Rho-associated protein kinase inhibitors and their preparation and application

Abstract

The present invention relates to Rho-associated protein kinase inhibitors and their preparation and application.Specifically, the compound of the present invention has a structure represented by formula I, in which each group and substituent is as defined herein.The present invention further discloses pharmaceutical compositions related to said compounds, preparation methods, and their use in the preparation of drugs for preventing or treating Rho-associated protein kinase (ROCK)-mediated diseases. [Formula 1] JPEG2025515296000097.jpg4478

Description

[Technical field]

[0001] The present invention relates to the field of biomedicine, specifically to Rho-associated protein kinase inhibitors and their preparation and application. [Background technology]

[0002] Rho-associated kinases (ROCKs) are serine / threonine kinases of the AGC kinase family, which includes two subtypes, ROCK1 and ROCK2. ROCK2 (ROCKα) was first identified as a RhoA-binding protein, and ROCK1 (ROCKβ or p160ROCK) was subsequently discovered as a RhoA-binding protein with high homology to ROCK2. RhoA is a GTPase that is activated after binding to GTP and promotes the activation of downstream effector factors. ROCKs have been extensively studied over the past 20 years and, as the main effector factors of RhoA protein, achieve their biological functions by phosphorylating downstream effector proteins (MYPT1, MLC, Moesin, etc.). Currently, more than 30 substrates of ROCKs have been identified, which are involved in the regulation of multiple processes, such as cytoskeleton dynamics, cell morphology, and cell contraction. The most studied and reported substrate is myosin phosphatase target subunit 1 (MYPT1), which is the myosin-binding subunit of myosin light chain phosphatase (MLCP). ROCKs mediate phosphorylation of MYPT1 at Thr697 and Thr855 sites to inhibit the catalytic activity of MLCP, thereby controlling the phosphorylation of myosin regulatory light chain (MLC) and affecting the generation of cellular contractile force. Studies have shown that the occurrence of fibrosis, cardiovascular disease, metabolic disease, neurological disease, and cancer are associated with ROCKs-mediated pathways, and therefore ROCKs are considered to be an important target point for the treatment of these diseases.

[0003] The amino acid sequence similarity between ROCK1 and ROCK2 reaches 64%, the kinase domain similarity reaches 92%, and the two subtypes share some common effector proteins. Currently, various small molecule ROCK inhibitors have been reported, where most inhibitors have equivalent inhibitory activity against both ROCKs subtypes. Currently, only two ROCK inhibitors have been approved for clinical use as topical drugs: Fasudil, which was the first approved drug for treating cerebral vasospasm in Japan and China, and Ripasudil, which was approved for treating glaucoma in Japan. Simultaneous inhibition of the two ROCKs subtypes can cause potential side effects such as hypotension, so there are currently no small molecule ROCK inhibitors suitable for systemic administration. The development of small molecule inhibitors targeting specific subtypes will be an important direction in drug development targeting ROCK. Summary of the Invention [Problem to be solved by the invention]

[0004] It is an object of the present invention to provide compounds of formula I, processes for their preparation and their use as inhibitors of RHO-associated coiled-coil-containing protein kinases. [Means for solving the problem]

[0005] A first aspect of the present invention provides a compound represented by formula I, or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, [ka] Where: X is [ka] is selected from the group consisting of R 21 , R 22 are independently H, C1-6 Alkyl group, C 3-10 cycloalkyl groups, Y is None, C(=O), O, S(=O) i , C.R. 23 R 24 , NR; R is H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, saturated or partially unsaturated C 3-10 A cyclic hydrocarbon group, a saturated or unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; C 6-12 aralkyl groups, wherein up to two ring members of the cyclic hydrocarbon group and the heterocyclic group are C(=O); R 23 , R 24 are each independently H, halogen, or C 1-6 Alkyl group, C 3-10 selected from the group consisting of cyclic hydrocarbon groups; Ring A is a saturated or partially unsaturated C 3-10 A cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 aryl groups, and 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); Ring C is saturated or partially unsaturated C 3-10 A cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 aryl groups, and 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); Ring D is absent or is a saturated or partially unsaturated C 3-10 A cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 aryl groups, and 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); Ring E is [ka] is selected from the group consisting of Ring G is a saturated or partially unsaturated C 3-10 A cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 aryl groups, and 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); R 1 is H, halogen, -CN, -NH2, C 1-6 Alkyl group, C 6-10 Aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, N-methyltetrahydropyrrolyl groups, N-methylpiperidinyl groups, acetyl groups, -C(=O)-(C 1-6 Alkylene) n -CF3, -(C 1-6 Alkylene) n -CF3, -C(=O)-(C 1-6 Alkylene) n -CN, -C(=O)-(saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group) n , -NH-C(=O)-(saturated or partially unsaturated C 3-10 -C(=O)-(a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S), -C(=O)-C1-6 Alkylene-(a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S), -C(=O)-(a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S), -C(=O)-C 1-6 Alkylene-NH-(C 1-6 alkyl), -C(=O)-C 1-6 Alkylene-N(C 1-6 Alkyl)2, N-methylpiperazine substituted acetyl group, -S(=O)2R 1a , -P(=O)R 1a R 1b , [ka] is selected from the group consisting of R 1a and R 1b are each independently H, a halogen, an amino group, a cyano group, a nitro group, or C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; C 6-12 Aralkyl group, -C(=O)R 5 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1-6 Alkylene-NR 5 R 6 , -C 1-6 Alkylene-OR 5 , -OC 1-6 Alkylene-NR 5 R 6 or R 1a and R 1b together with the atoms to which they are attached form a 3-12 membered heterocyclic or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; R 3 , R 4 , R 7 , R 8 , R 9 and R 10 Each occurrence of represents independently H, a halogen atom, an amino group, a cyano group, a nitro group, or C. 1-6 Alkyl groups, deuterated C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; C 6-12 Aralkyl group, -C(=O)R 5 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6, -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1-6 Alkylene-NR 5 R 6 , -C 1-6 Alkylene-OR 5 , -OC 1-6 Alkylene-NR 5 R 6 , -C 1-6 alkylene-O-(P=O)(OH)2; R 2 is H, halogen, amino group, cyano group, nitro group, C 1-6 Alkyl groups, deuterated C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; C 6-12 Aralkyl group, -C(=O)R 5 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5-S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1-6 Alkylene-NR 5 R 6 , -C 1-6 Alkylene-OR 5 , -OC 1-6 Alkylene-NR 5 R 6 , -C 1-6 Alkylene-O-(P=O)(OH)2, -C 1-6 Alkylene-O(C=O)R 11 , -C 1-6 Alkylene-O(P=O)(OR 12 )(NR 13 R 14 ), -C 1-6 Alkylene-O(P=O)(OR 12 )(OR 13 ) selected from the group consisting of R 11 , R 12 , R 13 , R 14 Each occurrence of is independent of H, C 1-6 Alkyl group, C 3-6 a cycloalkyl group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 an aryl group, a 3- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and a cation; The cation is Na + , K + , Ca 2+ , Mg 2+ , NH4 + is selected from the group consisting of Each occurrence of the alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbon, heterocyclic, aryl, heteroaryl and aralkyl groups is optionally selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6Alkynyl group, C 3-10 a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; C 6-12 Aralkyl group, =N-OR 5 , -C(=NH)NH2, -C(=O)R 5 , -OC(=O)R 5 , -C(=O)OR 5 , -OR 5 , -SR 5 , -S(=O)R 5 , -S(=O)2R 5 , -S(=O)2NR 5 R 6 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -NR 5 -C(=O)R 6 , -NR 5 -C(=O)OR 6 , -NR 5 -S(=O)2-R 6 , -NR 5 -C(=O)-NR 5 R 6 , -C 1-6 Alkylene-NR 5 R 6 , -C 1-6 Alkylene-OR 5 , -OC 1-6 Alkylene-NR 5 R 6 and is substituted by one or more substituents independently selected from the group consisting of: R 5 and R 6 Each occurrence of is independent of H, C 1-6 Alkyl group, C 3-10 a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S; C 6-12aralkyl groups; each occurrence of m is independently selected from the group consisting of 0, 1, 2, and 3; each occurrence of n is independently selected from the group consisting of 0, 1 and 2; i is selected from the group consisting of 1, 2; g is selected from the group consisting of 0, 1, 2, 3, and 4.

[0006] In another preferred embodiment, X is [ka] is selected from the group consisting of Y is selected from the group consisting of NH, NCH3.

[0007] In another preferred embodiment, Ring C is [ka] and Ring E is [ka] is selected from the group consisting of:

[0008] In another preferred embodiment, Ring A is a saturated or partially unsaturated C 3-10 A cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, C 6-10 aryl groups, and 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); Ring D is absent or is a saturated or partially unsaturated C 3-10and a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0009] In another preferred embodiment, [ka] teeth, [ka] is selected from the group consisting of:

[0010] In another preferred embodiment, ring D is absent or [ka] is selected from the group consisting of:

[0011] In another preferred embodiment, ring G is [ka] is selected from the group consisting of:

[0012] In another preferred embodiment, R 1 is H, -C(=O)-(C 1-6 Alkylene) n -CF3, -(C 1-6 Alkylene) n -CF3, -C(=O)-(saturated or partially unsaturated C 3-10 Cyclic hydrocarbon group) n , [ka] is selected from the group consisting of R 1a and R 1b together with the atoms to which they are attached form a 3-12 membered heterocyclic or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0013] In another preferred embodiment, R 1 H, [ka] is selected from the group consisting of:

[0014] In another preferred embodiment, R 2 is H, halogen, amino group, cyano group, nitro group, C 1-6 Alkyl groups, deuterated C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 an aryl group, a 5-14 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; -C(=O)R 5 , -OC(=O)R 5 , -C(=O)OR 5 , -C 1-6 Alkylene-O-(P=O)(OH)2, -C 1-6 Alkylene-O(C=O)R 11 , -C 1-6 Alkylene-O(P=O)(OR 12 )(NR 13 R 14 ), -C 1-6 Alkylene-O(P=O)(OR 12 )(OR 13 ) selected from the group consisting of R 11 , R 12 , R 13 , R 14 Each occurrence of is independent of H, C 1-6 Alkyl group, C 3-6 a cycloalkyl group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 an aryl group, a 3- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and a cation; The cation is Na + , K + , Ca 2+ , Mg 2+ , NH4 + is selected from the group consisting of:

[0015] In another preferred embodiment, R 2 -H, -C 1-6 Alkylene-O(C=O)R 11 , -C 1-6 Alkylene-O(P=O)(OR 12 )(NR 13 R 14 ), -C 1-6 Alkylene-O(P=O)(OR 12 )(OR 13 ) selected from the group consisting of R 11 , R 12 , R 13 , R 14 Each occurrence of is independent of H, C 1-6 an alkyl group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; 6-10 selected from the group consisting of an aryl group, a cation, The cation is Na + , K + , Ca 2+ , Mg 2+ , NH4 + is selected from the group consisting of:

[0016] In another preferred embodiment, the compound has a structure of any of the following formulas: [ka] [ka] Here, each group is as defined above.

