-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3,5-difluorophenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0425] First Step: Take compound 66a (0.3 g, 1.51 mmol), add DCM (15 mL), cool to 0 °C, add triphosgene (0.18 g, 0.60 mmol) dissolved in DCM dropwise, stir for 20 min, add DIEA (1.05 mL, 6.03 mmol) dropwise, stir for 20 min, add compound 73a (0.24 g, 1.51 mmol), warm to room temperature and stir overnight, monitor by TLC, add water and extract with DCM, rotary evaporate the organic phase and purify by column chromatography to give compound 90a (0.45 g, white solid). LC-MS: ESI [M+H] = 382.2. +

[0426] Second Step: Take compound 1j (46.75 mg, 0.39 mmol), compound 90a (150 mg, 0.39 mmol), copper(I) iodide (7.47 mg, 0.039 mmol), Pd(dppf)Cl2(28.72 mg, 0.039 mmol) and triethylamine (0.22 mL, 1.57 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, monitor by LCMS, rotary evaporate and purify by column chromatography to give compound 90 (75 mg, white solid). LC-MS: ESI [M+H] = 421.4. + 1 H NMR (400 MHz, DMSO) δ 8.43 (s, 2H), 8.08 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.20 - 7.03 (m, 5H), 4.94 (m, 1H), 4.19 - 3.98 (m, 2H), 3.25 (t, J = 8.7 Hz, 2H), 1.44 (d, J = 7.1 Hz, 3H).

[0427] Example 91: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(2-fluorophenyl)ethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0428] ​​First Step: Take compound 27a (0.3 g, 1.51 mmol), add DCM (15 mL), cool to 0 °C, drop in triphosgene (0.28 g, 0.93 mmol) dissolved in DCM, stir for 20 min, drop in DIEA (1.62 mL, 9.30 mmol), stir for 20 min, add compound 91a (0.24 g, 1.51 mmol), warm to room temperature and stir overnight, monitor by TLC, add water and extract with DCM, rotary evaporate the organic phase and purify by column chromatography to obtain compound 91b (0.46 g, white solid). LC-MS: ESI [M+H] = 380.2. +

[0429] Second Step: Take compound 1j (94.00 mg, 0.79 mmol), compound 91b (150 mg, 0.40 mmol), copper(I) iodide (7.51 mg, 0.040 mmol), Pd(dppf)Cl2(28.87 mg, 0.040 mmol) and triethylamine (0.22 mL, 1.58 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, monitor by LCMS, rotary evaporate and purify by column chromatography to obtain compound 91 (14 mg, white solid). LC-MS: ESI [M+H] = 419.4. + 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 2H), 8.21 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 6.9 Hz, 1H), 7.28 (dd, J = 13.3, 5.8 Hz, 1H), 7.22 - 7.14 (m, 2H), 7.13 (s, 2H), 5.15 (dd, J = 14.2, 7.2 Hz, 1H), 4.43 - 4.31 (m, 2H), 3.93 - 3.79 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H).

[0430] Example 92: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(pyrimidin-2-yl)ethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0431] ​​First Step: Take compound 27a (0.3 g, 1.51 mmol), add DCM (15 mL), cool to 0 °C, add triphosgene (0.28 g, 0.930 mmol) dissolved in DCM dropwise, stir for 20 min, add DIEA (1.620 mL, 9.300 mmol) dropwise, stir for 20 min, add compound 92a (0.24 g, 1.51 mmol), warm to room temperature and stir overnight, monitor by TLC, add water and extract with DCM, rotary evaporate the organic phase and purify by column chromatography to obtain compound 92b (0.35 mg, white solid). LC-MS: ESI [M+H] = 364.2. +

[0432] Second Step: Take compound 1j (98.13 mg, 0.82 mmol), compound 92b (150 mg, 0.41 mmol), Pd(dppf)Cl2(30.14 mg, 0.041 mmol), triethylamine (0.23 mL, 1.65 mmol) and cuprous iodide (I) (7.84 mg, 0.041 mmol), add DMF (5 mL), replace N2, warm to 100 °C and stir overnight, monitor by LCMS, rotary evaporate and purify by column chromatography to obtain compound 92 (51 mg, white solid). LC-MS: ESI [M+H] = 403.4. + 1 H NMR (400 MHz, DMSO) δ 8.79 (d, J = 4.9 Hz, 2H), 8.41 (s, 2H), 8.26 (d, J = 2.1 Hz, 1H), 7.94 (s, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 4.9 Hz, 1H), 7.13 (s, 2H), 4.82 - 5.02 (m, 1H), 4.46 - 4.33 (m, 2H), 3.97 - 3.76 (m, 2H), 1.49 (d, J = 7.1 Hz, 3H).

[0433] Example 93: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((1-(methyl-d3)-1H-pyrazol-4- yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0434] ​​First step: Take compound 27a (6.500 g, 30.226 mmol) and add dichloromethane 60 ml, stir and cool to 0 °C, add triphosgene (3.590 g, 12.090 mmol) in batches, stir for 30 min, add DIEA (19.530 g, 151.128 mmol) dropwise, stir for 30 min, add 39a (7.020 g, 33.248 mmol), then stir at 25 °C overnight. LC-MS monitoring, after the reaction is completed, add water to extract, dry the organic phase, and the obtained crude product is purified by column chromatography to obtain compound 93a (6.500 g, white solid). LC-MS: ESI [M+H] + = 381.0.

[0435] Second step: Take compound 93a (6.500 g, 17.051 mmol), trimethylsilyl acetylene (5.020 g, 51.153 mmol), Pd (PPh3)2Cl2 (1.200 g, 1.705 mmol), cuprous iodide (320.0 mg, 1.705 mmol), triethylamine (8.630 g, 85.255 mmol), add dioxane 60.0 ml, replace with nitrogen three times, warm to 100 °C and stir for 18 h, LC-MS monitoring, after the reaction is completed, dry, and the obtained crude product is directly used in the next step.

[0436] Third step: To the crude product of the previous step, add methanol 120.0 ml, add potassium carbonate (23.240 g, 168.126 mmol), stir at room temperature for 2 h, LC-MS monitoring, after the reaction is completed, filter, dry the filtrate, and the obtained crude product is purified by column chromatography to obtain compound 93c (5.000 g). LC-MS: ESI [M+H] + = 327.1.

[0437] Fourth step: Take compound 93c (0.200 g, 0.613 mmol), 93d (0.168 g, 0.797 mmol), Pd (dppf) Cl2 (0.044 g, 0.061 mmol), cuprous iodide (17.7 mg, 0.092 mmol), triethylamine (186.2 mg, 1.839 mmol), add DMF 3.0 ml, replace with nitrogen three times, warm to 100 °C and stir for 3 h, LC-MS monitoring, after the reaction is completed, dry, and the obtained crude product is purified by column chromatography to obtain compound 93 (50 mg, white solid). LC-MS: ESI [M+H] +=410.17;1H NMR (400MHz, DMSO-d6) δ8.50(d,J=2.9Hz,1H),8.22(d,J=2.1Hz,1H),8.05(d,J=0.7Hz,1H),7.90(d,J=2.0Hz,1H),7.74–7.65(m,2H), 7.60(d,J=7.4Hz,1H),7.51(dd,J=8.8,4.5Hz,1H),5.02–4.90(m,1H),4.37(t,J=4.5Hz,2H),3.93–3.75(m,2H),1.45(d,J=7.1Hz,3H).

[0438] Example 94: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((2-methyl-2H-1,2,3-triazol-4-yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide

[0439] Compound 94a (74.46 mg, 0.46 mmol), compound 93c (150 mg, 0.46 mmol), cuprous iodide (I) (8.75 mg, 0.046 mmol), Pd(dppf)Cl2 (33.63 mg, 0.046 mmol), and triethylamine (0.26 mL, 1.84 mmol) were weighed. DMF (5 mL) was added, and N2 was substituted. The mixture was heated to 100 °C and stirred for 3 h. The mixture was monitored by LC-MS, concentrated by rotary evaporation, and purified by column chromatography to obtain compound 94 (18 mg, white solid). LC-MS: ESI [M+H] + =408.4; 1 H NMR (400MHz, DMSO) δ8.51(d,J=2.9Hz,1H),8.31(d,J=2.1Hz,1H),8.08(s,1H),8.01(d,J=2.1Hz,1H),7.70(td,J=8.8,3.0Hz,1H),7.64( d,J=7.4Hz,1H),7.52(dd,J=8.7,4.5Hz,1H),4.96(m,1H),4.39(t,J=8.6Hz,2H),4.18(s,3H),3.94–3.77(m,2H),1.46(d,J=7.1Hz,3H).

[0440] Example 95: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(5-fluoropyridin-2-yl)ethyl)-6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide

[0441] First Step: Take compound 95a (5.000 g, 19.884 mmol) and add THF 100.0 ml, stir and cool to 0 °C, add sodium hydride (1.050 g, 43.745 mmol) in batches, stir for 30 min, add 95b (2.280 g, 21.872 mmol) dropwise, stir for 30 min, monitor by LC-MS, after the reaction is completed, add water, extract with ethyl acetate, dry the organic phase, and purify the obtained crude product by column chromatography to obtain compound 95c (1.500 g). LC-MS: ESI [M+H] + = 319.0.

[0442] Second Step: Take compound 95c (1.500 g, 4.701 mmol) and add acetic acid 20.0 ml, add iron powder (1.610 g, 28.815 mmol), stir at 75 °C for 3 h, monitor by LC-MS, after the reaction is completed, filter, wash the filter cake with methanol, dry the filtrate, add 1N aqueous hydrochloric acid to precipitate a yellow solid, filter, and dry the filter cake to obtain compound 95d (1.27 mg, yellow solid). LC-MS: ESI [M+H] + = 243.0.

[0443] Third Step: Take compound 95d (0.500 g, 1.789 mmol) and add boron trifluoride ether solution 6.50 ml, stir at 80 °C for 1 h, monitor by LC-MS, after the reaction is completed, cool, add 3N aqueous hydrochloric acid 10.0 ml dropwise, then stir at 100 °C for 3 h, then cool, adjust the pH to 7-8 with 3N aqueous sodium hydroxide solution, extract with ethyl acetate, dry the organic phase, and purify the obtained crude product by column chromatography to obtain compound 95e (0.380 g). LC-MS: ESI [M+H] + = 229.0.

[0444] Fourth Step: Take compound 95e (0.300 g, 1.310 mmol) and add dichloromethane 10 ml, stir and cool to 0 °C, add triphosgene (0.160 g, 0.524 mmol) in batches, stir for 30 min, add DIEA (1.020 g, 7.858 mmol) dropwise, stir for 30 min, add 39a (0.310 g, 1.441 mmol), and then stir at 25 °C overnight. Monitor by LC-MS, after the reaction is completed, add water and extract, dry the organic phase, and purify the obtained crude product by column chromatography to obtain compound 95f (300 mg, white solid). LC-MS: ESI [M+H] + = 395.04.

[0445] Step 5: Take compound 95f (0.200 g, 0.506 mmol), 1j (0.090 g, 0.759 mmol), Pd(dppf)Cl2(0.038 g, 0.052 mmol), copper iodide (15.3 mg, 0.079 mmol), triethylamine (204.2 mg, 2.024 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 16 h, monitor by LC-MS, dry up after reaction, the obtained crude product is purified by column chromatography to give compound 95 (40 mg, white solid). LC-MS: ESI [M+H]=434.17; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.51 (s, 2H), 8.26 (s, 1H), 7.78 (td, J = 8.8, 3.0 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.21 (s, 2H), 5.11 - 4.94 (m, 1H), 4.44 (t, J = 4.6 Hz, 2H), 4.02 - 3.80 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H). + = 434.17; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.51 (s, 2H), 8.26 (s, 1H), 7.78 (td, J = 8.8, 3.0 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.21 (s, 2H), 5.11 - 4.94 (m, 1H), 4.44 (t, J = 4.6 Hz, 2H), 4.02 - 3.80 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H).

[0446] Example 96: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(2- fluorophenyl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide

[0447] Step 1: Take compound 91b (0.500 mg, 1.315 mmol), trimethylsilyl acetylene (0.387 mg, 3.945 mmol), Pd(PPh3)2Cl2(0.092 g, 0.132 mmol), copper iodide (25.7 mg, 0.132 mmol), triethylamine (665.2 mg, 6.575 mmol), add dioxane 10.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 18 h, monitor by LC-MS, dry up after reaction, the obtained crude product is carried directly to next step.