[0017] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka]

[0018] In another preferred embodiment, the compound is selected from the group consisting of: [ka] [ka] [ka]

[0019] A second aspect of the invention provides a pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers and a prophylactically and / or therapeutically effective amount of one or more compounds according to the first aspect of the invention, or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof.

[0020] A third aspect of the present invention provides the use of a compound according to the first aspect of the present invention, or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labelled compound, metabolite or prodrug thereof, for use in the preparation of a medicament for the prevention and / or treatment of a Rho-associated protein kinase mediated disease.

[0021] In another preferred embodiment, the Rho-associated protein kinase is ROCK1 and / or ROCK2. In another preferred embodiment, the drug is a selective ROCK2 inhibitor.

[0022] In another preferred embodiment, the Rho-associated protein kinase-mediated disease is selected from the group consisting of autoimmune diseases, cardiovascular diseases, inflammation, central nervous system diseases, arterial thrombotic diseases, fibrotic diseases, neoplastic diseases, metabolic syndrome, insulin resistance, hyperinsulinemia, type 2 diabetes, impaired glucose tolerance, osteoporosis, and eye diseases.

[0023] In another preferred embodiment, the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (SLE, lupus), psoriasis, Crohn's disease, atopic dermatitis, eczema, or graft-versus-host disease (GVHD).

[0024] In another preferred embodiment, the cardiovascular disease is selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, and erectile dysfunction. In another preferred embodiment, the inflammation is selected from the group consisting of asthma, cardiovascular inflammation, ulcerative colitis, and renal inflammation.

[0025] In another preferred embodiment, the central nervous system disease is selected from the group consisting of neurodegeneration and spinal cord injury. In another preferred embodiment, the central nervous system disease is selected from the group consisting of Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

[0026] In another preferred embodiment, the arterial thrombotic disorder is selected from the group consisting of platelet aggregation and leukocyte aggregation. In another preferred embodiment, the fibrotic disease is selected from the group consisting of liver fibrosis, pulmonary fibrosis, and renal fibrosis. In another preferred embodiment, the neoplastic disease is selected from the group consisting of lymphoma, carcinoma, leukemia, astrocytoma, soft tissue sarcoma, sarcoma, and blastoma.

[0027] In another preferred embodiment, the cancer is selected from the group consisting of squamous cell carcinoma, small cell lung cancer, pituitary cancer, esophageal cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, brain cancer, testicular cancer, bile duct cancer, gallbladder cancer, gastric cancer, melanoma, and head and neck cancer.

[0028] In another preferred embodiment, the ophthalmic disease is selected from the group consisting of ocular hypertension, age-related macular degeneration (AMD), choroidal neovascularization (CNV), diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma, and retinopathy of prematurity (ROP).

[0029] In another preferred embodiment, the glaucoma is selected from the group consisting of primary open-angle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, congenital glaucoma, normal tension glaucoma, secondary glaucoma, and neovascular glaucoma.

[0030] In another preferred embodiment, the Rho-associated protein kinase-mediated disease is selected from the group consisting of lupus nephritis, atherosclerosis, rheumatoid arthritis (RA), hemangioma, angiofibroma, pulmonary fibrosis, hepatic fibrosis, psoriasis, corneal graft rejection, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, foreign body rejection, allergic inflammation, contact dermatitis, delayed hypersensitivity reaction, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, neuroinflammation, Osler-Weber syndrome, restenosis, fungal infection, parasitic infection, and viral infection. Effect of the Invention

[0031] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] After a long period of thorough research and structural optimization, the present inventors have unexpectedly prepared a new type of compound (compound represented by formula I) with excellent ROCK2 inhibitory activity, which has excellent ROCK2 inhibitory activity, better selectivity for ROCK2, better pharmacokinetics (e.g., in vivo exposure, tissue targeting, half-life, metabolic stability, etc.), better efficacy and safety in vivo. Based on this, the present inventors have completed the present invention.

[0033] term In the present invention, unless otherwise specified, the terms used have the common meanings known to those skilled in the art. In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0034] In the present invention, "C 1-6 "Alkyl group" refers to straight or branched chain alkyl groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like.

[0035] In the present invention, "C 2-6 The term "alkenyl group" refers to straight or branched chain alkenyl groups containing one double bond having 2 to 6 carbon atoms, including, but not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0036] In the present invention, "C 2-6The term "alkynyl group" refers to straight or branched chain alkynyl groups containing one triple bond having 2 to 6 carbon atoms, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0037] In the present invention, "C 3-6 The term "cyclic hydrocarbon group" means 3-6 Cycloalkyl groups, C 3-6 Cycloalkenyl group, C 3-6 "C" includes a group selected from the group consisting of cycloalkynyl groups. 3-10 The term "cyclic hydrocarbon group" has an analogous meaning.

[0038] In the present invention, "C 3-6 The term "cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms on the ring, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. 3-10 The term "cycloalkyl group" has an analogous meaning.

[0039] In the present invention, "C 1-6 The term "alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. 1-4 It is an alkoxy group.

[0040] In the present invention, the term "heterocyclic group" means [ka] and refers to a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including but not limited to:

[0041] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and preferably are 6-10 "Aryl group".6-10 The term "aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as a phenyl group, a naphthyl group, and the like.

[0042] In the present invention, the terms "aromatic heterocycle" or "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, a "5-14 membered heteroaryl group" refers to an aromatic heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and 2-13 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl group, a heterocyclic group, or a cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0043] In the present invention, "C 6-12 The term "aralkyl group" means a 6-12 Aryl-C 1-6 It refers to a group having an alkylene-structure. In the present invention, the term "deuterated" refers to substitution with deuterium.

[0044] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described correspondingly in the above specification or the substituent described in each example. Unless otherwise specified, a specific substituent can have a substituent selected from a specific group at any substitutable position of the group, and the substituent can be the same or different at each position. It should be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those stable combinations or scientifically achievable combinations. Examples of the substituent include (but are not limited to) halogen, a hydroxyl group, a carboxyl group (-COOH), a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3- to 12-membered heterocyclic group, an aryl group, a heteroaryl group, a C1-C8 aldehyde group, a C2-C10 acyl group, a C2-C10 ester group, an amino group, a C1-C6 alkoxy group, a C1-C10 sulfonyl group, and the like.

[0045] In the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each independently have the same meaning. The term "multiple" refers to 2 to 6, i.e. 2, 3, 4, 5 or 6. It is to be understood that when a particular group is simultaneously present in several different positions on a compound, its definition at each position is independent of each other and may be the same or different, i.e., the term "selected from the group consisting of" has the same meaning as the term "each independently selected from the group consisting of."

[0046] Compounds and their preparation The present invention provides a compound represented by formula I, or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, [ka] Here, each group is as defined above.

[0047] In another preferred embodiment, in the compound, X, Y, ring A, ring C, ring D, ring E, and R 1 , R 7 , R 8 , R 9 , R 10 , m are each independently the corresponding group in specific compounds described herein.

[0048] As used herein, the term "pharmaceutical acceptable salt" refers to a medicament-compatible salt formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salt formed by the compound of the present invention and an acid. Acids compatible with salt formation include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, etc., and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc.

[0049] Further preferred salts are salts formed by the compounds of the present invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanol ammonium salts and other pharma- ceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, t-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0050] The preparation method of the compound of the present invention having the structure of formula I described below does not limit the present invention in any way. The compound of the present invention can also be prepared by any combination of various synthetic methods described herein or known in the art, and such combination can be easily performed by a person skilled in the art. It is understood that the raw materials and reagents used in the processes for preparing the compounds of the present invention may be purchased through commercial channels, unless otherwise specified.

[0051] Pharmaceutical Compositions and Methods of Administration The pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount range. Here, the "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the disease condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / agent of the present invention, more preferably 5-1000 mg of the compound / agent of the present invention. Preferably, the "one agent" is one capsule or tablet.

[0052] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances, which must be suitable for human use, have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of each component of the composition to be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween R), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0053] The pharmaceutical composition is in the form of an injection, a capsule, a tablet, a pill, a powder or a granule. The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0054] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or vector), such as, for example, sodium citrate or dicalcium phosphate, or with ingredients such as (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarders, such as paraffin; (f) absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium dodecyl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0055] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0056] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0057] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar-agar, or mixtures of these substances.

[0058] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0059] The dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers or propellants that may be required.

[0060] The compounds of the present invention may be administered alone or in combination with other pharma- ceutically acceptable compounds. The therapeutic methods of the present invention can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0061] When a pharmaceutical composition is used, a safe and popular amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, where the dosage at the time of administration is the effective dosage considered, and for a person weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 5-1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the health condition of the patient, all of which are within the skill of a skilled physician.

[0062] Compared with the prior art, the present invention has the following advantages: (1) The compounds have superior pharmacokinetic properties, such as in vivo exposure, tissue targeting, half-life, and metabolic stability. (2) The compounds have better ROCK2 inhibitory activity, better selectivity for ROCK2, and better selectivity against other human kinases. (3) The compounds have better safety and better in vivo efficacy. (4) The compounds are expected to be used in the prevention and / or treatment of diseases associated with the regulation of Rho-associated protein kinases (ROCK1 and / or ROCK2).

[0063] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods that do not show specific conditions usually follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or those suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can all be applied to the method of the present invention. The preferred implementation methods and materials described herein are used for demonstration purposes only. Experimental materials and reagents used in the following examples are available from commercial channels unless otherwise stated.