[0448] Step 2: To the crude product of last step, add methanol 20.0 ml, add potassium carbonate (1.738 g, 12.578 mmol), stir at room temperature for 2 h, monitor by LC-MS, filter after reaction, dry up the filtrate, the obtained crude product is purified by column chromatography to give compound 96b (0.380 g). LC-MS: ESI [M+H]=326.1. + = 434.17; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.51 (s, 2H), 8.26 (s, 1H), 7.78 (td, J = 8.8, 3.0 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.21 (s, 2H), 5.11 - 4.94 (m, 1H), 4.44 (t, J = 4.6 Hz, 2H), 4.02 - 3.80 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H).

[0449] Step 3: Weigh out compounds 96b (0.380 g, 1.168 mmol), 72a (0.427 g, 1.752 mmol), Pd(dppf)Cl2 (0.084 g, 0.117 mmol), cuprous iodide (33.7 mg, 0.175 mmol), and triethylamine (472.2 mg, 4.672 mmol). Add 5.0 mL of DMF, purge with nitrogen three times, heat to 100 °C, and stir for 3 h. Monitor the reaction by LC-MS. After the reaction is complete, evaporate to dryness. The crude product is purified by column chromatography to obtain compound 96 (70 mg, white solid). LC-MS: ESI[M+H] + =442.1;1H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.24(d,J=2.1Hz,1H),8.05(s,1H),7.94(d,J=2.1Hz,1H),7.83(s,1H),7.63(d,J=7.3Hz,1H),7.47(td, J=7.7,1.8Hz,1H),7.33–7.23(m,1H),7.22–7.11(m,2H),5.21–5.07(m,1H),4.38(t,J=4.7Hz,2H),3.94–3.78(m,2H),1.43(d,J=7.0Hz,3H).

[0450] Example 97: (S)-7-((1,5-dimethyl-1H-pyrazol-4-yl)ethynyl)-N-(1-(5-fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide

[0451] Compounds 93c (0.150 g, 0.460 mmol), 97a (0.153 g, 0.689 mmol), Pd(dppf)Cl2 (0.033 g, 0.046 mmol), cuprous iodide (13.7 mg, 0.069 mmol), and triethylamine (139.2 mg, 1.379 mmol) were weighed and added to 3.0 mL of DMF. The mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 3 h. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was evaporated to dryness. The crude product was purified by column chromatography to obtain compound 97 (25 mg, white solid). LC-MS: ESI[M+H] += 421.2; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.56 (s, 1H), 7.51 (dd, J = 8.7, 4.5 Hz, 1H), 5.01 - 4.88 (m, 1H), 4.43 - 4.31 (m, 2H), 3.94 - 3.76 (m, 2H), 3.75 (s, 3H), 2.32 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H).

[0452] Example 98: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((1-(2-hydroxyethyl)-1H- pyrazol-4-yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0453] Compound 93c (0.150 g, 0.460 mmol), 98a (0.164 g, 0.689 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), cuprous iodide (13.7 mg, 0.069 mmol), triethylamine (139.2 mg, 1.379 mmol) were weighed, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and compound 98 (34 mg, white solid) was obtained by column chromatography and preparation purification. LC-MS: ESI [M+H] + = 437.2; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 0.7 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.7, 4.5 Hz, 1H), 4.99 - 4.88 (m, 2H), 4.37 (t, J = 4.5 Hz, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.91 - 3.77 (m, 2H), 3.75 - 3.68 (m, 2H), 1.45 (d, J = 7.1 Hz, 3H).

[0454] Example 99: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((1,3,5-trimethyl-1H-pyrazol-4- yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0455] Compound 93c (0.150 g, 0.460 mmol), 99a (0.162 g, 0.689 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), cuprous iodide (13.7 mg, 0.069 mmol), triethylamine (139.2 mg, 1.379 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 99 (25 mg, white solid). LC-MS: ESI [M+H] + = 435.2;1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 3.0 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.7, 4.5 Hz, 1H), 5.03 - 4.87 (m, 1H), 4.46 - 4.30 (m, 2H), 3.94 - 3.84 (m, 1H), 3.84 - 3.72 (m, 1H), 3.66 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H).

[0456] Example 100: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0457] Compound 93c (0.150 g, 0.460 mmol), 100a (0.126 g, 0.460 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), copper iodide (13.3 mg, 0.069 mmol), triethylamine (139.2 mg, 1.839 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h. LC-MS monitoring, after the reaction was completed, spin dry, the obtained crude product was purified by column chromatography to give compound 100 (70 mg, white solid). LC-MS: ESI [M+H] + = 475.1; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.23 (s, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.85 (s, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.7, 4.5 Hz, 1H), 5.23 - 5.09 (m, 2H), 5.02 - 4.85 (m, 1H), 4.38 (t, J = 4.5 Hz, 2H), 3.92 - 3.77 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

[0458] Example 101: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((1-isopropyl-1H-pyrazol-4- yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0459] Compound 93c (0.150 g, 0.460 mmol), 101a (0.110 g, 0.460 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), copper iodide (13.3 mg, 0.069 mmol), triethylamine (139.2 mg, 1.839 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h. LC-MS monitoring, after the reaction was completed, spin dry, the obtained crude product was purified by column chromatography to give compound 101 (70 mg, white solid). LC-MS: ESI [M+H] += 435.2; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 0.7 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.60 (d, J = 7.3 Hz, 1H), 7.51 (dd, J = 8.8, 4.5 Hz, 1H), 5.00 - 4.88 (m, 1H), 4.55 - 4.43 (m, 1H), 4.37 (t, J = 4.5 Hz, 2H), 3.91 - 3.77 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H), 1.41 (d, J = 6.6 Hz, 6H).

[0460] Example 102: (S)-7-((1-ethyl-1H-pyrazol-4-yl)ethynyl)-N-(1-(5-fluoropyridin-2-yl)ethyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide

[0461] Compound 93c (0.150 g, 0.460 mmol), 102a (0.102 g, 0.460 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), cuprous iodide (13.3 mg, 0.069 mmol), triethylamine (139.2 mg, 1.839 mmol) were weighed, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, LC-MS monitoring, rotary evaporation after the reaction was completed, the obtained crude product was purified by column chromatography to give compound 102 (66 mg, white solid). LC-MS: ESI [M+H] + = 435.2; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 0.7 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.60 (d, J = 7.3 Hz, 1H), 7.51 (dd, J = 8.8, 4.5 Hz, 1H), 5.00 - 4.88 (m, 1H), 4.55 - 4.43 (m, 1H), 4.37 (t, J = 4.5 Hz, 2H), 3.91 - 3.77 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H), 1.41 (d, J = 6.6 Hz, 6H).

[0462] Example 103: (S)-7-((1,3-dimethyl-1H-pyrazol-4-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0463] Compound 103a (102.06 mg, 0.46 mmol), compound 93c (150 mg, 0.46 mmol), copper(I) iodide (8.75 mg, 0.046 mmol), Pd(dppf)Cl2(33.63 mg, 0.046 mmol), DMF (5 mL) and triethylamine (0.26 mL, 1.84 mmol) were weighed, replaced with N2, warmed to 100 °C for 5 h with stirring, concentrated by rotary evaporation, and purified by column chromatography to obtain compound 103 (15 mg, yellow solid). LC-MS: ESI [M+H] + = 421.5; 1 H NMR (400 MHz, DMSO) δ 8.50 (d, J = 2.9 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.92 (s, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.7, 4.5 Hz, 1H), 4.95 (t, J = 7.1 Hz, 1H), 4.40 - 4.35 (m, 2H), 3.93 - 3.78 (m, 2H), 3.76 (s, 3H), 2.19 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H).

[0464] Example 104: (S)-7-((5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0465] First step: Compound 104a (1 g, 4.24 mmol) was weighed, DCM (30 mL) and DAST (2.24 mL, 16.95 mmol) were added, stirred at room temperature overnight, quenched with water, extracted with DCM, the organic phases were combined and concentrated by rotary evaporation, and purified by column chromatography to obtain compound 104b (0.91 g, yellowish solid). LC-MS: ESI [M+H] + = 259.0.

[0466] Second Step: Take compound 104b (118.60 mg, 0.46 mmol), compound 93c (150 mg, 0.46 mmol), copper(I)iodide (8.75 mg, 0.046 mmol), Pd(dppf)Cl2(33.63 mg, 0.046 mmol), triethylamine (0.26 mL, 1.84 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, spin concentrate, purify by column chromatography to obtain compound 104 (35 mg, white solid). LC-MS: ESI [M+H] + = 457.4. 1 H NMR (400 MHz, DMSO) δ 8.50 (d, J = 2.9 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.81 (s, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.38 (t, J = 48.2 Hz, 1H), 4.95 (m, 1H), 4.46 - 4.32 (m, 2H), 3.95 (s, 3H), 3.93 - 3.76 (m, 2H), 1.45 (d, J = 7.1 Hz, 3H).

[0467] Example 105: (R)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(2-hydroxy-1- phenylethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0468] First Step: Take compound 27a (500 mg, 2.33 mmol), add DCM (25 mL), cool down to 0 °C, add triphosgene (275.96 mg, 0.93 mmol), after 20 min add DIEA (1.62 mL, 9.30 mmol), after 20 min add compound 105a (403.72 mg, 2.33 mmol), warm up to room temperature, stir overnight, monitor by LCMS, quench with water, extract with DCM, combine the organic phase, spin concentrate, purify by column chromatography to obtain compound 105b (0.47 g, white solid). LC-MS: ESI [M+H] + = 378.2.

[0469] Second Step: Take compound 1j (47.25 mg, 0.40 mmol), compound 105b (150 mg, 0.40 mmol), copper(I) iodide (7.55 mg, 0.040 mmol), Pd(dppf)Cl2(29.02 mg, 0.040 mmol), add DMF (5 mL) and triethylamine (0.22 mL, 1.59 mmol), replace N2, warm up to 100 °C and stir overnight, monitor by LCMS, rotary evaporation to concentrate, column chromatography to purify to give compound 105 (40 mg, yellow solid). LC-MS: ESI [M+H] + = 417.4; 1 H NMR (400 MHz, DMSO) δ 8.42 (s, 2H), 8.25 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.32 (dd, J = 10.2, 4.8 Hz, 2H), 7.27 - 7.21 (m, 1H), 4.81 (d, J = 5.5 Hz, 1H), 4.38 (dd, J = 8.3, 3.5 Hz, 2H), 3.57 - 3.69 (m, 2H).

[0470] Example 106: (S)-7-((1-cyclobutyl-1H-pyrazol-4-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0471] Take compound 106a (114.03 mg, 0.46 mmol), compound 93a (150 mg, 0.46 mmol), copper(I) iodide (8.75 mg, 0.046 mmol), Pd(dppf)Cl2(33.63 mg, 0.046 mmol), add DMF (5 mL) and triethylamine (0.26 mL, 1.84 mmol), replace N2, warm up to 100 °C and stir for 5 h, monitor by LCMS, rotary evaporation to concentrate, column chromatography to purify to give compound 106 (40 mg, yellow solid). LC-MS: ESI [M+H] + = 447.5; 1H NMR (400 MHz, DMSO) δ 8.51 (d, J = 2.9 Hz, 1H), 8.25 - 8.19 (m, 2H), 7.90 (d, J = 2.0 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.61 (d, J = 7.7 Hz, 1H), 7.52 (dd, J = 8.7, 4.5 Hz, 1H), 4.96 (dd, J = 14.2, 7.1 Hz, 1H), 4.88 - 4.76 (m, 1H), 4.37 (t, J = 4.5 Hz, 2H), 3.93 - 3.78 (m, 2H), 2.48 - 2.32 (m, 4H), 1.84 - 1.72 (m, 2H), 1.46 (d, J = 7.1 Hz, 3H).

[0472] Example 107: (S)-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-((l-methyl-lH-pyrazol-4- yl)ethynyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-carboxamide

[0473] Compound 69a (0.200 g, 0.548 mmol), 74a (0.088 g, 0.821 mmol), Pd(dppf)Cl2(0.039 g, 0.055 mmol), cuprous iodide (15.5 mg, 0.082 mmol), triethylamine (166.5 mg, 1.643 mmol) were weighed out, DMF 5.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 16 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 107 (40 mg, white solid). LC-MS: ESI [M+H] + = 391.16; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.10 - 8.02 (m, 2H), 7.96 (d, J = 1.9 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.52 (dd, J = 8.8, 4.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 5.05 - 4.91 (m, 1H), 4.19 - 3.99 (m, 2H), 3.85 (s, 3H), 3.24 (t, J = 8.7 Hz, 2H), 1.48 (d, J = 7.1 Hz, 3H).

[0474] Example 108: (S)-N-(l-(2,4-difluorophenyl)ethyl)-7-((l-methyl-lH-pyrazol-4- yl)ethynyl)-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazine-l-carboxamide

[0475] Compound 81a (0.200 g, 0.502 mmol), 74a (0.080 g, 0.753 mmol), Pd(dppf)Cl2(0.036 g, 0.050 mmol), copper iodide (14.5 mg, 0.075 mmol), triethylamine (152.5 mg, 1.507 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 2 h, monitored by LC-MS, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 108 (140 mg, white solid). LC-MS: ESI [M+H] + = 424.2; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 2.1 Hz, 1H), 8.05 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.51 (td, J = 8.8, 6.6 Hz, 1H), 7.19 (ddd, J = 10.7, 9.3, 2.6 Hz, 1H), 7.07 (td, J = 8.6, 2.6 Hz, 1H), 5.18 - 5.02 (m, 1H), 4.36 (t, J = 4.7 Hz, 2H), 3.84 (s, 5H), 1.42 (d, J = 7.0 Hz, 3H).

[0476] Example 109: (S)-N-(1-(2-fluorophenyl)ethyl)-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0477] Compound 91b (0.200 g, 0.526 mmol), compound 74a (0.084 g, 0.789 mmol), Pd(dppf)Cl2(0.038 g, 0.052 mmol), copper iodide (15.5 mg, 0.079 mmol), triethylamine (152.5 mg, 1.578 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 2 h, monitored by LC-MS, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 109 (70 mg, white solid). LC-MS: ESI [M+H] += 406.16; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 2.1 Hz, 1H), 8.05 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.47 (td, J = 7.7, 1.8 Hz, 1H), 7.32 - 7.24 (m, 1H), 7.21 - 7.11 (m, 2H), 5.20 - 5.08 (m, 1H), 4.42 - 4.28 (m, 2H), 3.94 - 3.75 (m, 5H), 1.43 (d, J = 7.1 Hz, 3H).

[0478] Example 110: (S)-7-((1-cyclopropyl-1H-pyrazol-4-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0479] Compound 110a (129.09 mg, 0.55 mmol), compound 93c (150 mg, 0.46 mmol), copper(I) iodide (8.75 mg, 0.046 mmol), Pd(dppf)Cl2(33.63 mg, 0.046 mmol), DMF (5 mL) and triethylamine (0.26 mL, 1.84 mmol) were weighed, replaced with N2, warmed to 100 °C for 5 h with stirring, monitored by LCMS, concentrated by rotary evaporation, and purified by column chromatography to obtain compound 110 (15 mg, yellow solid). LC-MS: ESI [M+H] + = 433.5; 1 H NMR (400 MHz, DMSO) δ 8.51 (d, J = 2.9 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.16 (s, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.70 (td, J = 8.8, 2.9 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.52 (dd, J = 8.7, 4.5 Hz, 1H), 4.95 (t, J = 7.1 Hz, 1H), 4.38 (t, J = 4.5 Hz, 2H), 3.85 (dt, J = 8.8, 4.4 Hz, 2H), 3.79 - 3.69 (m, 1H), 1.46 (d, J = 7.1 Hz, 3H), 1.09 - 1.02 (m, 2H), 1.00 - 0.93 (m, 2H).

[0480] Example 111: (S)-N-(1-(3,5-difluorophenyl)ethyl)-7-((1-methyl-1H-pyrazol-4- yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0481] Compound 73b (0.150 g, 0.377 mmol), 74a (0.060 g, 0.565 mmol), Pd(dppf)Cl2(0.028 g, 0.038 mmol), copper(I)iodide (10.5 mg, 0.057 mmol), triethylamine (112.5 mg, 1.130 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 2 h, LC-MS monitoring, rotary evaporation after the reaction was completed, the obtained crude product was purified by column chromatography to give compound 111 (70 mg, white solid). LC-MS: ESI [M+H] + = 424.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 2.1 Hz, 1H), 8.05 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.15 - 7.03 (m, 3H), 4.96 - 4.83 (m, 1H), 4.37 (t, J = 4.6 Hz, 2H), 3.92 - 3.76 (m, 5H), 1.42 (d, J = 7.0 Hz, 3H).

[0482] Example 112: (S)-N-(1-(4-fluorophenyl)ethyl)-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0483] Compound 74a (62.80 mg, 0.59 mmol), compound 68a (150 mg, 0.40 mmol), copper(I)iodide (7.51 mg, 0.040 mmol), Pd(dppf)Cl2(28.87 mg, 0.040 mmol) were weighed out, DMF (5 mL) and triethylamine (0.22 mL, 1.58 mmol) were added, replaced with N2, warmed to 100 °C and stirred for 3 h, LCMS monitoring, rotary evaporation, column chromatography purification to give compound 112 (50 mg, white solid). LC-MS: ESI [M+H] + = 406.4; 1H NMR (400 MHz, DMSO) δ 8.20 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.68 (s, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.41 (dd, J = 8.6, 5.6 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 4.95 - 4.84 (m, 1H), 4.36 (t, J = 4.3 Hz, 2H), 3.84 (s, 3H), 3.82 (d, J = 4.3 Hz, 2H), 1.43 (d, J = 7.0 Hz, 3H).

[0484] Example 113: (S)-N-(l-(3-fluorophenyl)ethyl)-7-((l-methyl-lH-pyrazol-4-yl)ethynyl)- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxamide

[0485] Compound 74a (62.80 mg, 0.59 mmol), compound 27a (150 mg, 0.40 mmol), copper(I) iodide (7.51 mg, 0.040 mmol), Pd(dppf)Cl2(28.87 mg, 0.040 mmol), DMF (5 mL) and triethylamine (0.22 mL, 1.58 mmol) were weighed, N2was replaced, and stirred at 100 °C for 3 h. LCMS monitoring, rotary evaporation, and column chromatography purification gave compound 113 (50 mg, white solid). LC-MS: ESI [M+H] + = 406.4; 1 H NMR (400 MHz, DMSO) δ 8.20 (d, J = 2.1 Hz, 1H), 8.05 (s, 1H), 7.89 (d, J = 2.1 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 2.4 Hz, 1H), 4.90 (t, J = 7.2 Hz, 1H), 4.36 (t, J = 4.5 Hz, 2H), 3.87 - 3.81 (m, 5H), 1.43 (d, J = 7.1 Hz, 3H).

[0486] Example 114: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(l-(3-fluoropyridin-2-yl)ethyl)- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxamide

[0487] First Step: Take compound 27a (500 mg, 2.33 mmol), add DCM (20 mL), cool to 0 °C, add triphosgene (275.96 mg, 0.93 mmol), after 20 min add DIEA (1202.05 mg, 9.30 mmol), after 20 min add compound 114a (495.42 mg, 2.33 mmol), warm to room temperature, stir overnight, monitor by LCMS, quench with water, extract with DCM, combine the organic phases and concentrate by rotary evaporation, purify by column chromatography to give compound 114b (0.62 g, white solid). LC-MS: ESI [M+H] + = 381.2.

[0488] Second Step: Take compound 1j (46.88 mg, 0.40 mmol), compound 114b (150 mg, 0.40 mmol), copper(I) iodide (7.49 mg, 0.040 mmol), Pd(dppf)Cl2(28.79 mg, 0.040 mmol), add DMF (5 mL) and triethylamine (0.22 mL, 1.57 mmol), replace N2, warm to 100 °C, stir overnight, monitor by LCMS, concentrate by rotary evaporation, purify by column chromatography to give compound 114 (55 mg, white solid). LC-MS: ESI [M+H] + = 419.4; 1 H NMR (400 MHz, DMSO) δ 8.45 - 8.38 (m, 3H), 8.22 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.40 (dt, J = 8.5, 4.4 Hz, 1H), 5.22 (t, J = 6.9 Hz, 1H), 4.43 - 4.29 (m, 2H), 3.90 - 3.76 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H).

[0489] Example 115: (S)-N-(1-(3-fluoropyridin-2-yl)ethyl)-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0490] Compound 74a (62.64 mg, 0.59 mmol), compound 114b (150 mg, 0.39 mmol), copper(I) iodide (7.49 mg, 0.039 mmol), Pd(dppf)Cl2(28.79 mg, 0.039 mmol) were added into DMF (5 mL) and triethylamine (0.22 mL, 1.57 mmol), replaced with N2, warmed to 100 °C and stirred overnight. LCMS monitoring, concentrated by rotary evaporation, purified by column chromatography to give compound 115 (50 mg, yellow solid). LC-MS: ESI [M+H]=407.4; + 1 H NMR (400 MHz, DMSO) δ 8.44 - 8.38 (m, 1H), 8.19 (d, J = 2.1 Hz, 1H), 8.06 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.74 - 7.62 (m, 3H), 7.41 (dt, J = 8.5, 4.4 Hz, 1H), 5.22 (t, J = 6.9 Hz, 1H), 4.43 - 4.27 (m, 2H), 3.92 - 3.72 (m, 5H), 1.44 (d, J = 7.0 Hz, 3H).

[0491] Example 116: (S)-7-((6,7-dihydro-5H-pyrazolo[5,l-b][l,3]oxazin-3-yl)ethynyl)-N-(l-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-l-carboxamide

[0492] Compound 116a (172.40 mg, 0.69 mmol), compound 93c (150 mg, 0.46 mmol), copper(I) iodide (8.75 mg, 0.046 mmol), Pd(dppf)Cl2(33.63 mg, 0.046 mmol) were added into DMF (5 mL) and triethylamine (0.26 mL, 1.84 mmol), replaced with N2, warmed to 100 °C and stirred for 3 h. LCMS monitoring, concentrated by rotary evaporation, purified by column chromatography to give compound 116 (25 mg, white solid). LC-MS: ESI [M+H]=449.5; + 1 ​​H NMR (400 MHz, DMSO) δ 8.59 (d, J = 2.9 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.59 (m, 2H), 5.04 (m, 1H), 4.46 (dd, J = 9.2, 4.4 Hz, 4H), 4.17 (t, J = 6.1 Hz, 2H), 4.03 - 3.82 (m, 2H), 2.28 (d, J = 1.1 Hz, 2H), 1.54 (d, J = 7.1 Hz, 3H).

[0493] Example 117: (S)-7-((6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-3-yl)ethynyl)-N-(l-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-l-carboxamide

[0494] Compound 93c (150 mg, 0.460 mmol), 117a (150 mg, 0.598 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), cuprous iodide (13.7 mg, 0.069 mmol), triethylamine (139.2 mg, 1.379 mmol) were weighed, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C, stirred for 3 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 117 (60 mg, white solid). LC-MS: ESI [M+H] + = 449.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.71 (s, 1H), 7.68 (dd, J = 8.8, 2.9 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.7, 4.5 Hz, 1H), 5.00 - 4.91 (m, 1H), 4.88 (s, 2H), 4.41 - 4.33 (m, 2H), 4.17 - 4.10 (m, 2H), 4.10 - 4.03 (m, 2H), 3.92 - 3.75 (m, 2H), 1.45 (d, J = 7.1 Hz, 3H).

[0495] Example 118: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- carboxamide

[0496] First Step: Take compound 95f (450 mg, 1.139 mmol), trimethylsilyl acetylene (335 mg, 3.416 mmol), Pd(PPh3)2Cl2(0.079 g, 0.114 mmol), cuprous iodide (21.7 mg, 0.114 mmol), triethylamine (576.2 mg, 5.693 mmol), add dioxane 10.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 18 h, monitor by LC-MS, after reaction is completed, spin dry, the obtained crude is directly used for next step.

[0497] Second Step: To the crude of last step, add methanol 15.0 ml, add potassium carbonate (1.507 g, 10.908 mmol), stir at room temperature for 2 h, monitor by LC-MS, after reaction is completed, filter, spin dry the filtrate, the obtained crude is purified by column chromatography to get compound 118b (0.360 g). LC-MS: ESI [M+H]=341.1. +

[0498] Third Step: Take compound 118b (200 mg, 0.588 mmol), 72a (286 mg, 1.175 mmol), Pd(dppf)Cl2(0.043 g, 0.059 mmol), cuprous iodide (16.7 mg, 0.088 mmol), triethylamine (178.2 mg, 1.763 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 16 h, monitor by LC-MS, after reaction is completed, spin dry, the obtained crude is purified by column chromatography and then by prep-HPLC to get compound 118 (35 mg, white solid). LC-MS: ESI [M+H]=456.2; + 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.73 - 7.66 (m, 1H), 7.55 - 7.46 (m, 2H), 5.03 - 4.83 (m, 1H), 4.36 (t, J = 4.6 Hz, 2H), 3.93 - 3.69 (m, 2H), 2.44 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H).