[0065] Example 1-1. Preparation of Compound A1 [ka]

[0066] Step 1. Compound 3 Compound 1 (2.0 g, 9.8 mmol, 1.0 eq), compound 2 (1.5 g, 11.8 mmol, 1.2 eq), HATU (5.6 g, 14.7 mmol, 1.5 eq) and diisopropylethylamine (6.3 g, 49.0 mmol, 5.0 eq) are added sequentially to anhydrous dichloromethane (60 mL), and the reaction solution is stirred for 2 h at 25° C. The reaction solution is concentrated, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate=4 / 1) to give compound 3 (1.6 g, 58% yield) as a colorless oil. LCMS: [M+H] + =279.0.

[0067] Step 2. Compound 5 Compound 3 (1.0 g, 3.58 mmol, 1.0 eq), compound 4 (7.0 g, 71.60 mmol, 20.0 eq), Pd(PPh3)2Cl2 (500 mg, 0.716 mmol, 0.2 eq) and copper(I) iodide (136 mg, 0.716 mmol, 0.2 eq) were added to triethylamine (10 mL) in sequence, the reaction system was replaced with nitrogen gas three times, and the temperature was raised to 90 ° C and stirred for 3 hours. The reaction solution was cooled to 25 ° C and then concentrated, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4 / 1) to obtain compound 5 (1.0 g, yield 94%). LCMS: [M+H] + =297.2.

[0068] Step 3. Compound 6 Compound 5 (1.0 g, 3.38 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (0.9 g, 3.38 mmol, 1.0 eq) is added, and the resulting solution is stirred at room temperature for 0.5 h. The residue obtained after concentrating the reaction solution is purified by silica gel column chromatography (n-hexane / ethyl acetate=4 / 1) to give compound 6 (0.65 g, 87%). LCMS: [M+H] + =225.1.

[0069] Step 4. Compound A1 Compound 7 (50 mg, 0.184 mmol, 1.0 eq) is dissolved in anhydrous N,N-dimethylformamide (2 mL), bis(triphenylphosphine)palladium(II) dichloride (13 mg, 0.0184 mmol, 0.1 eq), copper(I) iodide (4 mg, 0.0184 mmol, 0.1 eq) and triethylamine (372 mg, 3.68 mmol, 20.0 eq) are added, and the reaction system is replaced with nitrogen gas three times. The reaction solution is heated to 100 ° C under a nitrogen gas atmosphere, and a solution of compound 6 (103 mg, 0.460 mmol, 2.5 eq) in N,N-dimethylformamide (1 mL) is slowly added dropwise to the reaction solution, and after the addition is completed, the mixture is stirred at 100 ° C for 2 hours. The reaction solution is cooled to room temperature and concentrated, and the residue is purified by Pre-HPLC to obtain compound A1 (8 mg). LCMS: [M+H] + =460.2.

[0070] 1 H NMR(400MHz,DMSO-d6)δ 12.79(s,1H),9.78(s,1H),8.26(d,J=6.0Hz,1H),8.02(s,2H),7.60(s, 4H), 6.75 (d, J=6.0Hz, 1H), 6.73-6.68 (m, 2H), 4.64 (s, 4H), 3.95 (s, 3H).

[0071] Example 1-2. Preparation of Compound A2 [ka]

[0072] Step 1. Compound A2 Compound 8 (100 mg, 0.408 mmol, 1.0 eq) is dissolved in anhydrous N,N-dimethylformamide (2 mL), bis(triphenylphosphine)palladium(II) dichloride (29 mg, 0.0408 mmol, 0.1 eq), copper(I) iodide (8 mg, 0.0408 mmol, 0.1 eq) and triethylamine (826 mg, 8.16 mmol, 20.0 eq) are added, and the reaction system is replaced with nitrogen gas three times. The reaction solution is heated to 100 ° C under a nitrogen gas atmosphere, and a solution of compound 6 (228 mg, 1.02 mmol, 2.5 eq) in N,N-dimethylformamide (1 mL) is slowly added dropwise to the reaction solution, and after the addition is completed, the mixture is stirred at 100 ° C for 2 hours. The reaction solution is cooled to room temperature and concentrated, and the residue is purified by Pre-HPLC to obtain compound A2 (20.2 mg). LCMS: [M+H] + =434.2.

[0073] 1 H NMR(400MHz,DMSO-d6)δ 13.03(s,1H),9.76(s,1H),8.23(d,J=6.0Hz,1H),8.06(s,2H),7.56(d,J=8. 8Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 6.74-6.67 (m, 3H), 4.65 (s, 4H), 3.95 (s, 3H).

[0074] Example 1-3. Preparation of Compound A4 [ka] Step 1. Compound 11 Compound 9 (370 mg, 2.27 mmol, 1.2 eq) and compound 10 (301 mg, 1.89 mmol, 1.0 eq) are dissolved in n-butanol (10 mL) and diisopropylethylamine (733 mg, 5.67 mmol, 3.0 eq) is added. The reaction mixture is stirred at 95° C. for 20 h. After monitoring the completion of the reaction by LCMS, the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / ethyl acetate=1 / 1) to give compound 11 (250 mg, 39%) as a yellow solid. LCMS: [M+H] + =286.0.

[0075] Step 2. Compound A4 Compound 11 (250 mg, 0.875 mmol, 1.0 eq) and compound 6 (196 mg, 0.875 mmol, 1.0 eq) are dissolved in dioxane (30 mL), potassium phosphate monohydrate (705 mg, 3.06 mmol, 3.5 eq) is added, and finally Pd2(dba)3 (80 mg, 0.086 mmol, 0.10 eq) and X-Phos (83 mg, 0.175 mmol, 0.2 eq) are added. Under nitrogen gas protection, the reaction mixture is stirred at 100 °C for 20 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / ethyl acetate = 5 / 1 to 1 / 1, then dichloromethane / methanol = 40:1) to obtain compound A4 (64.1 mg, 15%) as a yellow solid. LCMS: [M+H] + =502.2.

[0076] 1 H NMR(400MHz,DMSO-d6)δ 12.90(br s,1H),8.63(s,1H),8.14-8.07(m,2H),7.92(br s,1H),7.69(d,J=8.8Hz,2H),7.60(d,J=8.8Hz,2H),6.69(d,J=4.0Hz,1H),6.66(d,J=4.0Hz,1H),4.63(br s,4H),3.92(s,3H),2.23(s,3H).

[0077] Example 1-4. Preparation of Compound A5 [ka]

[0078] Step 1. Compound 13 Compound 12 (370 mg, 2.27 mmol, 1.2 eq) and compound 10 (301 mg, 1.89 mmol, 1.0 eq) are dissolved in isopropanol (5 mL) and diisopropylethylamine (733 mg, 5.67 mmol, 3.0 eq) is added. The reaction mixture is stirred at 95° C. for 16 h. After monitoring the completion of the reaction by LCMS, the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / ethyl acetate=1 / 1) to give compound 13 (150 mg, 23%) as a yellow solid. LCMS: [M+H] + =286.0.

[0079] Step 2. Compound A5 Compound 13 (150 mg, 0.525 mmol, 1.0 eq) and compound 6 (117 mg, 0.875 mmol, 1.0 eq) are dissolved in dioxane (15 mL), potassium phosphate monohydrate (423 mg, 3.06 mmol, 3.5 eq) is added, and finally Pd2(dba)3 (48 mg, 0.053 mmol, 0.10 eq) and X-Phos (50 mg, 0.105 mmol, 0.2 eq) are added. Under nitrogen gas protection, the reaction mixture is stirred at 95 °C for 20 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / ethyl acetate = 5 / 1 to 0 / 1) to obtain the crude product. The crude product is purified by silica gel column chromatography (dichloromethane / methanol=150 / 1 to 40 / 1) to give compound A5 (64.1 mg, 16%) as a yellow solid. LCMS: [M+H] + =474.3.

[0080] 1 H NMR(400MHz,DMSO-d6)δ 12.90(br s,1H),9.65(s,1H),8.13(br s,1H),7.89(br s,1H),7.63-7.53(m,4H),6.72-6.69(m,2H),6.60(s,1H),4.64(br s,4H),3.94(s,3H),2.31(s,3H).

[0081] Example 1-5. Preparation of Compound A6 [ka]

[0082] Step 1. Compound 15 Compound 14 (1.3 g, 7.34 mmol, 2.4 eq) and compound 10 (487 mg, 3.06 mmol, 1.0 eq) are dissolved in n-butanol (25 mL) and diisopropylethylamine (1.19 g, 9.18 mmol, 3.0 eq) is added. The reaction mixture is stirred at 120° C. for 48 h. After monitoring the completion of the reaction by LCMS, the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to give compound 15 (300 mg, 32%) as a yellow solid. LCMS: [M+H] + =300.0.

[0083] Step 2. Compound A6 Compound 3 (300 mg, 1.0 mmol, 1.0 eq) and compound 4 (224 mg, 1.0 mmol, 1.0 eq) are dissolved in dioxane (30 mL), potassium phosphate monohydrate (807 mg, 3.5 mmol, 3.5 eq) is added, and finally Pd2(dba)3 (92 mg, 0.1 mmol, 0.10 eq) and X-Phos (95 mg, 0.2 mmol, 0.2 eq) are added. Under nitrogen gas protection, the reaction mixture is stirred at 110 °C for 16 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / ethyl acetate = 10 / 1 to 1 / 1) to obtain the crude product (200 mg). The crude product is slurried in dichloromethane / ethyl acetate / petroleum ether (20 mL / 20 mL / 10 mL) for 5 hours, filtered, and the solvent removed from the solid under reduced pressure to give compound A6 (158.1 mg, 32%) as a yellow solid. LCMS: [M+H] + =488.2.

[0084] 1 H NMR(400MHz,DMSO-d6)δ 12.89(br s,1H),8.51(s,1H),8.14(br s,1H),7.90(br s,1H),7.63(d,J=8.8Hz,2H),7.57(d,J=8.8Hz,2H),6.69-6.64(m,2H),4.63(br s,4H),3.91(s,3H),2.37(s,3H),2.21(s,3H).

[0085] Examples 1-6. Preparation of Compound A7 [ka]

[0086] Step 1. Compound 17 Compound 16 (370 mg, 2.22 mmol, 1.2 eq) and compound 10 (294 mg, 1.85 mmol, 1.0 eq) are dissolved in isopropanol (30 mL) and diisopropylethylamine (716 mg, 5.54 mmol, 2.5 eq) is added. The reaction mixture is stirred at 50° C. for 16 h. After monitoring the completion of the reaction by LCMS, the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane / ethyl acetate=1 / 1) to give compound 17 (500 mg, 93%) as a yellow solid. LCMS: [M+H] + =290.0.