[0499] ​​Example 119: (S)-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-methyl-7-((l-methyl-lH- pyrazol-4-yl)ethynyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxamide

[0500] Compound 95f (150 mg, 0.380 mmol), 74a (60 mg, 0.569 mmol), Pd(dppf)Cl2(0.027 g, 0.038 mmol), copper iodide (10.5 mg, 0.057 mmol), triethylamine (115.5 mg, 1.139 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 2 h. LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 119 (12 mg, white solid). LC-MS: ESI [M+H] + = 421.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.9 Hz, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.73 - 7.65 (m, 2H), 7.53 - 7.46 (m, 2H), 4.99 - 4.86 (m, 1H), 4.34 (t, J = 4.5 Hz, 2H), 3.90 - 3.73 (m, 6H), 2.42 (s, 3H), 1.44 (d, J = 7.0 Hz, 3H).

[0501] Example 120: (S)-N-(l-(2-fluorophenyl)ethyl)-6-methyl-7-((l-methyl-lH-pyrazol-4- yl)ethynyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxamide

[0502] First step: Compound 95e (0.150 g, 0.655 mmol) was weighed out and added to dichloromethane 10 ml, stirred and cooled to 0 °C, then triphosgene (0.080 g, 0.262 mmol) was added in batches, stirred for 30 min, DIEA (0.340 g, 2.619 mmol) was added dropwise, stirred for 30 min, then 91a (0.090 g, 0.655 mmol) was added, then stirred at 25 °C overnight. LC-MS monitoring, after the reaction was completed, water was added for extraction, the organic phase was rotary evaporated, and the obtained crude product was purified by column chromatography to give compound 120a (0.200 g, white solid). LC-MS: ESI [M+H] + = 394.1.

[0503] Second Step: Take compound 120a (0.150 g, 0.380 mmol), 74a (0.060 g, 0.569 mmol), Pd(dppf)Cl2(0.027 g, 0.038 mmol), copper(I)iodide (10.5 mg, 0.057 mmol), triethylamine (115.5 mg, 1.139 mmol), add DMF 3.0 ml, replace N2 for three times, warm up to 100 °C, stir for 2 h, monitor by LC-MS, dry after reaction, the obtained crude product is purified by column chromatography to obtain compound 120 (15 mg, white solid). LC-MS: ESI [M+H] + = 420.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 8.05 (s, 1H), 7.67 (s, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 6.9 Hz, 1H), 7.22 - 7.10 (m, 2H), 5.20 - 5.04 (m, 1H), 4.45 - 4.21 (m, 2H), 3.84 (s, 5H), 2.41 (s, 3H), 1.42 (d, J = 7.0 Hz, 3H).

[0504] Example 121: (S)-7-((1,5-dimethyl-1H-pyrazol-4-yl)ethynyl)-N-(1-(2- fluorophenyl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0505] First Step: Take compound 91b (600 mg, 1.58 mmol), trimethylsilyl acetylene (0.67 mL, 4.73 mmol), copper(I)iodide (30.05 mg, 0.16 mmol), Pd(dppf)Cl2(115.47 mg, 0.16 mmol), triethylamine (0.88 mL, 6.31 mmol), add dioxane (20 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, filter, rinse the filter residue with methanol, concentrate the filtrate by rotary evaporation, add methanol (20 mL), potassium carbonate (1.4 g, 7.55 mmol), stir at room temperature for 2 h, monitor by LCMS, filter, rinse the filter residue with methanol, concentrate the filtrate by rotary evaporation, purify by column chromatography to obtain compound 121a (400 mg, light yellow solid). LC-MS: ESI [M+H] + = 326.3.

[0506] Second Step: Take compound 97a (133.08 mg, 0.60 mmol), compound 121a (150 mg, 0.46 mmol), copper(I) iodide (8.78 mg, 0.046 mmol), Pd(dppf)Cl2(33.74 mg, 0.046 mmol), triethylamine (0.26 mL, 1.84 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir overnight, monitor by LCMS, rotary evaporation to concentrate, column chromatography to purify to give compound 121 (50 mg, yellowish solid). LC-MS: ESI [M+H] + = 420.5. 1 H NMR (400 MHz, DMSO) δ 8.16 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.56 (s, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.17 (dd, J = 11.7, 9.1 Hz, 2H), 5.15 (s, 1H), 4.37 (d, J = 3.6 Hz, 2H), 3.94 - 3.78 (m, 2H), 3.74 (s, 3H), 2.32 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H).

[0507] Example 122: (S)-6-((1,5-dimethyl-1H-pyrazol-4-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0508] First Step: Take compound 69a (600 mg, 1.64 mmol), trimethylsilyl acetylene (0.70 mL, 4.93 mmol), copper(I) iodide (31.29 mg, 0.16 mmol), Pd(dppf)Cl2(120.21 mg, 0.16 mmol), triethylamine (0.91 mL, 6.57 mmol), add dioxane (20 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, filter, rinse the filter residue with methanol, rotary evaporation to concentrate the filtrate, add methanol (20 mL), potassium carbonate (2.2 g, 15.7 mmol), stir at room temperature for 2 h, monitor by LCMS, filter, rinse the filter residue with methanol, rotary evaporation to concentrate the filtrate, column chromatography to purify to give compound 122a (300 mg, yellowish solid). LC-MS: ESI [M+H] + = 311.3.

[0509] Second Step: Take compound 97a (139.52 mg, 0.63 mmol), compound 122a (150 mg, 0.48 mmol), copper(I) iodide (9.21 mg, 0.048 mmol), Pd(dppf)Cl2(35.37 mg, 0.048 mmol), triethylamine (0.27 mL, 1.93 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir overnight, monitor by LCMS, rotary evaporation to concentrate, column chromatography to purify to obtain compound 122 (30 mg, white solid). LC-MS: ESI [M+H] + = 405.5. 1 H NMR (400 MHz, DMSO) δ 8.50 (d, J = 2.9 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 3.0 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J = 4.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 4.99 (m, 1H), 4.08 (d, J = 10.1 Hz, 2H), 3.75 (s, 3H), 3.25 (d, J = 8.7 Hz, 2H), 2.33 (s, 3H), 1.48 (d, J = 7.1 Hz, 3H).

[0510] Example 123: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((5-(2-hydroxyethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)ethynyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4] oxazin-1- formamide

[0511] First Step: Take compound 123a (2.000 g, 5.728 mmol), add methanol 10.0 ml, add 4N hydrochloric acid in dioxane 20.0 ml, stir at room temperature for 16 h, monitor by LC-MS, rotary evaporation to concentrate after the reaction is completed, the obtained crude product is purified by column chromatography to obtain compound 123b (1.650 g, white solid). LC-MS: ESI [M+H] + = 250.0.

[0512] Second Step: Take compound 123b (1.000 g, 3.502 mmol) add THF 20.0 ml, add 2- iodoethanol (1.81 g, 10.507 mmol), triethylamine (1.770 g, 17.512 mmol), stir at room temperature for 16 h, monitor by LC-MS, rotary evaporation to concentrate after the reaction is completed, the obtained crude product is purified by column chromatography to obtain compound 123c (0.770 g). LC-MS: ESI [M+H]+ = 294.0.

[0513] Step 3: Compound 123c (0.150 g, 0.460 mmol), 93c (0.202 g, 0.689 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), copper iodide (13.7 mg, 0.069 mmol), triethylamine (139.2 mg, 1.379 mmol) were weighed out and added to DMF 3.0 ml, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, monitored by LC-MS, after the reaction was completed, spin dry, the obtained crude was purified by column chromatography to give compound 123 (51 mg, white solid). LC-MS: ESI [M+H] + = 492.2; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.60 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.8, 4.5 Hz, 1H), 5.02 - 4.90 (m, 1H), 4.56 (t, J = 5.4 Hz, 1H), 4.44 - 4.30 (m, 2H), 4.09 (t, J = 5.4 Hz, 2H), 3.94 - 3.78 (m, 2H), 3.76 (s, 2H), 3.62 - 3.54 (m, 2H), 3.02 - 2.93 (m, 2H), 2.65 (t, J = 5.9 Hz, 2H), 1.45 (d, J = 7.0 Hz, 3H).

[0514] Example 124: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-6-((5-(2-hydroxyethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carboxamide

[0515] Compound 122a (0.150 g, 0.483 mmol), 123c (0.212 g, 0.689 mmol), Pd(dppf)Cl2(0.035 g, 0.048 mmol), copper iodide (13.7 mg, 0.073 mmol), triethylamine (146.7 mg, 1.450 mmol) were weighed out and added to DMF 3.0 ml, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, monitored by LC-MS, after the reaction was completed, spin dry, the obtained crude was purified by column chromatography to give compound 124 (52 mg, white solid). LC-MS: ESI [M+H] += 476.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.52 (dd, J = 8.8, 4.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 5.05 - 4.94 (m, 1H), 4.56 (t, J = 5.4 Hz, 1H), 4.17 - 3.96 (m, 4H), 3.78 (s, 2H), 3.65 - 3.56 (m, 2H), 3.24 (t, J = 8.8 Hz, 2H), 2.97 (dd, J = 6.3, 4.7 Hz, 2H), 2.66 (t, J = 5.8 Hz, 2H), 1.48 (d, J = 7.0 Hz, 3H).

[0516] Example 125: (S)-7-((1,2-dimethyl-1H-imidazol-5-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-carboxamide

[0517] Compound 93c (0.150 g, 0.460 mmol), 125a (0.122 g, 0.552 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), cuprous iodide (13.7 mg, 0.069 mmol), triethylamine (139.2 mg, 1.379 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 125 (56 mg, white solid). LC-MS: ESI [M+H] + = 421.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.78 (td, J = 8.8, 3.0 Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.60 (dd, J = 8.8, 4.5 Hz, 1H), 7.27 (s, 1H), 5.11 - 4.99 (m, 1H), 4.53 - 4.43 (m, 2H), 4.04 - 3.85 (m, 2H), 3.66 (s, 3H), 2.41 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).

[0518] Example 126: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-3-yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0519] Compound 93c (0.150 g, 0.460 mmol), 126a (0.122 g, 0.506 mmol), Pd(dppf)Cl2(0.033 g, 0.046 mmol), cuprous iodide (13.7 mg, 0.069 mmol), triethylamine (139.2 mg, 1.379 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 126 (44 mg, white solid). LC-MS: ESI [M+H] + = 447.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.78 (td, J = 8.8, 3.0 Hz, 1H), 7.69 (d, J = 10.8 Hz, 2H), 7.60 (dd, J = 8.8, 4.5 Hz, 1H), 5.12 - 4.95 (m, 1H), 4.52 - 4.36 (m, 2H), 4.15 (t, J = 6.1 Hz, 2H), 4.03 - 3.84 (m, 2H), 2.87 (t, J = 6.3 Hz, 2H), 2.13 - 2.00 (m, 2H), 1.94 - 1.82 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H).

[0520] Example 127: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((5,6,7,8-tetrahydroimidazo[1,2- a]pyridin-3-yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-formamide

[0521] First Step: Take compound 127a (1.000 mg, 4.973 mmol), trimethylsilyl acetylene (1.470 g, 14.920 mmol), Pd(PPh3)2Cl2 (0.350 g, 0.497 mmol), cuprous iodide (90.7 mg, 0.497 mmol), triethylamine (3.020 g, 29.840 mmol), add 10.0 ml of dioxane, replace with nitrogen three times, stir at 100 °C for 18 h, monitor by LC-MS, after the reaction is completed, spin dry, and the obtained crude product is directly used for the next step.

[0522] Second Step: To the crude product of the previous step, add 20.0 ml of methanol, add potassium carbonate (6.330 g, 45.792 mmol), stir at room temperature for 2 h, monitor by LC-MS, after the reaction is completed, filter, spin dry the filtrate, and the obtained crude product is purified by column chromatography to obtain compound 127c (0.640 g). LC-MS: ESI [M+H] + = 147.1.

[0523] Third Step: Take compound 93c (0.200 g, 0.525 mmol), 127c (0.076 g, 0.525 mmol), Pd(dppf)Cl2 (0.038 g, 0.052 mmol), cuprous iodide (15.7 mg, 0.079 mmol), triethylamine (159.2 mg, 1.574 mmol), add 3.0 ml of DMF, replace with nitrogen three times, stir at 100 °C for 3 h, monitor by LC-MS, after the reaction is completed, spin dry, and the obtained crude product is purified by column chromatography and then by preparative purification to obtain compound 127 (38 mg, white solid). LC-MS: ESI [M+H] + = 447.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.78 (td, J = 8.8, 3.0 Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.33 (s, 1H), 5.09 - 5.00 (m, 1H), 4.53 - 4.41 (m, 2H), 4.02 (t, J = 6.0 Hz, 2H), 3.99 - 3.84 (m, 2H), 2.84 (t, J = 6.3 Hz, 2H), 2.10 - 1.97 (m, 3H), 1.97 - 1.85 (m, 2H), 1.54 (d, J = 7.1 Hz, 3H).

[0524] Example 128: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-6-((5,6,7,8-tetrahydroimidazo[1,2- a]pyridin-3-yl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyrrole-1-carboxamide

[0525] Compound 69a (0.200 g, 0.548 mmol), 127c (0.120 g, 0.821 mmol), Pd(dppf)Cl2(0.038 g, 0.055 mmol), cuprous iodide (15.7 mg, 0.082 mmol), triethylamine (166.2 mg, 1.643 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 128 (60 mg, white solid). LC-MS: ESI [M+H] + = 432.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 2.9 Hz, 1H), 8.19 (d, J = 1.9 Hz, 1H), 8.06 (d, J = 1.8 Hz, 1H), 7.77 (td, J = 8.8, 3.0 Hz, 1H), 7.60 (dd, J = 8.8, 4.5 Hz, 1H), 7.33 (d, J = 10.8 Hz, 2H), 5.12 - 5.01 (m, 1H), 4.24 - 4.09 (m, 2H), 4.03 (t, J = 5.9 Hz, 2H), 3.33 (t, J = 8.8 Hz, 2H), 2.83 (t, J = 6.3 Hz, 2H), 2.06 - 1.95 (m, 2H), 1.96 - 1.86 (m, 2H), 1.56 (d, J = 7.0 Hz, 3H).

[0526] Example 129: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-6-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyrrole-1-carboxamide

[0527] Compound 129a (152.59 mg, 0.58 mmol), compound 69a (150 mg, 0.48 mmol), triethylamine (0.27 mL, 1.93 mmol), Pd(dppf)Cl2(35.37 mg, 0.048 mmol), copper(I)iodide (9.21 mg, 0.048 mmol) were taken in DMF (5 mL), N2was purged, warmed to 100 °C for 3 h with stirring, monitored by LCMS, concentrated by rotary evaporation, purified by column chromatography to afford compound 129 (10 mg, yellowish solid). LC-MS: ESI [M+H] + = 446.5; 1 H NMR (400 MHz, DMSO) δ 8.54 (d, J = 2.8 Hz, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.76 (d, J = 2.8 Hz, 1H), 7.58 (dd, J = 8.8, 4.5 Hz, 1H), 7.39 (d, J = 6.9 Hz, 1H), 5.07 - 4.94 (m, 1H), 4.48 (s, 2H), 4.20 - 4.05 (m, 6H), 3.32 (t, J = 8.6 Hz, 2H), 2.98 (s, 3H), 1.49 (d, J = 7.1 Hz, 3H).

[0528] Example 130: (S)-6-((6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-3-yl)ethynyl)-N-(l-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-carboxamide

[0529] Compound 117a (145.03 mg, 0.58 mmol), compound 122a (150 mg, 0.48 mmol), triethylamine (0.27 mL, 1.93 mmol), Pd(dppf)Cl2(35.37 mg, 0.048 mmol), copper(I)iodide (9.21 mg, 0.048 mmol) were taken in DMF (5 mL), N2was purged, warmed to 100 °C for 3 h with stirring, monitored by LCMS, concentrated by rotary evaporation, purified by column chromatography to afford compound 130 (27 mg, yellowish solid). LC-MS: ESI [M+H] + = 433.5; 1H NMR (400 MHz, DMSO) δ 8.50 (d, J = 2.9 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.73 (s, 1H), 7.69 (td, J = 8.8, 2.9 Hz, 1H), 7.52 (dd, J = 8.8, 4.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 5.06 - 4.94 (m, J = 7.1 Hz, 1H), 4.89 (s, 2H), 4.09 (dt, J = 10.6, 6.1 Hz, 6H), 3.24 (s, 2H), 1.47 (d, J = 7.1 Hz, 3H).

[0530] Example 131: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-6-((4,5,6,7-tetrahydropyrazolo[1,5- a]pyridin-3-yl)ethynyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0531] First Step: Take compound 126a (143.89 mg, 0.58 mmol), compound 122a (150 mg, 0.48 mmol), triethylamine (0.27 mL, 1.93 mmol), Pd(dppf)Cl2(35.37 mg, 0.048 mmol), copper(I)iodide (9.21 mg, 0.048 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, spin to concentrate, purify by column chromatography to get compound 131 (38 mg, white solid). LC-MS: ESI [M+H] + = 431.5; 1 H NMR (400 MHz, DMSO) δ 8.59 (d, J = 2.8 Hz, 1H), 8.13 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.77 (dd, J = 8.8, 2.9 Hz, 1H), 7.72 (s, 1H), 7.61 (dd, J = 8.7, 4.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 5.08 (t, J = 7.2 Hz, 1H), 4.25 - 4.08 (m, 4H), 3.32 (t, J = 8.7 Hz, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.11 - 2.00 (m, 2H), 1.94 - 1.83 (m, 2H), 1.56 (d, J = 7.1 Hz, 3H).

[0532] Example 132: (S)-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-((l-(methyl-d3)-lH-pyrazol-4- yl)ethynyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-carboxamide

[0533] Compound 93d (122.40 mg, 0.58 mmol), compound 122a (150 mg, 0.48 mmol), triethylamine (0.27 mL, 1.93 mmol), Pd(dppf)Cl2(35.37 mg, 0.048 mmol), copper(I)iodide (9.21 mg, 0.048 mmol) were weighed into DMF (5 mL), replaced with N2, warmed to 100 °C for 3 h with stirring, monitored by LCMS, concentrated by rotary evaporation, purified by column chromatography to give compound 132 (32 mg, white solid). LC-MS: ESI [M+H] + = 394.4; 1 H NMR (400 MHz, DMSO) δ 8.50 (d, J = 2.9 Hz, 1H), 8.07 (s, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.69 (s, 2H), 7.52 (dd, J = 8.7, 4.5 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.99 (m, 1H), 4.17 - 4.00 (m, 2H), 3.24 (s, 2H), 1.47 (d, J = 7.1 Hz, 3H).

[0534] Example 133: (S)-7-((l-(cyanomethyl)-lH-pyrazol-4-yl)ethynyl)-N-(l-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazin-l-carboxamide

[0535] First step: Compound 133a (1 g, 5.16 mmol) was weighed into DMF (5 mL), potassium carbonate (1.42 g, 10.31 mmol) was added, bromoacetonitrile (0.36 mL, 5.16 mmol) was added, stirred at room temperature for 1 h, monitored by LCMS, filtered, the filter residue was rinsed with methanol, the filtrate was concentrated by rotary evaporation, purified by column chromatography to give compound 133b (0.75 g, white solid). LC-MS: ESI [M+H] + = 234.0.

[0536] Second Step: Take compound 133b (117.82 mg, 0.51 mmol), compound 93c (150 mg, 0.46 mmol), triethylamine (0.26 mL, 1.84 mmol), copper(I) iodide (8.75 mg, 0.046 mmol), Pd(dppf)Cl2(33.63 mg, 0.046 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir overnight, monitor by LCMS, rotary evaporation to concentrate, column chromatography to purify to give compound 133 (55 mg, white solid). LC-MS: ESI [M+H] + = 432.4; 1 H NMR (400 MHz, DMSO) δ 8.59 (d, J = 2.9 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.30 (s, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.95 (s, 1H), 7.78 (td, J = 8.8, 3.0 Hz, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.60 (dd, J = 8.7, 4.5 Hz, 1H), 5.60 (s, 2H), 5.04 (m, 1H), 4.47 (s, 2H), 4.03 - 3.85 (m, 2H), 1.55 (d, J = 7.1 Hz, 3H).

[0537] Example 134: (S)-6-((1,2-dimethyl-1H-imidazol-5-yl)ethynyl)-N-(1-(5-fluoropyridin-2- yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0538] Take compound 125a (128.78 mg, 0.58 mmol), compound 122a (150 mg, 0.48 mmol), triethylamine (0.27 mL, 1.93 mmol), Pd(dppf)Cl2(35.37 mg, 0.048 mmol), copper(I) iodide (9.21 mg, 0.048 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, rotary evaporation to concentrate, column chromatography to purify to give compound 134 (100 mg, yellow solid). LC-MS: ESI [M+H] + = 405.5; 1H NMR (400 MHz, DMSO) δ 8.60 (d, J = 2.1 Hz, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.85 (t, J = 8.7 Hz, 1H), 7.67 (dd, J = 8.6, 4.4 Hz, 1H), 7.54 (d, J = 6.1 Hz, 1H), 5.11 - 4.98 (m, 1H), 4.29 - 4.08 (m, 2H), 3.76 (s, 3H), 3.36 (t, J = 8.6 Hz, 2H), 2.64 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H).

[0539] Example 135: (S)-N-(l-(5-fluoropyridin-2-yl)ethyl)-6-((7-methyl-5,6,7,8- tetrahydroimidazo[l,2-a]pyrazin-3-yl)ethynyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine- 1 -carboxamide

[0540] First Step: Take compound 135a (2.000 g, 6.619 mmol), add methanol 10.0 ml, add 4N hydrochloric acid in dioxane 30.0 ml, stir at room temperature for 16 h, monitor by LC-MS, after the reaction is completed, spin dry, the obtained crude product is directly used in the next step. LC-MS: ESI [M+H] + = 202.0.

[0541] Second Step: Take compound 135b (1.500 g, 6.289 mmol), add methanol 30.0 ml, add triethylamine (0.640 g, 6.289 mmol) and stir for 5 min, cool to 0 °C, add paraformaldehyde (0.760 g, 25.155 mmol), sodium acetate (1.370 g, 10.062 mmol), add acetic acid to adjust the pH of the solution to 5-6, stir for 30 min, then add sodium cyanoborohydride (0.630 g, 10.062 mmol), stir at room temperature for 16 h, monitor by LC-MS, after the reaction is completed, spin dry, the obtained crude product is purified by column chromatography to obtain compound 135c (0.790 g). LC-MS: ESI [M+H] + = 216.0.

[0542] Step 3: Take compound 135c (0.790 g, 3.656 mmol), trimethylsilyl acetylene (1.080 g, 10.968 mmol), Pd(PPh3)2Cl2(0.260 g, 0.366 mmol), copper iodide (70.7 mg, 0.366 mmol), triethylamine (2.220 g, 21.936 mmol), add dioxane 10.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 18 h, monitor by LC-MS, after reaction is completed, spin dry, the obtained crude is directly used for next step.

[0543] Step 4: To the crude from last step, add methanol 15.0 ml, add potassium carbonate (5.030 g, 36.420 mmol), stir at room temperature for 2 h, monitor by LC-MS, after reaction is completed, filter, spin dry the filtrate, the obtained crude is purified by column chromatography to get compound 135e (0.415 g). LC-MS: ESI [M+H]= 162.1. +

[0544] Step 5: Take compound 69a (0.150 g, 0.411 mmol), 135e (0.132 g, 0.821 mmol), Pd(dppf)Cl2(0.030 g, 0.041 mmol), copper iodide (11.7 mg, 0.062 mmol), triethylamine (124.6 mg, 1.232 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 3 h, monitor by LC-MS, after reaction is completed, spin dry, the obtained crude is purified by column chromatography and then by prep-HPLC to get compound 135 (90 mg, white solid). LC-MS: ESI [M+H]= 446.2; + 1 H NMR (400 MHz, DMSO-d6) d 8.50 (d, J = 2.9 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.52 (dd, J = 8.8, 4.5 Hz, 1H), 7.29 (s, 1H), 7.25 (d, J = 7.5 Hz, 1H), 5.05 - 4.93 (m, 1H), 4.17 - 4.01 (m, 2H), 3.98 (t, J = 5.5 Hz, 2H), 3.55 (s, 2H), 3.26 (t, J = 8.7 Hz, 2H), 2.81 (dd, J = 6.2, 4.8 Hz, 2H), 2.38 (s, 3H), 1.48 (d, J = 7.1 Hz, 3H).

[0545] ​​Example 136: (S)-7-((5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazole-1-carboxamide

[0546] First Step: Take compound 136a (0.500 g, 2.463 mmol), trimethylsilyl acetylene (0.730 g, 7.388 mmol), Pd(PPh3)2Cl2(0.170 g, 0.246 mmol), cuprous iodide (50.7 mg, 0.246 mmol), triethylamine (1.520 g, 14.775 mmol), add dioxane 5.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 18 h, monitor by LC-MS, after reaction is completed, spin dry, the obtained crude is directly used for next step.