[0087] Step 2. Compound A7 Compound 17 (250 mg, 0.86 mmol, 1.0 eq) and compound 6 (193 mg, 1.0 mmol, 1.0 eq) are dissolved in dioxane (20 mL), potassium phosphate monohydrate (695 mg, 3.02 mmol, 3.5 eq) is added, and finally Pd2(dba)3 (87 mg, 0.095 mmol, 0.10 eq) and X-Phos (68 mg, 0.143 mmol, 0.15 eq) are added, and the reaction mixture is stirred at 90 °C for 20 h under nitrogen gas protection conditions. The reaction solution is cooled to room temperature, diluted with dichloromethane / methanol (50 mL, 10:1), the reaction solution is passed through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain a residue, which is purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1 to 1 / 1) to obtain a crude product. The crude product is slurried in dichloromethane / dioxane / methanol (20 mL / 5 mL / 1 mL) for 5 h, then concentrated under reduced pressure at low temperature (30° C.) to remove dichloromethane and methanol, the resulting mixture is filtered, and the solid is stripped of solvent under reduced pressure to give compound A7 (59 mg, 15%) as a white solid. LCMS: [M+H] + =478.1.

[0088] 1H NMR(400MHz,DMSO-d6)δ 12.92(br s,1H),9.77(s,1H),8.39(s,1H),8.16(br s,1H),7.91(br s,1H),7.74(d,J=8.8Hz,2H),7.62(d,J=8.8Hz,2H),6.71-6.58(m,2H),4.62(br s,4H),3.93(s,3H).

[0089] Example 1-7. Preparation of Compound A8 [ka]

[0090] Step 1. Compound 19 Compound 18 (323 mg, 1.86 mmol, 1.0 eq) is dissolved in tetrahydrofuran (8 mL), followed by the addition of diisopropylethylamine (600 mg, 4.65 mmol, 3.0 eq) and 10 (400 mg, 1.55 mmol, 1.0 eq) under ice bath conditions. After the addition is complete, the reaction is stirred under ice bath conditions for 1.5 hours. After the reaction is complete, the reaction is diluted with ethyl acetate (100 mL), washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The concentrated crude product is purified by silica gel column chromatography (PE / EA=3 / 1) to give compound 19 (280 mg, 46%) as a yellow solid. LCMS: [M+H] + =297.7.

[0091] Step 2. Compound A8 Compound 19 (202 mg, 0.68 mmol, 1.0 eq) is dissolved in dioxane (10 mL), followed by the addition of compound 6 (183 mg, 0.82 mmol, 1.2 eq), potassium phosphate monohydrate (548 mg, 2.38 mmol, 3.5 eq), X-Phos (65 mg, 0.14 mmol, 0.2 eq) and Pd2(dba)3 (62 mg, 0.07 mmol, 0.1 eq) in sequence. After the addition is complete, the atmosphere is replaced with nitrogen gas and the reaction is stirred at 110° C. under a nitrogen atmosphere for 16 hours. The reaction is cooled to room temperature and concentrated. The residue is purified by silica gel column chromatography (dichloromethane / methanol=15 / 1) to give the crude product (65 mg). The crude product is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A8 (8.3 mg, 2%) as a yellow solid. LCMS: [M+H] + =485.2.

[0092] 1 H NMR(400MHz,DMSO-d6)δ 12.81(br s,1H),10.04(s,1H),8.79(s,1H),8.20-7.90(m,2H),7.63(d,J=8.4Hz,2H), 7.53(d,J=8.4Hz,2H),6.77(d,J=4.0Hz,1H),6.71(d,J=4.4Hz,1H),4.63(br s,4H),3.90(s,3H).

[0093] Examples 1-8. Preparation of Compound A9 [ka]

[0094] Step 1. Compound 22 Compound 20 (150 mg, 1.0 mmol, 1.0 eq) was dissolved in dioxane (3 mL), then compound 21 (159 mg, 1.0 mmol, 1.0 eq) was added, diisopropylethylamine (142 mg, 1.1 mmol, 1.1 eq) was added again, the reaction solution was stirred at 25°C for 1 hour, the reaction solution was slowly added to water, extracted twice with ethyl acetate, the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 22 (350 mg, 94%) as a white solid. LCMS: [M+H] + =373.1.

[0095] Step 2. Compound 23 Compound 22 (50 mg, 0.13 mmol, 1.0 eq) is dissolved in dioxane (3 mL), then compound 6 (30 mg, 0.13 mmol, 1.0 eq), potassium phosphate monohydrate (90 mg, 0.39 mmol, 3.0 eq), X-Phos (12 mg, 0.026 mmol, 0.2 eq) and Pd2(dba)3 (12 mg, 0.013 mmol, 0.1 eq) are added, and after the addition is complete the reaction is stirred at 90° C. for 2 h under nitrogen gas protection. Cooled to room temperature, the reaction is spun dry and the residue is purified by silica gel column chromatography (DCM / MeOH=10 / 1) to give compound 23 (70 mg, 95%) as a pale yellow solid. LCMS: [M+H] + =561.2.

[0096] Step 3. Compound A9 Compound 23 (140 mg, 0.25 mmol, 1.0 eq) is dissolved in a mixed solvent of dioxane and water (3 mL / 1 mL), and then potassium carbonate (103.5 mg, 0.75 mmol, 3.0 eq) is added at 0° C. and reacted at 110° C. for 2 hours. After completion of the reaction, the mixture is concentrated to obtain a crude product, which is separated and purified by prep-HPLC (mobile phase 0.1% FA / acetonitrile / water) to obtain compound A9 (9.6 mg, 8%) as a white solid. LCMS: [M+H] + =461.2.

[0097] 1 H NMR(400MHz,DMSO-d6)δ 12.88(s,1H),10.50(s,1H),8.70(s,1H),8.11(s,1H),7.88(s,1H),7.65(d,J=8.4H z,2H),7.57(d,J=7.6Hz,2H),6.79(d,J=4.4Hz,1H),6.71(d,J=4.4Hz,1H),4.66(br s,4H),3.91(s,3H).

[0098] Examples 1-9. Preparation of Compound A10 [ka]

[0099] Step 1. Compound 25 Compound 24 (500 mg, 2.62 mmol, 1.0 eq) and compound 10 (420 mg, 2.62 mmol, 1.0 eq) are dissolved in isopropanol (24 mL), diisopropylethylamine (3380 mg, 26.20 mmol, 10.0 eq) is added, and the reaction mixture is stirred at 80° C. for 18 hours. After monitoring the completion of the reaction by LCMS, the reaction is cooled to room temperature, concentrated under reduced pressure to 10 mL, the reaction suspension is filtered, and the filter cake is rinsed with isopropanol, and the resulting wet product is dried to give compound 25 (800 mg, 97%) as a yellow solid. LCMS: [M+H] + =314.0.

[0100] Step 2. Compound A10 Compound 25 (300 mg, 0.956 mmol, 1.0 eq) and compound 6 (214 mg, 0.956 mmol, 1.0 eq) are dissolved in dioxane (10 mL), potassium phosphate monohydrate (660 mg, 2.868 mmol, 3.0 eq) is added, and finally Pd2(dba)3 (87 mg, 0.095 mmol, 0.10 eq) and X-Phos (68 mg, 0.143 mmol, 0.15 eq) are added, and the reaction mixture is stirred at 90 ° C for 6 h under nitrogen gas protection conditions. The reaction solution is cooled to room temperature, diluted with dichloromethane / methanol (50 mL, 10:1), the reaction solution is passed through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain a residue, which is purified by silica gel column chromatography (dichloromethane / methanol = 93 / 7) to obtain compound A10 (66.3 mg, 14%) as a yellow solid. LCMS: [M+H] + =502.2.

[0101] 1 H NMR(400MHz,DMSO-d6)δ 9.34(s,1H),8.04(s,2H),7.66(d,J=8.8Hz,2H),7.61(d,J=8.8Hz,2H),6.76-6.64(m,2H),5.00(s,2H),4.88(s,2H),4.62(br s,4H),3.94(s,3H).

[0102] Example 1-10. Preparation of Compound A11 [ka]

[0103] Step 1. Compound 27 Compound 26 (600 mg, 2.068 mmol, 1.0 eq) and compound 21 (536 mg, 2.068 mmol, 1.0 eq) were dissolved in n-butanol (20 mL), diisopropylethylamine (1.3 g, 10.340 mmol, 5.0 eq) was added to the reaction solution, and the reaction solution was stirred at 100° C. for 16 hours under a nitrogen gas atmosphere. After the reaction was completed, the mixture was cooled and concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol=15:1) to obtain compound 27 (600 mg, 70%) as a pale yellow solid. LCMS: [M+H] + =413.2.

[0104] Step 2. Compound 28 Compound 27 (300 mg, 0.727 mmol, 1.0 eq) and 4-dimethylaminopyridine (9 mg, 0.073 mmol, 0.1 eq) are dissolved in tetrahydrofuran (15 mL), di-t-butyl dicarbonate (158 mg, 0.727 mmol, 1.0 eq) is added to the reaction solution, and the mixture is stirred at room temperature for 16 hours. After the reaction is completed, the mixture is concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to obtain compound 28 (350 mg, 94%) as a yellow solid. LCMS: [M+H] + =513.3.

[0105] Step 3. Compound 29 Compound 28 (350mg, 0.682mmol, 1.0eq), compound 5 (152mg, 0.682mmol, 1.0eq) and potassium phosphate monohydrate (470mg, 2.046mmol, 3.0eq) are dissolved in dioxane (8mL), then Pd2(dba)3 (62mg, 0.068mmol, 0.1eq) and X-Phos (65mg, 0.136mmol, 0.2eq) are added to the reaction solution, the reaction solution is stirred at 100℃ under nitrogen gas atmosphere for 1.5 hours, after the reaction is completed, it is cooled, passed through diatomaceous earth and washed with ethyl acetate, the filtrate is concentrated to obtain the crude product, the crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:3) to obtain compound 29 (360mg, 75%) as a yellow solid. LCMS: [M+H] + =701.2.