[0547] Second Step: To the crude from last step, add methanol 10.0 ml, add potassium carbonate (3.140 g, 22.691 mmol), stir at room temperature for 2 h, monitor by LC-MS, after reaction is completed, filter, spin dry the filtrate, the obtained crude is purified by column chromatography to get compound 136c (0.300 g). LC-MS: ESI [M+H]= 149.1. +

[0548] Third Step: Take compound 93a (0.200 g, 0.525 mmol), 136c (0.116 g, 0.787 mmol), Pd(dppf)Cl2(0.038 g, 0.052 mmol), cuprous iodide (15.7 mg, 0.079 mmol), triethylamine (159.2 mg, 1.574 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 3 h, monitor by LC-MS, after reaction is completed, spin dry, the obtained crude is purified by column chromatography and then by prep-HPLC to get compound 136 (45 mg, white solid). LC-MS: ESI [M+H]= 449.2; + 1 ​​H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.51 (dd, J = 8.8, 4.4 Hz, 1H), 7.32 (s, 1H), 5.01 - 4.89 (m, 1H), 4.75 (s, 2H), 4.45 - 4.33 (m, 2H), 4.09 - 3.95 (m, 5H), 3.95 - 3.78 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H).

[0549] Example 137: (S)-6-((5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)ethynyl)-N-(1-(5- fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxamide

[0550] Compound 69a (0.200 g, 0.548 mmol), 136c (0.121 g, 0.821 mmol), Pd(dppf)Cl2(0.040 g, 0.055 mmol), cuprous iodide (15.7 mg, 0.082 mmol), triethylamine (166.2 mg, 1.643 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 137 (95 mg, white solid). LC-MS: ESI [M+H] + = 433.2; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.9 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.69 (td, J = 8.8, 3.0 Hz, 1H), 7.52 (dd, J = 8.7, 4.5 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J = 7.5 Hz, 1H), 5.05 - 4.91 (m, 1H), 4.75 (s, 2H), 4.17 - 4.01 (m, 7H), 3.26 (t, J = 8.7 Hz, 2H), 1.48 (d, J = 7.1 Hz, 3H).

[0551] Example 138: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((7-methyl-5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- formamide

[0552] Compound 93c (0.150 g, 0.393 mmol), 136c (0.126 g, 0.787 mmol), Pd(dppf)Cl2(0.028 g, 0.039 mmol), cuprous iodide (11.7 mg, 0.059 mmol), triethylamine (119.6 mg, 1.180 mmol) were weighed out, DMF 3.0 ml was added, replaced with nitrogen for three times, warmed to 100 °C and stirred for 3 h, LC-MS monitoring, after the reaction was completed, rotary evaporation was performed, and the obtained crude product was purified by column chromatography to give compound 138 (58 mg, white solid). LC-MS: ESI [M+H] + = 462.2; 1 H NMR (400 MHz, DMSO-d6) d 8.50 (d, J = 2.9 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.69 (td, J = 8.8, 2.9 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 8.8, 4.5 Hz, 1H), 7.27 (s, 1H), 5.01 - 4.91 (m, 1H), 4.46 - 4.32 (m, 2H), 3.96 (t, J = 5.5 Hz, 2H), 3.93 - 3.76 (m, 2H), 3.55 (s, 2H), 2.81 (dd, J = 6.2, 4.8 Hz, 2H), 2.39 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H).

[0553] Example 139: (S)-N-(1-(5-fluoropyridin-2-yl)ethyl)-7-((5-methyl-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrazin-3-yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- formamide

[0554] Compound 139a (200 mg, 0.76 mmol), compound 93c (206.74 mg, 0.63 mmol), triethylamine (0.35 mL, 2.53 mmol), copper(I) iodide (12.07 mg, 0.063 mmol), Pd(dppf)Cl2(46.36 mg, 0.063 mmol), DMF (5 mL), replace N2, warm to 100 °C, stir overnight, LCMS monitor, rotary evaporation, column chromatography to give compound 139 (50 mg, yellow solid). LC-MS: ESI [M+H] + = 417.5; 1 H NMR (400 MHz, DMSO) δ 8.64 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.91 (td, J = 8.7, 2.7 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.83 (s, 1H), 7.71 (dd, J = 8.8, 4.5 Hz, 1H), 5.12 - 4.96 (m, 1H), 4.77 (s, 1H), 4.52 (s, 1H), 4.49 (d, J = 5.4 Hz, 2H), 4.41 (dd, J = 10.3, 6.1 Hz, 2H), 3.97 (dt, J = 13.3, 4.1 Hz, 1H), 3.87 (dt, J = 9.1, 4.3 Hz, 2H), 3.74 (s, 1H), 2.98 (s, 3H), 1.50 (d, J = 7.1 Hz, 3H).

[0555] Example 140: (S)-N-(1-(6-fluoropyridin-2-yl)ethyl)-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -carboxamide

[0556] First step: take compound 27a (0.61 g, 2.83 mmol), add DCM (20 mL), cool to 0 °C, drop triphosgene (0.34 g, 1.13 mmol) dissolved in DCM, stir for 20 min, drop DIEA (1.97 mL, 11.32 mmol), stir for 20 min, add compound 140a (0.5 g, 2.83 mmol), warm to room temperature, stir overnight, TLC monitor, add water and DCM to extract, rotary evaporation of organic phase, column chromatography to give compound 140b (0.52 g, white solid). LC-MS: ESI [M+H] + = 381.2.

[0557] Second Step: Take compound 74a (50.11 mg, 0.47 mmol), compound 140b (150 mg, 0.39 mmol), triethylamine (0.22 mL, 1.57 mmol), copper(I) iodide (7.49 mg, 0.039 mmol), Pd(dppf)Cl2(28.79 mg, 0.039 mmol), add DMF (5 mL), replace N2, warm up to 100 °C, stir for 3 h, monitor by LCMS, rotary evaporation to concentrate, column chromatography to purify to give compound 140 (25 mg, white solid). LC-MS: ESI [M+H] + = 407.4. 1 H NMR (400 MHz, DMSO) δ 8.21 (d, J = 2.1 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.38 (dd, J = 7.4, 2.4 Hz, 1H), 7.04 - 7.00 (m, 1H), 4.86 (t, J = 7.1 Hz, 1H), 4.38 (t, J = 4.4 Hz, 2H), 3.93 - 3.86 (m, 2H), 3.84 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H).

[0558] Example 141: (S)-7-((1-(Difluoromethyl)-1H-pyrazol-4-yl)ethynyl)-N-(1-(6- fluoropyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide

[0559] First Step: Take compound 140b (3.350 g, 8.788 mmol), trimethylsilyl acetylene (2.590 g, 26.363 mmol), Pd(PPh3)2Cl2(0.062 g, 0.879 mmol), copper(I) iodide (170.7 mg, 0.879 mmol), triethylamine (4.450 g, 43.939 mmol), add dioxane 10.0 ml, replace N2 for three times, warm up to 100 °C, stir for 18 h, monitor by LC-MS, rotary evaporation to concentrate after reaction, the obtained crude product is directly used for next step.

[0560] Second Step: To the crude product of last step, add methanol 40.0 ml, add potassium carbonate (12.140 g, 87.827 mmol), stir at room temperature for 2 h, monitor by LC-MS, filter after reaction, rotary evaporation to concentrate the filtrate, the obtained crude product is purified by column chromatography to give compound 141b (1.720 g). LC-MS: ESI [M+H] + = 327.1.

[0561] Third Step: Take compound 141b (0.172 g, 0.527 mmol), 72a (0.193 g, 0.790 mmol), Pd(dppf)Cl2(0.039 g, 0.052 mmol), copper iodide (15.7 mg, 0.079 mmol), triethylamine (160.2 mg, 1.583 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 16 h, monitor by LC-MS, dry after reaction, the obtained crude product is purified by column chromatography to give compound 141 (45 mg, white solid). LC-MS: ESI [M+H] + = 443.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.95 (s, 1H), 7.86 (dd, J = 7.8, 2.8 Hz, 2H), 7.73 (s, 1H), 7.53 - 7.49 (m, 1H), 7.28 (dd, J = 7.5, 2.6 Hz, 1H), 6.93 (dd, J = 8.1, 2.7 Hz, 1H), 4.86 - 4.71 (m, 1H), 4.30 (t, J = 4.5 Hz, 2H), 3.86 - 3.66 (m, 2H), 1.35 (d, J = 7.1 Hz, 3H).

[0562] Example 142: (S)-7-((1H-pyrazol-4-yl)ethynyl)-N-(1-(5-fluoropyridin-2-yl)ethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxamide

[0563] Third Step: Take compound 141b (0.172 g, 0.527 mmol), 72a (0.193 g, 0.790 mmol), Pd(dppf)Cl2(0.039 g, 0.052 mmol), copper iodide (15.7 mg, 0.079 mmol), triethylamine (160.2 mg, 1.583 mmol), add DMF 3.0 ml, replace with nitrogen for three times, warm up to 100 °C, stir for 16 h, monitor by LC-MS, dry after reaction, the obtained crude product is purified by column chromatography to give compound 141 (45 mg, white solid). LC-MS: ESI [M+H] + = 393.1; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.9 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.93 (s, 2H), 7.91 (d, J = 2.1 Hz, 1H), 7.75 (td, J = 8.8, 3.0 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.57 (dd, J = 8.8, 4.5 Hz, 1H), 5.03 - 4.91 (m, 1H), 3.95 - 3.79 (m, 3H), 1.47 (d, J = 7.1 Hz, 3H).

[0564] Example 143: (S)-7-((2-aminopyrimidin-5-yl)ethynyl)-N-(1-(3,5-difluorophenyl)ethyl)- 3,4-dihydro-1,5-naphthyridine-1 (2H)-carboxamide

[0565] First Step: Compound 32a (0.300 g, 1.408 mmol) was weighed into dichloromethane 10 ml, under stirring, temperature was lowered to 0 °C, triphosgene (0.170 g, 0.563 mmol) was added in batches, stirred for 30 min, DIEA (0.720 g, 5.632 mmol) was added dropwise, stirred for 30 min, 73a (0.220 g, 1.408 mmol) was added, then stirred at 25 °C overnight. LC-MS monitoring, post-processing: water extraction, the organic phase was rotary evaporated, the obtained crude product was purified by column chromatography to obtain compound 143a (0.448 g, white solid). LC-MS: ESI [M+H] + = 396.0.

[0566] Second Step: Compound 143a (0.200 g, 0.505 mmol), 1j (0.120 g, 1.009 mmol), Pd(dppf)Cl2(0.036 g, 0.050 mmol), cuprous iodide (14.7 mg, 0.076 mmol), triethylamine (178.5 mg, 1.767 mmol) were weighed into DMF 3.0 ml, replaced with nitrogen for three times, temperature was raised to 100 °C, stirred for 16 h, LC-MS monitoring, post-processing: rotary evaporation, the obtained crude product was purified by column chromatography and then prepared to obtain compound 143 (49 mg, white solid). LC-MS: ESI [M+H] + = 435.2; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 2H), 8.19 (d, J = 1.9 Hz, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.16 (s, 2H), 7.14 - 7.03 (m, 4H), 4.96 - 4.82 (m, 1H), 3.80 - 3.62 (m, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.02 - 1.91 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H).

[0567] Biological activity test:

[0568] 1. In vitro kinase activity assay experiment

[0569] In a reaction tube, buffer (8 mM) MOPS, pH 7.0, 0.2 mM EDTA, 10 mM MnCl2), the tested kinase, the substrate of the tested kinase, 10 mM magnesium acetate and γ33P-ATP solution, and different concentrations of compounds were sequentially added, then MgATP was added to the reaction to start the enzyme reaction process, and incubated at room temperature for 40 minutes. Finally, 5 microliters of 3% phosphate buffer were used to terminate the reaction, and 10 microliters of the reaction solution were titrated onto a Filtermat A membrane, washed with 75 mM phosphate solution for 5 minutes three times, washed with methanol once, and finally dried the Filtermat A membrane and subjected to scintillation counting. The magnitude of the scintillation count value reflects the degree of phosphorylation of the substrate, thereby characterizing the kinase activity. IC 50 Data measured by Eurofins.

[0570] Table 2. Results of RIPK1 kinase inhibition of the tested compounds

[0571] In Table 2, + represents: IC 50 ≥ 500 nM; ++ represents: 500 nM > IC 50 ≥ 100 nM; +++ represents: IC 50 < 100 nM.

[0572] Conclusion: The compounds of the present application have significant inhibitory effect on RIPK1 kinase.