[0106] Step 4. Compound 30 Compound 29 (360 mg, 0.513 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), p-toluenesulfonic acid monohydrate (975 mg, 5.130 mmol, 10.0 eq) was added to the reaction solution, and the reaction solution was stirred at 0° C. for 8 hours. After the reaction was completed, N-methylimidazole was added to the system to neutralize excess p-toluenesulfonic acid, and the resulting reaction mixture was concentrated to obtain a crude product. The crude product was separated and purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to obtain compound 30 (100 mg) as a yellow solid, and the remaining crude product was used directly in the next reaction. LCMS: [M+H] + =487.2.

[0107] 1 H NMR(400MHz,DMSO-d6)δ 9.06(s,1H),8.26(s,1H),7.68(d,J=8.4Hz,2H),7.59(d,J=8.4Hz,2H),6.70(d,J=4.0Hz, 1H),6.68(s,1H),6.55(s,1H),4.56-4.47(m,4H),4.06(s,2H),3.97(s,2H),3.93(s,3H).

[0108] Step 5. Compound A11 Compound 30 (100 mg) is dissolved in acetonitrile and dichloromethane (8 mL / 6 mL), 37% formaldehyde aqueous solution (72 mg, 0.891 mmol) is added to the reaction solution, the reaction mixture is stirred at room temperature for 5 minutes, sodium cyanoborohydride (126 mg, 0.594 mmol, 2.0 eq) is then added to the reaction solution, the reaction solution is stirred at room temperature for 30 minutes, after the reaction is completed, the reaction solution is directly concentrated under reduced pressure, and the residue is separated and purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to obtain compound A11 (53.5 mg, ) as a yellow solid. LCMS: [M+H] + =515.2.

[0109] 1 H NMR(400MHz,DMSO-d6)δ12.89(br s,1H),9.37(s,1H),8.03(br s,2H),7.66-7.60(m,4H),6.71(s,2H),4.64(br s,4H),4.26(s,4H),3.93(s,3H),2.29(s,3H).

[0110] Examples 1-11. Preparation of Compound A12 [ka]

[0111] Step 1. Compound 33 Compound 31 (1.0 g, 5.37 mmol, 1.1 eq) is dissolved in a mixed solvent of dioxane / water (10 / 1, 20 mL / 2 mL), then compound 32 (1.4 g, 4.89 mmol, 1.0 eq), potassium carbonate (2.0 g, 14.49 mmol, 3.0 eq) and Pd(dppf)Cl2 (355 mg, 0.15 mmol, 0.1 eq) are quickly added. After replacing the air with nitrogen gas three times, the reaction solution is stirred at 100 °C under nitrogen gas atmosphere for 16 h. The reaction solution is cooled to room temperature and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 33 (750 mg, 58%) as a yellow solid. LCMS: [M+H] + =258.1.

[0112] Step 2. Compound 35 Compound 33 (690 mg, 2.69 mmol, 1.0 eq) is dissolved in isopropanol (10 mL), then compound 34 (1.2 g, 8.06 mmol, 3.0 eq) and diisopropylethylamine (1.4 g, 10.74 mmol, 4.0 eq) are added. The reaction is stirred at 80° C. for 6 h. Cooled to room temperature, the reaction is diluted with ethyl acetate (100 mL), then washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 2) to give compound 35 (800 mg, 81%) as a yellow solid. LCMS: [M+H] + =370.1.

[0113] Step 3. Compound 36 Compound 35 (750 mg, 2.03 mmol, 1.0 eq) is dissolved in dichloromethane (30 mL) and then TFA (30 mL) is added. The reaction is stirred at 25° C. for 1 h. The reaction is spun to dryness, the residue is dissolved in ethyl acetate, the pH value is adjusted to 7 with aqueous sodium carbonate, and the aqueous phase is extracted with ethyl acetate (40 mL×3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 36 (750 mg, 100%) as a yellow solid. LCMS: [M+H] + =286.2.

[0114] Step 4. Compound 37 Compound 36 (400 mg, 1.4 mmol, 1.0 eq) is dissolved in tetrahydrofuran (5 mL), then Boc2O (327 mg. 2.1 mmol, 1.5 eq) and DMAP (34 mg. 0.28 mmol, 0.2 eq) are added. The reaction is stirred at 25° C. for 1 h. The reaction is concentrated and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give compound 37 (350 mg, 65%) as a yellow solid. LCMS: [M+H] + =386.2.

[0115] Step 5. Compound 38 Compound 37 (200 mg, 0.45 mmol, 1.0 eq) is dissolved in dioxane (5 mL), and then compound 8 (101 mg, 0.45 mmol, 1.0 eq), potassium phosphate monohydrate (363 mg, 1.58 mmol, 3.5 eq), X-Phos (86 mg, 0.18 mmol, 0.4 eq) and Pd2(dba)3 (83 mg, 0.09 mmol, 0.2 eq) are quickly added. After purging with nitrogen gas three times, the reaction solution is stirred at 100 °C under nitrogen gas atmosphere for 4 hours. The reaction solution is cooled to room temperature, diluted with ethyl acetate (60 mL), washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 38 (90 mg, 42%) as a yellow solid. LCMS: [M+H] + =574.3.

[0116] Step 6. Compound A12 Compound 38 (90 mg, 0.16 mmol, 1.0 eq) is dissolved in a mixture of dioxane / water (10 / 1, 20 mL / 2 mL) and then potassium carbonate (331 mg, 2.4 mmol, 15.0 eq) is added. The reaction is stirred at 110° C. for 6 h. The reaction is concentrated and the residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A12 (25.5 mg, 21%) as a yellow solid. LCMS: [M+H] + =474.3.

[0117] 1 H NMR(400MHz,DMSO-d6)δ 12.93(br s,1H),9.76(s,1H),8.27(d,J=6.0Hz,1H),7.91-8.26(m,2H),7.53(s,1H),7.47(d,J =8.8Hz,1H),7.38(d,J=8.4Hz,1H),6.77(d,J=6.0Hz,1H),6.73-6.70(m,2H),4.66(br s,4H),3.96(s,3H),2.38(s,3H).

[0118] Examples 1-12. Preparation of Compound A14 [ka]

[0119] Step 1. Compound 41 Compound 39 (830 mg, 3.74 mmol, 1.0 eq) is dissolved in dioxane (5 mL), then compound 40 (707 mg, 4.11 mmol, 1.1 eq), potassium carbonate (2.58 g, 18.6 mmol, 5.0 eq) and Pd(dppf)Cl2 (272 mg, 0.37 mmol, 0.1 eq) are added sequentially. After the addition is complete, the temperature is raised to 110° C. and stirred for 16 hours. The reaction solution is directly spun dry to give the crude product compound 41, which is used directly in the next reaction without purification. LCMS: [M+H] + =188.2.

[0120] Step 2. Compound 42 The crude product, compound 41, is dissolved in DCM (50 mL), then Boc2O (872 mg, 4.0 mmol, 1.0 eq) is added and stirred at room temperature for 16 h. The reaction mixture is extracted with ethyl acetate / water, washed with saturated saline, dried over anhydrous sodium sulfate, and the residue is purified by silica gel column chromatography (PE / EA=1:1) to give compound 42 (160 mg, two steps: 15%) as a colorless oil. LCMS: [M+H] + =288.2.

[0121] Step 3. Compound 43 Compound 42 (160 mg, 0.56 mmol, 1.0 eq) is dissolved in dichloromethane (3 mL), then trifluoroacetic acid (3 mL) is added and the reaction is stirred for 2 h at 25° C. The reaction is directly spun to dryness to give the crude product, compound 43. LCMS: [M+H] + =188.2.

[0122] Step 4. Compound 44 The crude product compound 44 is dissolved in isopropanol (3 mL), and compound 34 (83 mg, 0.56 mmol, 1.0 eq) and diisopropylethylamine (1.45 g, 11.2 mmol, 20.0 eq) are added in sequence, and the reaction solution is stirred at 80° C. for 16 hours. The reaction solution is extracted with ethyl acetate / water, washed with saturated saline, dried over anhydrous sodium sulfate, and the residue is purified by silica gel column chromatography (PE / EA=1:1) to give compound 44 (98 mg, two steps 58%) as a yellow solid. LCMS: [M+H] + =300.1.

[0123] Step 5. Compound A14 Compound 44 (88 mg, 0.29 mmol, 1.0 eq) is dissolved in dioxane (10 ml), and then compound 6 (66 mg, 0.29 mmol, 1.0 eq), potassium phosphate (369 mg, 1.74 mmol, 6.0 eq) and Pd2(dba)3 (26 mg, 0.029 mmol, 6.0 eq), X-Phos (13.8 mg, 0.029 mmol, 0.1 eq) are added in sequence. After the addition is complete, the temperature is raised to 120° C. and stirred for 15 hours. The reaction solution is concentrated, and the residue obtained after concentration is purified by prep-HPLC (mobile phase 0.1% formic acid / acetonitrile / water) to give compound A14 (10.5 mg, 7%) as a gray solid. LCMS: [M+H] + =488.2.

[0124] 1 H NMR(400MHz,DMSO-d6)δ 12.22(br s,1H),9.82(s,1H),8.27(d,J=6.0Hz,1H),7.65(d,J=8.4Hz,2H),7.28(d,J=8.4Hz,2H),6.79(d,J=6.0Hz,1H),6.71(s,2H),4.65(br s, 4H), 3.94 (s, 3H), 2.20 (s, 6H).

[0125] Examples 1-13. Preparation of Compound A15 [ka]

[0126] Step 1. Compound 47 Compound 45 (100 mg, 0.606 mmol, 1.0 eq) and p-toluenesulfonic acid monohydrate (17 mg, 0.091 mmol, 0.15 eq) are dissolved in dichloromethane (4 mL), and then compound 46 (152 mg, 1.818 mmol, 3.0 eq) is added. After the addition is complete, the reaction is reacted at 25° C. for 3 hours under nitrogen gas atmosphere. After monitoring the reaction completion by LC-MS, the solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / dichloromethane=10 / 1) to give compound 47 (140 mg, 93%) as a yellow oily liquid. LCMS: [M+Na] + =271.2.

[0127] Step 2. Compound 49 Compound 47 (130 mg, 0.522 mmol, 1.0 eq), compound 48 (265 mg, 1.044 mmol, 2.0 eq), Pd(dppf)Cl2 (38 mg, 0.052 mmol, 0.1 eq) and potassium acetate (153 mg, 1.566 mmol, 3.0 eq) are added to 1,4-dioxane (4 mL). After the addition is complete, the atmosphere is replaced with nitrogen gas and the reaction mixture is reacted at 90° C. under nitrogen gas atmosphere for 16 hours. After monitoring the reaction completion by LC-MS, the reaction mixture is passed through diatomaceous earth and the diatomaceous earth is rinsed with ethyl acetate, and the filtrate obtained is directly evaporated under reduced pressure to obtain the crude product compound 49, which is used directly in the next reaction. LCMS: [M+Na] + =319.2.

[0128] Step 3. Compound 50 The crude product of the previous step, compound 49, is dissolved in dioxane / water (4mL / 1mL), and then compound 6 (179mg, 1.044mmol, 2.0eq), Pd(dppf)Cl2 (76mg, 0.104mmol, 0.2eq) and potassium carbonate (360mg, 2.610mmol, 5.0eq) are added. After the addition is complete, the atmosphere is replaced with nitrogen gas, and the reaction mixture is reacted at 90°C under nitrogen gas atmosphere for 16 hours. After monitoring the reaction completion by LC-MS, the reaction mixture is passed through diatomaceous earth and the diatomaceous earth is rinsed with ethyl acetate, and the obtained filtrate is directly evaporated under reduced pressure, and the residue is eluted by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain compound 50 (100mg, 73%) as a pale yellow solid. LCMS: [M+Na] + =262.2.

[0129] Step 4. Compound 51 Compound 50 (100 mg, 0.383 mmol, 1.0 eq) and compound 16 (96 mg, 0.575 mmol, 1.5 eq) are dissolved in isopropanol (4 mL), followed by the addition of diisopropylethylamine (247 mg, 1.915 mmol, 5.0 eq). After the addition is complete, the reaction is reacted at 50° C. for 8 hours under nitrogen gas atmosphere. After monitoring the reaction completion by LC-MS, the solvent is removed under reduced pressure, and the residue is eluted by silica gel column chromatography (petroleum ether / dichloromethane=1 / 1) to give compound 51 (90 mg, 40%) as a yellow solid. LCMS: [M+H] + =392.2.

[0130] Step 5. Compound 52 Compound 51 (250 mg, 0.638 mmol, 1.0 eq) is dissolved in dichloromethane (3 mL) and then trifluoroacetic acid (3 mL) is added to the solution. After the addition is complete, the reaction is allowed to react at 25 °C for 2 h. The solvent is removed under reduced pressure and the residue is adjusted to pH (9-10) with saturated sodium carbonate solution, the solution is filtered and the solid is collected to give compound 52 (130 mg, 66%) as an off-white solid. LCMS: [M+H] + =308.0.

[0131] Step 6. Compound A15 Compound 52 (100 mg, 0.325 mmol, 1.0 eq), compound 6 (73 mg, 0.325 mmol, 1.0 eq), Pd2(dba)3 (45 mg, 0.049 mmol, 0.15 eq), X-Phos (31 mg, 0.065 mmol, 0.2 eq) and potassium phosphate monohydrate (224 mg, 0.975 mmol, 3.0 eq) are added to 1,4-dioxane (4 mL). After the addition is complete, the atmosphere is replaced with nitrogen gas and the reaction solution is reacted at 100 °C under a nitrogen gas atmosphere for 3 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution was cooled to room temperature, and then the reaction mixture was passed through diatomaceous earth and the diatomaceous earth was rinsed with dichloromethane. The resulting organic phase was evaporated under reduced pressure, and the residue was eluted by silica gel column chromatography (dichloromethane / methanol=13 / 1) to obtain the crude product, which was purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to obtain compound A15 (2.0 mg, 1%) as a yellow solid. LCMS: [M+H] + =496.1.

[0132] 1 H NMR(400MHz,DMSO-d6)δ 12.57(s,0.5H),9.82(s,1H),8.41(d,J=3.6Hz,1H),8.14(s,1H),7.79(d,J=8.4Hz,2H),7.57(d,J=8.4Hz,2H),6.70(s,2H),4.67(br s,4H),3.93(s,3H).

[0133] Examples 1-14. Preparation of Compound A16 [ka]

[0134] Step 1. Compound 54 Compound 53 (1.08 g, 3.69 mmol, 1.2 eq) and compound 40 (524 mg, 3.07 mmol, 1.0 eq) are dissolved in 1,4 dioxane (12 mL), then potassium carbonate (1.27 g, 9.21 mmol, 3.0 eq), Pd(dppf)Cl2 (336 mg, 0.46 mmol, 0.15 eq) and water (3 mL) are added. The reaction is stirred at 100 °C for 3 h under nitrogen gas atmosphere. The reaction is cooled to room temperature, diluted with ethyl acetate, passed through diatomaceous earth, and the filtrate is concentrated to give a residue, which is purified by flash column silica gel chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 54 (330 mg, 41%) as a yellow solid. LCMS: [M+H] + =258.2.

[0135] Step 2. Compound 55 Compound 54 (330 mg, 1.28 mmol, 1.0 eq) and compound 16 (638 mg, 3.84 mmol, 3.0 eq) are dissolved in isopropanol (8 mL), and then diisopropylethylamine (495 mg, 3.84 mmol, 3.0 eq) is added. The reaction is stirred at 60° C. for 4 h under nitrogen gas atmosphere. After monitoring the reaction completion by LC-MS, the reaction is concentrated to remove the solvent to give a residue, which is purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=65 / 35) to give compound 55 (350 mg, 70%) as a yellow solid. LCMS: [M+H] + =388.1.

[0136] Step 3. Compound 56 Compound 55 (730 mg, 1.88 mmol, 1.0 eq) is dissolved in dichloromethane (4 mL) and then trifluoroacetic acid (22 mL) is added. The reaction is stirred at room temperature for 2 h. The reaction is concentrated to give a residue, which is diluted with ethyl acetate. The pH is then adjusted to alkaline with saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and concentrated to give crude compound 56 (569 mg, 100%) as a yellow solid. LCMS: [M+H] + =304.1.

[0137] Step 4. Compound 57 Compound 56 (569 mg, 1.87 mmol, 1.0 eq) is added to tetrahydrofuran (5 mL), followed by DMAP (45 mg, 0.37 mmol, 0.2 eq) and Boc2O (325 mg, 1.49 mmol, 0.8 eq). The reaction is stirred at room temperature for 3 h. The reaction is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=80 / 20) to give compound 57 (470 mg, 78%) as a white solid. LCMS: [M+H] + =404.1.

[0138] Step 5. Compound 58 Compound 57 (200 mg, 0.49 mmol, 1.0 eq) was dissolved in dioxane (8 mL) and then compound 6 (163 mg, 0.73 mmol, 1.5 eq), potassium phosphate (338 mg, 1.47 mmol, 3.0 eq), X-Phos (42 mg, 0.09 mmol, 0.2 eq) and Pd2(dba)3 (64 mg, 0.07 mmol, 0.15 eq) were added and the reaction was stirred at 100° C. for 2 h under nitrogen gas after the addition was complete. After cooling to room temperature, the reaction was diluted with ethyl acetate, passed through diatomaceous earth and the filtrate was concentrated to give the crude product, and the crude product, compound 58, was directly introduced into the next reaction. LCMS: [M+H] +=592.2.

[0139] Step 6. Compound A16 The crude product, compound 58 (110 mg, 0.18 mmol, 1.0 eq) is dissolved in a mixture of dioxane (4 mL) and water (4 mL), and then potassium carbonate (248 mg, 1.8 mmol, 10.0 eq) is added. The reaction solution is stirred at 110° C. for 2 h. The reaction solution is diluted with ethyl acetate, then washed with water and saturated saline solution in succession, dried over anhydrous sodium sulfate, and concentrated. The residue is separated and purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A16 (77.5 mg, 87%) as a white solid. LCMS: [M+H] + =492.1.

[0140] 1 H NMR(400MHz,DMSO-d6)δ 12.63-12.55(m,1H),9.79(s,1H),8.40(d,J=3.6Hz,1H),7.77-7.75(m,2H),7.67(br.s ,1H),7.46-7.44(m,2H),6.70-6.68(m,2H),4.62(br.s,4H),3.92(s,3H),2.39(s,3H).

[0141] Examples 1-15. Preparation of Compound A17 [ka]

[0142] Step 1. Compound 61 Compound 59 (500 mg, 2.45 mmol, 1.0 eq), compound 60 (476 mg, 3.68 mmol, 1.5 eq), HATU (1.68 g, 4.41 mmol, 1.8 eq) and diisopropylethylamine (1.26 g, 9.8 mmol, 4.0 eq) are dissolved in DMF (20 mL) and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution is diluted with water and extracted three times with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified by column chromatography (PE:EA=83:17) to give compound 61 (664 mg, 90%) as a white solid. LCMS: [M+H] + =280.1.

[0143] Step 2. Compound 63 Compound 61 (600 mg, 2.15 mmol, 1.0 eq), compound 62 (632 mg, 6.45 mmol, 3.0 eq), CuI (123 mg, 0.645 mmol, 0.3 eq) and Pd(PPh3)2Cl2 (151 mg, 0.215 mmol, 0.1 eq) are dissolved in triethylamine (10 mL). The reaction is protected with nitrogen gas and stirred at 90 °C for 2 h. After completion of the reaction, the reaction is diluted with water and extracted three times with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give crude compound 63 (1.05 g, 100%) as a brown liquid. LCMS: [M+H] + =298.1.

[0144] Step 3. Compound 64 Compound 63 (1.05 g, 2.15 mmol, 1.0 eq) and tetrabutylammonium fluoride trihydrate (845 mg, 3.22 mmol, 1.5 eq) are dissolved in tetrahydrofuran (10 mL). The reaction is stirred at room temperature for 30 min. After completion of the reaction, the reaction is diluted with water and extracted three times with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by column chromatography (PE:EA=90:10) to give compound 64 (220 mg, 50% two steps) as a white solid. LCMS: [M+H] + =226.0.