[0573] 2. Screening of RIPK1 inhibitors at the cellular level

[0574] HT-29 cells were cultured in DMEM medium supplemented with 10% FBS and 1% penicillin / streptomycin; L929 cells were cultured in MEM medium supplemented with 10% FBS and 1% penicillin / streptomycin; and U937 cells were cultured in RPMI medium supplemented with 10% FBS and 1% penicillin / streptomycin. When the cells reached the logarithmic growth phase, the cells were collected for testing. After resuspending the cells, they were counted using a hemocytometer. Cell suspension was added to each well (8000 cells / well for L929 and HT-29, 1000 cells / well for U937). 4 Cells were seeded in 96-well plates and cultured overnight at 37°C with 5% CO2. The next day, the test drug was diluted to the appropriate concentration with culture medium, and the prepared test compound was added to the corresponding wells of the 96-well plate. Each sample was set up in 3 replicates. At the same time, an inducing agent control group (cells + inducer), a cell control group (0 drug added), and a blank group containing only culture medium (no cells) were set up. After the drug-added cells were induced with the inducing agent TNF-α / Smac mimetic / z-VAD-FMK for 24 h, 20 μl of 5 mg / mL MTT working solution was added to each well and incubated for 2-4 h. After observing obvious purple formazan crystals at the bottom of the 96-well plate under a microscope, the culture supernatant in the well was carefully aspirated with a 5 mL syringe. Finally, 100 μL of DMSO was added to each well. After the purple crystals were fully dissolved, the absorbance was measured at 570 nm using a microplate reader. After incubating U937 cells with MTT working solution for 2-4 hours, add 50 μl of 20% SDS solution to each well and incubate overnight. The absorbance is then measured at 570 nm using a microplate reader the next day. Cell viability is calculated as: [(A(with test drug) - A(blank)) / (A(without drug) - A(blank))] x 100%; A represents the absorbance value. Finally, the cell viability curve is fitted using GraphPad Prism 8.0 software, and the EC50% (e.g., 4-year cytokine concentration) of the test compound in inhibiting programmed cell death is calculated. 50 value.

[0575] Table 3. Results of the tested compounds on the anti-necrosis and anti-apoptosis effects of U937 and L929 cells.

[0576] In Table 3, + indicates: EC 50 >50nM;++ means: 50nM > IC 50 ≥10nM; +++ means <10nM; - means not detected.

[0577] Conclusion: The compounds of this invention significantly inhibit necrotizing apoptosis in U937 and L929 cells.

[0578] 3. Pharmacokinetic evaluation of the compound in Balb / c mice

[0579] Objective: To understand the pharmacokinetics of the compound.

[0580] Experimental basis: Technical guidelines for nonclinical pharmacokinetic studies of chemical drugs, 2014.

[0581] Experimental scheme: Through intravenous administration (10mg·kg -1 ) and gavage administration (10mg·kg -1 ) of Balb / c mice, the pharmacokinetics of the compound was investigated.

[0582] Sample preparation: Weigh the compound, dissolve it in DMSO, and then add sodium chloride injection to prepare a 1mg·mL -1 compound solution for administration.

[0583] Sample collection: 6 Balb / c mice (Chengdu Dasuo Experimental Animal Co., Ltd., license No. SCXK (Chuan) 2020-030), male, 3 for intravenous administration (IV) at 10mg·kg -1 , 3 for gavage administration (PO) at 10mg·kg -1 , and 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h and 48h after administration, about 0.05mL blood was collected. The collected blood was centrifuged at 3500rpm for 15min, and the supernatant plasma was collected and stored at -40℃ for testing. The blood drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and the pharmacokinetic parameters such as peak time (Cmax), area under the curve (AUC(0-t)), half-life (T1 / 2), clearance (CL), tissue distribution (Vdss), and bioavailability (F) were calculated. The pharmacokinetic evaluation results are shown in Table 4.

[0584] Table 4 Pharmacokinetic test results of the compound in Balb / c mice

[0585] Conclusion: The compound of the present application, especially the preferred compound, has good pharmacokinetic properties in Balb / c mice, including good oral bioavailability, exposure, half-life, and clearance.

[0586] 4. Evaluation of compound distribution in rat cerebrospinal fluid and plasma

[0587] Experimental procedure: Weigh the compound and add a small amount of DMSO, then add sodium chloride injection to prepare a 5mg·mL -1 compound solution for administration. Rats, male, 5mg·kg -1Intravenous administration, 0.25h, 2h after administration, cerebrospinal fluid and whole blood (n=1) were collected. Whole blood was centrifuged at 3500rpm for 15min, and the supernatant plasma was collected. 10μL of plasma and 10μL of cerebrospinal fluid were taken into a centrifuge tube, 40μL of 20ng·ml -1 Acetonitrile precipitation of internal standard SAHA, vortex for 30s, centrifuge at 13000rpm for 15min, and take the supernatant into a sample bottle for testing. The standard curve range is: 1-1000ng·ml -1 .

[0588] Table 5 Test results of compound distribution in rat cerebrospinal fluid and plasma after administration

[0589] Conclusion: The present application has good brain penetration potential, especially the preferred compound has a high distribution concentration in rat cerebrospinal fluid.

[0590] 5. Compound 1 for TNFα-induced inflammatory factor IL-6 determination in mouse SIRS model

[0591] 6-8 week old, 18-20g weight C57BL / 6 female mice were adaptively fed for 3d, and then randomly divided into groups: control group, model group, 2.5mg / kg reference compound Ref-1, 0.02mg / kg compound 1, 0.1mg / kg compound 1, 0.5mg / kg compound 1 and 2.5mg / kg compound 1, a total of 7 groups. The mice were induced by injecting 8μg / mouse TNFα through the tail vein, and the eyeball blood was taken after 6 hours after TNFα injection, and the IL-6 content in the mouse serum was determined. The reference compound Ref-1 was synthesized according to the synthesis method of example 48 of patent WO2021160109.

[0592] Conclusion: The results are shown in Figure 1. The average of IL-6 in serum was 13.70 pg / ml in Control group, 14032.15 pg / ml in Model group, 6213.85 pg / ml in 2.5 mg / kg reference compound Ref-1 group, 7179.18 pg / ml in 0.02 mg / kg Compound 1 group, 6848.07 pg / ml in 0.1 mg / kg Compound 1 group, 2371.30 pg / ml in 0.5 mg / kg Compound 1 group, and 822.93 pg / ml in 2.5 mg / kg Compound 1 group, respectively. Compared with Control group, Model group had significant difference, P<0.0001; compared with Model group, all dosing groups had significant difference. Compared with 2.5 mg / kg reference compound Ref-1 group, 0.5 mg / kg Compound 1 group and 2.5 mg / kg Compound 1 group had significant difference, P value was 0.05 and 0.001, respectively. The pharmacodynamic evaluation of the compounds was: 2.5 mg / kg Compound 1 group > 0.5 mg / kg Compound 1 group > 2.5 mg / kg reference compound Ref-1 group > 0.1 mg / kg Compound 1 group > 0.02 mg / kg Compound 1 group, and Compound 1 had dose-dependent effect.

[0593] 6. Measurement of inflammatory factor IL-6 in TNFα-induced SIRS model of mice by Compound 51

[0594] 6-8 week old, 18-20 g weight C57BL / 6 female mice were adaptively fed for 3 days, and then randomly divided into groups: Control group, Model group, 5 mg / kg reference compound DNL-788, 0.0125 mg / kg Compound 51, 0.25 mg / kg Compound 51, 5 mg / kg Compound 51, and 2.5 mg / kg Compound 51, totally 7 groups. The mice were induced by injection of 8 μg / each TNFα through the tail vein, and the blood was taken from the eyeball 6 hours after the injection of TNFα. The serum of the mice was measured for IL-6 content. The reference compound DNL788 (HY-148787) was purchased from Shanghai MedChemExpress Company.

[0595] The experimental results are shown in Figure 2. Compared with the control group, the model group has a significant difference, P<0.0001; the average values of IL-6 in the serum are: 20.48 pg / ml for the control group; 9270.95 pg / ml for the model group; 1180.34 pg / ml for the 5 mg / kg DNL788; 7748.54 pg / ml, 3038.96 pg / ml and 1485.48 pg / ml for the 0.0125 mg / kg, 0.25 mg / kg and 5 mg / kg compound 51 respectively. The preliminary evaluation of the pharmacodynamics of the compound is: 5 mg / kg compound 51 group>0.25 mg / kg compound 51 group>0.0125 mg / kg compound 51 group>5 mg / kg DNL788 group.

[0596] Conclusion: The compound of the present application can dose-dependently inhibit the production of inflammatory factor IL-6 in the SIRS model of mice induced by TNFα, and the inhibitory effect is significantly better than that of the reference compound DNL788.

[0597] 7. Evaluation of the pharmacodynamics of compound 51 in the model of autoimmune encephalomyelitis (EAE) induced by MOG35-55

[0598] Experimental method: 6-8 week old, 18-20 g weight C57BL / 6 male mice were adaptively fed for one week, and randomly divided into 7 groups: Control, Model, 3 mg / kg Fingolimod, 25 mg / kg DNL788, 12.5 / 25 / 50 mg / Kg compound 51. 10 in the control group, 5 in the Fingolimod group, and 9 in the remaining groups. On the first day, the model animals were given myelin oligodendrocyte glycoprotein MOG (35-55) 10 mg / kg, i.h; pertussis toxin PTX 25 μg / kg, i.p; on the third day, the model animals were given PTX 25 μg / Kg, i.p; on the 11th day, the model animals were grouped according to the clinical score and started to be given drugs, the control group was given the same volume of solvent control, the body weight of each group was weighed daily and the clinical score was recorded; on the 25th day, each group reached the experimental endpoint and was euthanized, and the samples were taken.

[0599] Detection index: (1) body weight and clinical score changes of each group; (2) the lumbar enlargement (L1-L5) of the sample was fixed and subjected to HE, LoYeZ staining to observe the histopathological changes.

[0600] The experimental results are shown in Figures 3-5. Compound 51 restored the body weight of EAE mice and significantly improved the clinical evaluation. HE and LoYeZ staining showed that the myelin sheath of the spinal cord of normal mice was arranged in order, the texture was clear, the myelin sheath density was high, and demyelination was rare. A large number of myelin sheath loss was observed in the spinal cord of EAE model mice, such as loose structure and reduced density, accompanied by a large number of inflammatory cell aggregation. After administration of compound 51, the spinal cord vacuole lesion was improved, the demyelination was reduced, and the inflammatory cell aggregation was reduced in a dose-dependent manner.

[0601] Conclusion: Compound 51 has good disease remission effect on the multiple sclerosis disease model, and the treatment effect is better than that of the reference compound DNL788.

[0602] 8. Pharmacodynamic evaluation of compound 51 on CPZ-induced demyelination multiple sclerosis model

[0603] Experimental method: 6-8 week old, 18-20 g body weight C57BL / 6 male mice were adaptively fed for one week, and randomly divided into 6 groups: Control, Model, 3 mg / kg Fingolimod, 25 mg / kg DNL788, 25 / 50 mg / kg compound 51. Control group 10, Model group, Fingolimod group 12, DNL788 group 6, compound 51 each dose group 7. From the first day of administration to the end of the 9th week, the model animals were given Cuprizone (CPZ) 400 mg / kg, p.o; from the 6th week, randomly divided and started administration, the control group was given the same volume of solvent control, body weight was measured twice a week; at the end of the 9th week, each group reached the experimental endpoint and was euthanized, and the samples were taken.

[0604] Detection index: (1) Body weight change of each group; (2) whole brain was taken, coronal section was made, and after fixation, HE, LoYeZ staining was performed to observe the histopathological changes.

[0605] The experimental results are shown in Figures 6-7. Compound 51 had no significant effect on the body weight of CPZ-induced demyelination multiple sclerosis model animals after administration. Histopathological examination showed that compound 51 (25-50mpk) improved the vacuole-like lesion of the corpus callosum in a dose-dependent manner, and reduced the range of myelin loss.

[0606] Conclusion: Compound 51 has good disease remission effect on the CPZ-induced multiple sclerosis disease model.

[0607] 9. Test of the selectivity of compound 51 on kinase profile

[0608] Compound 51 was tested for single concentration inhibition rate against 390 human kinase targets from Eurofins at a concentration of 1 uM. The results of the test (test conducted by Eurofins and provided activity test data) are shown in Table 6.

[0609] Conclusion: Compound 51 has strong inhibitory activity against RIPK1 only at a concentration of 1 uM, showing good kinase profile selectivity.

[0610] Table 6 Inhibition test of Compound 51 against 390 kinase targets at a concentration of 1 uM

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, characterized in that: The structure of formula I is as follows: wherein: represents a single or double bond; X1is selected from CR 3a or N, X2is selected from CR 3b or N, X3is selected from CR 3c or N; R 3a , R 3b , and R 3c are independently selected from hydrogen or halogen; Y1and Y2are independently selected from C or N, and wherein one is N, the other is C; Y3is selected from -CR 4a -, -C(O)-, -C(R 4b R 4c) -, -C(R 4b R 4c) C(R 4d R 4e) -, -C(R 4b R 4c) O-, -OC(R 4d R 4e) -, -NR 4f - or N; Y4is selected from -CR 5a -, -C(O)-, -C(R 5b R 5c) -, -C(R 5b R 5c) C(R 5d R 5e) -, -C(R 5b R 5c) O-, -OC(R 5d R 5e) -, -NR 5f - or N; R 4a and R 5a are independently selected from hydrogen, deuterium, halogen, 3- to 6-membered cycloalkyl, or C 1-4 alkyl substituted with 0-3 substituents selected from hydrogen, deuterium, cyano, hydroxyl, amino, or halogen; 4a and R 5a , wherein the substituents are selected from hydrogen, deuterium, cyano, hydroxyl, amino, or halogen; R 4b , R 4c , R 4d , R 4e , R 5b , R 5c , R 5d and R 5e are independently selected from hydrogen, deuterium, fluorine, 3- to 6- membered cycloalkyl, or C 1-4 alkyl substituted with 0-3 substituents selected from hydrogen, deuterium, or fluorine; or, R 4b , R 4c , R 4d , R 4e , R 5b , R 5c , R 5d and R 5e ; or, R 4b and R 4c , together with the atoms to which they are attached, form a 3- to 4- membered cycloalkyl; R 4f and R 5f Independently selected from 3- to 6-membered cycloalkyl groups or C groups substituted with 0-3 substituents. 1-4 Alkyl; R 4f and R 5f In this context, the substituent is selected from hydrogen, deuterium, or fluorine; Z is selected from C or N; R1is selected from hydrogen, deuterium, halogen, cyano, -N(R 6a R 6b ), -CON(R 6a R 6b ), -OR 6a , -SR 6a , -COR 6b , -COOR 6b , -NR 6a COR 6b , -NHCON(R 6a R 6b ), -SO2R 6a , -SO2N(R 6a R 6b ) or the following group substituted with 0-6 substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered spirocycloalkyl, 5-10 membered heterospriocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; in R1, the substituents are selected from deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl; in R1, the 3-6 membered heterocycloalkyl, 5-10 membered heterospriocycloalkyl, 6-10 membered heterobridged cycloalkyl, 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, S, O; R 6a and R 6b are independently selected from hydrogen, deuterium, or the following groups substituted with 0-6 substituents: C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl; R 6a and R 6b wherein said substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl; R 6a and R 6b wherein said 4-6 membered heterocycloalkyl or 5-10 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S, O; Ring A is selected from a 5-10 membered heteroaromatic ring or a 5-10 membered fused heteroaromatic ring; in Ring A, the 5-10 membered heteroaromatic ring or the 5-10 membered fused heteroaromatic ring contains 1-4 heteroatoms selected from at least one of N, S, O; L is selected from or R 7a and R 7b C independently selected from hydrogen, deuterium, or C substituted with 0-3 substituents. 1-4 Alkyl; R 7a and R 7b In this context, the substituent is selected from deuterium, halogen, hydroxyl, or amino groups; R 7c selected from hydrogen, deuterium, fluorine, cyano, hydroxyl, amino, or C 1-4 alkyl substituted with 0-3 substituents selected from deuterium, halogen, hydroxyl, or amino; R 7c alkyl substituted with 0-3 substituents selected from deuterium, halogen, hydroxyl, or amino; R Ring B is selected from a benzene ring or a 5-10 membered heteroaromatic ring; in Ring B, the 5-10 membered heteroaromatic ring contains 1-3 heteroatoms selected from at least one of N, S, O; R2is selected from hydrogen, deuterium, halogen, cyano, amino, or the following groups substituted with 0-3 substituents: C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; in ring B, the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S, O; n1is selected from 0, 1, 2, 3, 4, 5 or 6; n2is selected from 0, 1, 2, 3, 4, 5 or 6; n3is selected from 0, 1, 2, 3, 4, 5 or 6; n4is selected from 0, 1, 2 or 3; the pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, nitroxide, isotopically labeled, metabolite or prodrug.

2. The compound of claim 1, wherein: R 4a and R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, fluorinated methyl, or cyclopropyl; R 4b , R 4c , R 4d , R 4e , R 5b , R 5c , R 5d and R 5e are independently selected from hydrogen, deuterium, fluorine, chlorine, deuterated methyl, fluorinated methyl or cyclopropyl; or, R 4b and R 4c form, together with the atom to which they are attached, a cyclopropyl group; R 4f and R 5f is independently selected from hydrogen, deuterium, methyl, deuterated methyl, fluorinated methyl, or cyclopropyl.

3. The compound of claim 1, wherein: X1, X2, X3are at most one selected from N, R 4a , R 4b and R 4c are independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, fluorinated methyl or cyclopropyl; Preferably, the structural unit selected from the group consisting of: or More preferably, the structural unit selected from the group consisting of: or 4. The compound of claim 1, wherein: R1is selected from the group consisting of hydrogen, deuterium, halogen, cyano, -NHR 6a , -OR 6a , -COR 6b , -NHCOR 6b , -NHCONHR 6a or the following groups which are substituted with 0 to 6 substituents: C 1-4 alkyl, 3- to 6-membered cycloalkyl or 4- to 6-membered oxacycloalkyl; in R1, the substituents are selected from the group consisting of deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy or 3- to 4-membered cycloalkyl; R 6a and R 6b are independently selected from hydrogen, deuterium, or the following groups substituted with 0-3 subsitutents: C 1-4 alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered oxacycloalkyl, phenyl, or 5- to 6-membered heteroaryl; R 6a and R 6b wherein said subsitutents are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3- to 4-membered cycloalkyl; R 6a and R 6b wherein said 5- to 6-membered heteroaryl contains 1-2 N heteroatoms; Preferably, R1is selected from hydrogen, deuterium, halogen, cyano, -NHR 6a , -OR 6a , -COR 6b , -NHCOR 6b , -NHCONHR 6a or the following groups, which are substituted with 0 to 3 substituents: methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl or oxetanyl; in R1, the substituents are selected from deuterium, fluorine, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy, fluoromethoxy or cyclopropyl; R 6a and R 6b are independently selected from hydrogen, deuterium, or the following groups substituted with 0-3 substituents: methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, oxetanyl, phenyl, or R 6a and R 6b wherein the substituents are selected from: deuterium, fluorine, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy, fluoromethoxy or cyclopropyl; More preferably, R1is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, deuterated methyl, fluorinated methyl, methoxy, deuterated methoxy, fluorinated methoxy, ethyl, cyclopropyl, cyclobutyl, oxetanyl, -NH2, 5. The compound of claim 1, wherein: Ring A is selected from the following groups: or R 8a and R 8b are independently selected from hydrogen, deuterium, -CON(R 9a R 9b ), -COR 9b , -COOR 9b or the following groups substituted with 0-6 substituents: C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered spiro cycloalkyl, 5-10 membered hetero spiro cycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered hetero bridged cycloalkyl, 6-10 membered aryl, or 5-10 membered heteroaryl; R 8a and R 8b , the substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl; R 8a and R 8b , the 3-6 membered heterocycloalkyl, 5-10 membered hetero spiro cycloalkyl, 6-10 membered hetero bridged cycloalkyl, 5-10 membered heteroaryl contain 1-3 heteroatoms selected from at least one of N, S, O. R 9b selected from hydrogen, deuterium, or the following groups substituted with 0-6 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, or 5-10 membered heteroaryl; R 9b wherein said substituents are selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3-4 membered cycloalkyl; R 9b wherein said 4-6 membered heterocycloalkyl or 5-10 membered heteroaryl contains 1-3 heteroatoms selected from at least one of N, S, O; R 8a and R 8b are independently selected from hydrogen, deuterium, -COR 9b or the following groups which are substituted with 0-3 substituents: C 1-4 alkyl, 3- to 6-membered cycloalkyl, or 4- to 6-membered oxacycloalkyl; R 8a and R 8b wherein said substituents are selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3- to 4-membered cycloalkyl; R 9b selected from hydrogen, deuterium, or the following groups substituted with 0-3 substituents: C 1-4 alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered oxacycloalkyl, or phenyl; R 9b wherein said substituents are selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, or 3- to 4-membered cycloalkyl; More preferably, R 8a and R 8b are independently selected from hydrogen, deuterium, -COR 9b or the following groups which are substituted with 0-3 substituents: methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, or oxetanyl; R 8a and R 8b wherein said substituents are selected from deuterium, halogen, -OH, -NH2, -CN, methyl, fluoromethyl, methoxy, fluoromethoxy, or cyclopropyl; R 9b selected from hydrogen, deuterium, or the following groups substituted with 0-3 substituents: methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, oxetanyl, phenyl, or R 9b In particular, the substituents are selected from the group consisting of: deuterium, halogen, -OH, -NH2, -CN, methoxy, fluoromethoxy or cyclopropyl. Most preferably, R 8a and R 8b are independently selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl, oxetanyl, or 6. The compound of claim 1, wherein: Structural unit selected from the group consisting of: or 7. The compound of claim 1, wherein: R 7a and R 7b is independently selected from hydrogen, deuterium, methyl, deuterated methyl, fluorinated methyl, hydroxymethyl; n3 is selected from 0, 1, 2 or 3; n4 is selected from 1 ; Preferably, L is selected from or 8. The compound of claim 1, wherein: n1is selected from 0, 1, 2 or 3; n2is selected from 0, 1, 2 or 3.

9. The compound of claim 1, wherein: Ring B is selected from a benzene ring, a pyridine ring, a pyrazine ring; R2is selected from hydrogen, deuterium, fluorine, chlorine, cyano, amino, methyl, fluoromethyl, deuteromethyl, methoxy, fluoromethoxy, deuteromethoxy, thiomethyl or fluorothiomethyl; Preferably, the structural unit selected from the group consisting of: or 10. The compound of claim 1, wherein: The compound is selected from: or 11. The compound of claim 3, wherein: Structural unit is also selected from the group consisting of: or Preferably, the structural unit is also selected from the group consisting of: or 12. The compound of claim 4, wherein: R1is also selected from the group consisting of hydroxy, 13. The compound of claim 5, wherein: Ring A is also selected from the following groups: or 14. The compound of claim 6, wherein: Structural unit is also selected from the following groups: or 15. The compound of claim 7, wherein: R 7a and R 7b are also independently selected from ethyl, cyclopropyl, or R 7a and R 7b are linked to form a cyclopropane; Preferably, L is also selected from or 16. The compound of claim 9, wherein: Ring B is also selected from a thiazole ring; Preferably, the structural unit is also selected from the group consisting of: or 17. The compound of claim 1, wherein: The compound is selected from: or 18. The compound of claim 14, wherein: Structural unit is also selected from the group consisting of: or 19. The compound of claim 16, wherein: Structural unit is also selected from the group consisting of:

20. The compound of claim 1, wherein: The compound is selected from: or 21. A pharmaceutical composition, characterized by: which is a compound of any one of claims 1-20 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopically labeled, metabolite or prodrug thereof as an active ingredient, together with a pharmaceutically acceptable carrier.

22. Use of a compound of any one of claims 1-20 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopically labeled, metabolite or prodrug thereof and the pharmaceutical composition of claim 21 in the preparation of a RIPK1 inhibitor.

23. Use of the compound or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitroxide, isotopically labeled, metabolite or prodrug of any one of claims 1-20 and the pharmaceutical composition of claim 21 in the manufacture of a medicament for preventing and / or treating a RIPK1 kinase related disease.

24. The use according to claim 22, characterized in that: The RIPK1 kinase related disease is an inflammatory disease, an immune disease, a nervous system disease or a tumor.

25. Use according to claim 23 or 24, characterized in that: The RIPK1 kinase related disease is amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, Parkinson's disease, spinal muscular atrophy, stroke, human immunodeficiency virus associated dementia, autism, schizophrenia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic onset juvenile idiopathic arthritis, psoriasis, dermatitis, systemic lupus erythematosus, systemic inflammatory response syndrome, pancreatitis, encephalitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, ulcerative colitis, Crohn's disease, retinal degenerative disease, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, Sjogren's syndrome, systemic scleroderma, solid organ ischemia-reperfusion injury, cerebral ischemia, ischemic heart disease, acute kidney injury, ischemic brain injury, sepsis, diabetes or atherosclerosis.

26. Use according to claim 23 or 24, characterized in that: The RIPK1 kinase related disease is leukemia, lymphoma, macroglobulinemia, heavy chain disease, sarcoma, carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, endometrial cancer, testicular cancer, lung cancer, bladder cancer, glioma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, schwannoma, neurofibroma, retinoblastoma, melanoma, skin cancer, renal cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, small intestine cancer, gallbladder cancer, pediatric tumor, urothelial carcinoma, ureteral tumor, thyroid cancer, osteoma, neuroblastoma, brain tumor or myeloma.

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