[0145] Step 4. Compound 66 Compound 64 (220 mg, 0.978 mmol, 1.0 eq), compound 65 (365 mg, 0.978 mmol, 1.0 eq), Pd2(dba)3 (90 mg, 0.0978 mmol, 0.1 eq), X-Phos (187 mg, 0.391 mmol, 0.4 eq) and potassium phosphate monohydrate (675 mg, 2.93 mmol, 3.0 eq) are dissolved in dioxane (10 mL). The reaction is protected with nitrogen gas and stirred at 100° C. for 2 hours. After monitoring the completion of the reaction by LCMS, the reaction is cooled and the solution of crude compound 66 is used directly in the next reaction. LCMS: [M+H] + =561.1.

[0146] Step 4. Compound A17 Potassium carbonate (195 mg, 1.41 mmol, 3.0 eq) and water (1 mL) are added directly to the reaction mixture of the crude product compound 66 from the previous step and stirred at 110 °C for 2 h. After the reaction is complete, the reaction mixture is filtered and the filtrate is concentrated. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A17 (70 mg, 20% two steps) as a white solid. LCMS: [M+H] + =461.1. 1H NMR(400MHz,DMSO-d6)δ 9.95(s,1H),8.28(d,J=6.0Hz,1H),8.04(s,2H),7.65-7.58(m,4H),7.20(s,1H),6 .79(d,J=6.0Hz,1H),4.89(t,J=12.0Hz,2H),4.49(t,J=12.0Hz,2H),4.07(s,3H).

[0147] Examples 1-16. Preparation of Compound A18 [ka]

[0148] Step 1. Compound 68 Compound 67 (2.9 g, 14.21 mmol, 1.0 eq) is dissolved in DMF (30 mL), HATU (6.49 g, 17.06 mmol, 1.2 eq) is added, and after stirring for 10 min, compound 60 (1.84 g, 14.21 mmol, 1.0 eq) and diisopropylethylamine (5.51 g, 42.64 mmol, 3.0 eq) are added, and the reaction mixture is stirred at room temperature for 2 h. After confirming the completion of the reaction by LCMS, the reaction mixture is diluted with ethyl acetate, washed with water, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (EA:PE=1:10) to give compound 68 (2.8 g, 70%) as a white solid. LCMS: [M+H] + =279.0.

[0149] Step 2. Compound 69 Compound 68 (2.7 g, 9.67 mmol, 1.0 eq) was dissolved in triethylamine (30 mL) and copper(I) iodide (553 mg, 2.9 mmol, 0.3 eq) and Pd(PPh3)2Cl2 (679 mg, 0.967 mmol, 0.1 eq) and compound 62 (2.85 g, 29.02 mmol, 3.0 eq) were added. The reaction mixture was stirred at 90 °C for 16 h under nitrogen gas atmosphere. After completion of the reaction was confirmed by LCMS, water (100 mL) was added to the reaction solution, which was then extracted three times with ethyl acetate (150 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 69 (595 mg, 80%) as a black solid, which was used directly in the next reaction. LCMS: [M+H] + =297.1.

[0150] Step 2. Compound 70 The crude product of the previous step, compound 69 (2.2 g, 7.65 mmol, 1.0 eq), is dissolved in THF (10 mL) and tetrabutylammonium fluoride trihydrate (4.8 g, 15.3 mmol, 2.0 eq) is added. The mixture is stirred at room temperature for 1 h. After monitoring the completion of the reaction by LCMS, water (100 mL) is added to the reaction solution, which is then extracted three times with ethyl acetate (150 mL). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (EA:PE=1:9) to give compound 70 (1.2 g, 70% yield for two steps) as a yellow solid. LCMS: [M+H] + =225.1.

[0151] Step 3. Compound A18 Compound 70 (150 mg, 0.67 mmol, 1.0 eq) and compound 65 (250 mg, 0.67 mmol, 1.0 eq) are dissolved in dioxane (5 mL), X-Phos (47 mg, 0.1 mmol, 0.15 eq) and potassium phosphate monohydrate (462 mg, 2.01 mmol, 3.0 eq) are added, and finally Pd2(dba)3 (61 mg, 0.06 mmol, 0.1 eq) is added. Under nitrogen gas protection, the reaction mixture is stirred at 100 °C for 18 h. After monitoring the reaction completion by LCMS, the reaction mixture is filtered through diatomaceous earth, the filtration residue is washed with ethyl acetate, and the filtrate is concentrated to give the residue. The residue is purified by prep-HPLC (mobile phase: 0.1% HCOOH / acetonitrile / water) to give compound A18 (36 mg, 11%) as a yellow solid. LCMS: [M+H] + =460.2.

[0152] 1 H NMR(400MHz,DMSO-d6)δ 12.88(br s,1H),9.66(s,1H),8.22(d,J=6.0Hz,1H),8.09(br s,1H),7.93(br s,1H),7.59(s,4H),7.56(d,J=1.6Hz,1H),6.92(d,J=1.6Hz,1H),6.70(d,J=6.0Hz,1H),4.66(br s,4H),3.85(s,3H).

[0153] Example 1-17. Preparation of Compound A19 [ka]

[0154] Step 1. Compound 72 Compound 71 (2.0 g, 9.0 mmol, 1.0 eq) is dissolved in THF (16 mL), lithium hydroxide monohydrate (2.1 g, 90.0 mmol, 10.0 eq) and water (10 mL) are added, and the reaction mixture is stirred at 25° C. for 1 h. After monitoring the completion of the reaction by LCMS, water (80 mL) is added to the reaction mixture, followed by extraction with ethyl acetate (50 mL×3), the aqueous phase is collected, the aqueous phase is adjusted to pH=3 by adding hydrochloric acid in dioxane (5 mL), and extracted with ethyl acetate, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to give crude compound 72 (1.6 g, 86%) as a yellow solid. LCMS: [M+H] + =206.9.

[0155] Step 2. Compound 73 Compound 72 (800 mg, 3.8 mmol, 1.0 eq) is dissolved in DMF (10 mL) at room temperature, HATU (2.88 g, 7.6 mmol, 2.0 eq) is added, and after stirring for 10 min, compound 3 (600 mg, 4.6 mmol, 1.2 eq) and diisopropylethylamine (2.4 g, 19.0 mmol, 5.0 eq) are added, and the reaction mixture is stirred at 25 ° C for 2 h. After monitoring the reaction completion by LCMS, water (60 mL) is added to the reaction solution, and then extracted with ethyl acetate (40 mL × 3), and the combined organic phase is washed with saturated saline and dried over anhydrous sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (0-10% PE / EA) to give compound 73 (700 mg, 65%) as a white solid. LCMS: [M+H] + =282.0.

[0156] Step 3. Compound 74 Compound 73 (700 mg, 2.49 mmol, 1.0 eq) is dissolved in triethylamine (15 mL), copper(I) iodide (93 mg, 0.49 mmol, 0.2 eq) and Pd(PPh3)2Cl2 (168 mg, 0.24 mmol, 0.1 eq) and compound 62 (732 mg, 7.47 mmol, 3.0 eq) are added, and the reaction mixture is stirred at 90 °C for 3 h under nitrogen gas atmosphere. After monitoring the reaction completion by LCMS, water (100 mL) is added to the reaction solution, and then extracted with ethyl acetate (80 mL x 3), and the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 74 (595 mg, 80%) as a white solid. LCMS: [M+H] + =300.1.

[0157] Step 4. Compound 75 The crude product, compound 74 (595 mg, 1.98 mmol, 1.0 eq) is dissolved in THF (8 mL), tetrabutylammonium fluoride trihydrate (1.2 g, 3.96 mmol, 2.0 eq) is added, and the mixture is stirred at 25° C. for 1 h. After the completion of the reaction is confirmed by LCMS, water (50 mL) is added to the reaction solution, which is then extracted with ethyl acetate (30 mL×3). The combined organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give a residue, which is purified by silica gel column chromatography (0-30% PE / EA) to give compound 75 (300 mg, 66%) as a yellow solid. LCMS: [M+H] + =228.1.

[0158] Step 6. Compound 76 Compound 75 (107 mg, 0.47 mmol, 1.0 eq) and compound 65 (170 mg, 0.47 mmol, 1.0 eq) were dissolved in dioxane (10 mL), X-Phos (33 mg, 0.07 mmol, 0.15 eq) and potassium phosphate monohydrate (324 mg, 1.41 mmol, 3.0 eq) were added, and finally Pd2(dba)3 (36 mg, 0.04 mmol, 0.1 eq) was added. The reaction mixture was stirred at 100 °C for 3 h under nitrogen gas protection. After monitoring the completion of the reaction by LCMS, water (30 mL) was added to the reaction solution, which was then extracted with ethyl acetate (40 mL×3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to give a residue, which was purified by silica gel column chromatography (0-70% PE / EA) to give compound 76 (119 mg, 45%) as a yellow solid. LCMS: [M+H] + =563.2.

[0159] Step 7. Compound A19 Compound 76 (110 mg, 0.19 mmol, 1.0 eq) is dissolved in dichloromethane (6 mL), trifluoroacetic acid (4 mL) is added, and the reaction mixture is stirred at room temperature for 1 h. After monitoring the completion of the reaction by LCMS, the reaction mixture is concentrated under reduced pressure to obtain a residue, which is dissolved in DMF (4 mL) and filtered, and the filtrate is purified by prep-HPLC (mobile phase: 0.1% HCOOH / acetonitrile / water) to obtain compound A19 (3.5 mg, 4%) as a yellow solid. LCMS: [M+H] + =463.1.

[0160] 1 H NMR(400MHz,DMSO-d6)δ 12.91(s,1H),9.82(s,1H),8.28(d,J=6.0Hz,1H),8.14(s,1H),7.89(s, 1H),7.69-7.47(m,6H),6.78(d,J=6.4Hz,1H),4.98(s,2H),4.55(s,2H).

[0161] Example 1-18. Preparation of Compound A20 [ka]

[0162] Step 1. Compound 78 Compound 77 (3.7 g, 13.4 mmol, 1.0 eq) is dissolved in triethylamine (30 mL), copper(I) iodide (508 mg, 2.68 mmol, 0.2 eq) and Pd(PPh3)2Cl2 (940 mg, 1.34 mmol, 0.1 eq) and compound 62 (6.5 g, 67 mmol, 5.0 eq) are added, and the reaction mixture is stirred at 90 °C for 2 h under nitrogen gas atmosphere. After monitoring the reaction completion by LCMS, water (120 mL) is added to the reaction solution, and then extracted with ethyl acetate (30 mL x 3), the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 78 (1.97 g, 49%). LCMS: [M+H] + =295.1.

[0163] Step 2. Compound 79 Compound 78 (1.97 g, 6.69 mmol, 1.0 eq) is dissolved in THF (10 mL), tetrabutylammonium fluoride trihydrate (4.22 g, 13.38 mmol, 2.0 eq) is added, and the mixture is stirred at room temperature for 1 h. After monitoring the completion of the reaction by LCMS, water (60 mL) is added to the reaction solution, followed by extraction with ethyl acetate (20 mL x 3), the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give a residue, which is purified by silica gel column chromatography (0-12% EA / PE) to give compound 79 (900 mg, 60%) as a yellow solid. LCMS: [M+H] + =223.1.

[0164] Step 3. Compound 80 Compound 79 (165 mg, 0.8 mmol, 1.0 eq) and compound 65 (300 mg, 0.8 mmol, 1.0 eq) are dissolved in dioxane (8 mL), X-Phos (57 mg, 0.12 mmol, 0.15 eq) and potassium phosphate monohydrate (552 mg, 2.4 mmol, 3.0 eq) are added, and finally Pd2(dba)3 (73 mg, 0.08 mmol, 0.1 eq) is added, and the reaction mixture is stirred and reacted at 100 °C for 2 h under nitrogen gas protection conditions. After monitoring the reaction completion by LCMS, water (40 mL) is added to the reaction solution, and then extracted with ethyl acetate (30 mL × 3), the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give a residue, which is purified by silica gel column chromatography (50%-70% EA / PE) to give compound 80 (95 mg, 21%) as a yellow solid. LCMS: [M+H] + =558.2.

[0165] Step 4. Compound A20 Compound 80 (95.0 mg, 0.17 mmol, 1.0 eq) is dissolved in dioxane (5 mL), potassium carbonate (187.0 mg, 1.36 mmol, 8.0 eq) and water (4 mL) are added, and the reaction mixture is stirred and reacted for 2 hours at 110° C. After monitoring the completion of the reaction by LCMS, the reaction mixture is concentrated under reduced pressure to obtain a residue, which is dissolved in DMF (4 mL) and filtered, and the filtrate is purified by prep-HPLC (mobile phase: 0.1% HCOOH / acetonitrile / water) to obtain compound A20 (23.5 mg, 30%) as a yellow solid. LCMS: [M+H] + =458.1.

[0166] 1H NMR(400MHz,DMSO-d6)δ 12.88(br s,1H),9.83(s,1H),8.30(d,J=6.0Hz,1H),8.14-8.04(m,3H),7.93-7.91(m,2H),7.6 4-7.58(m,4H),6.82(d,J=6.0Hz,1H),5.05(t,J=12.4Hz,2H),4.54(t,J=12.4Hz,2H).

[0167] Example 1-19. Preparation of Compound A21 [ka]

[0168] Step 1. Compound 82 Compound 81 (2.0 g, 9.9 mmol, 1.0 eq) is dissolved in DMF (20 mL), HATU (5.65 g, 14.9 mmol, 1.5 eq) is added, and after stirring for 10 min, compound 60 (1.28 g, 9.9 mmol, 1.0 eq) and diisopropylethylamine (5.12 g, 39.60 mmol, 4.0 eq) are added. The reaction mixture is continued to stir at room temperature for 5 h. After monitoring the completion of the reaction by LCMS, the reaction is quenched by adding water (60 mL) to the reaction solution, and then extracted with ethyl acetate (50 mL x 3). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue is purified by silica gel column chromatography (PE / EA=4 / 1) to give compound 82 (1.7 g, 62%) as a white solid. LCMS: [M+H] + =277.0.

[0169] Step 2. Compound 83 Compound 82 (1.0 g, 3.6 mmol, 1.0 eq) is dissolved in triethylamine (10 mL), and copper(I) iodide (137 mg, 0.72 mmol, 0.2 eq) and Pd(PPh3)2Cl2 (253 mg, 0.36 mmol, 0.1 eq) and compound 62 (1.0 g, 10.8 mmol, 3.0 eq) are added. The reaction mixture is stirred at 90 °C under nitrogen gas atmosphere for 1 h. After monitoring the completion of the reaction by LCMS, the reaction solution is concentrated and the residue is purified by silica gel column chromatography (EA / PE=1 / 3) to give compound 83 (0.9 g, 85%). LCMS: [M+H] + =295.1.

[0170] Step 3. Compound 84 Compound 83 (0.9 g, 3.06 mmol, 1.0 eq) is dissolved in tetrahydrofuran (20 mL) and tetrabutylammonium fluoride trihydrate (1.1 g, 3.67 mmol, 1.2 eq) is added. The mixture is stirred at 25° C. for 0.5 h. After completion of the reaction is confirmed by LCMS, the reaction solution is concentrated and the residue is purified by silica gel column chromatography (EA / PE=1 / 2) to give compound 84 (300 mg, 44%) as a yellow solid. LCMS: [M+H] + =223.1.

[0171] Step 4. Compound 85 Compound 84 (200 mg, 0.45 mmol, 1.0 eq) and compound 65 (150 mg, 0.41 mmol, 0.9 eq) are dissolved in dioxane (5 mL), X-Phos (43 mg, 0.09 mmol, 0.2 eq) and potassium phosphate monohydrate (311 mg, 1.35 mmol, 3.0 eq) are added, and finally Pd2(dba)3 (41 mg, 0.05 mmol, 0.1 eq) is added. Under nitrogen gas protection, the reaction mixture is stirred at 100 °C for 1 h. After the completion of the reaction is confirmed by LCMS, water (40 mL) is added to the reaction mixture, and then extracted with ethyl acetate (30 mL x 3). The combined organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give the residue. The residue is purified by column (silica gel, DCM / MeOH = 20 / 1) to give compound 85 (200 mg, 80%). LCMS: [M+H] + =558.2.

[0172] Step 5. Compound A21 Compound 85 (190.0 mg, 0.34 mmol, 1.0 eq) is dissolved in dioxane (2 mL), potassium carbonate (141.0 mg, 1.02 mmol, 3.0 eq) and water (0.4 mL) are added. The reaction mixture is stirred at 110° C. for 6 hours. After completion of the reaction is shown by LCMS, the reaction mixture is concentrated under reduced pressure to give a residue. The residue is dissolved in DMF (4 mL) and filtered, and the filtrate is purified by prep-HPLC (mobile phase: 0.1% HCOOH / acetonitrile / water) to give compound A21 (5.5 mg, 4%) as a yellow solid. LCMS: [M+H] + =458.1.

[0173] 1H NMR(400MHz,DMSO-d6)δ 12.89(br s,1H),9.86(s,1H),8.93(d,J=2.0Hz,1H),8.31(d,J=6.0Hz,1H),8.21-8.16(m,1H),8.1 3-7.88(m,2H),7.85(d,J=8.0Hz,1H),7.66-7.58(m,4H),6.82(d,J=6.0Hz,1H),4.89(br s,2H),4.54(br s,2H).

[0174] Examples 1-20. Preparation of Compound A22 [ka]

[0175] Step 1. Compound 87 Compound 34 (500 mg, 3.356 mmol, 1.0 eq) and compound 86 (468 mg, 3.188 mmol, 1.0 eq) are dissolved in isopropanol (10 mL), diisopropylethylamine (2.2 mg, 16.780 mmol, 5.0 eq) is added, and the reaction mixture is stirred at 80° C. for 2 h. After monitoring the completion of the reaction by LCMS, the reaction is cooled to room temperature, the reaction is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 2) to give compound 87 (520 mg, 60%) as a yellow solid. LCMS: [M+H] + =260.1.

[0176] Step 2. Compound A22 Compound 87 (150 mg, 0.578 mmol, 1.0 eq) and compound 6 (116 mg, 0.520 mmol, 0.9 eq) are dissolved in dioxane (10 mL), potassium phosphate monohydrate (399 mg, 1.734 mmol, 3.0 eq) is added, and finally Pd2(dba)3 (53 mg, 0.058 mmol, 0.10 eq) and X-Phos (41 mg, 0.087 mmol, 0.15 eq) are added, and the reaction mixture is stirred at 95 °C for 16 h under nitrogen gas protection. The reaction is cooled to room temperature, diluted with dichloromethane / methanol (50 mL, 10:1), passed through diatomaceous earth, and the filtrate is concentrated under reduced pressure to give a residue, which is purified by silica gel column chromatography (dichloromethane / methanol=93 / 7) to give compound A22 (59.0 mg, 23%) as a yellow solid. LCMS: [M+H] + =448.2.

[0177] 1 H NMR(400MHz,DMSO-d6)δ 13.10(s,1H),9.33(s,1H),8.23-8.08(m,2H),7.40(d,J=8.8Hz,1H),7.21(d,J=8.4Hz,1H),6.69(d,J=4.4Hz,1H),6.65(d,J=4.4Hz,1H),4.61(br s,4H),3.89(s,3H),2.40(s,3H).

[0178] Examples 1-21. Preparation of Compound A27 [ka]

[0179] Step 1. Compound 89 Compound 16 (193.15 mg, 1.15 mmol, 1.2 eq), compound 88 (280 mg, 0.97 mmol, 1.0 eq) and diisopropylethylamine (373.5 mg, 2.89 mmol, 3.0 eq) are added to isopropanol (5 mL). The reaction is allowed to react at 80° C. for 16 h. The reaction is cooled and the solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography (PE / EA=2 / 1) to give compound 89 (280 mg, 69%) as a pale yellow solid. LCMS: [M+H] + =421.1.

[0180] Step 2. Compound 90 Compound 89 (230 mg, 0.546 mmol, 1.0 eq) is dissolved in dioxane (30 mL), then compound 6 (124.7 mg, 0.546 mmol, 1.0 eq), potassium phosphate monohydrate (440.36 mg, 1.912 mmol, 3.5 eq), X-Phos (109.3 mg, 0.109 mmol, 0.2 eq) and Pd2(dba)3 (50.04 mg, 0.0546 mmol, 0.1 eq) are added. After the addition is complete, the reaction is reacted at 90° C. for 3 hours under nitrogen gas atmosphere. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography (PE / EA=1 / 1) to give compound 90 (200 mg, 60%) as a pale yellow solid. LCMS: [M+H] + =609.2.

[0181] Step 3. Compound A27 Compound 90 (190 mg, 0.312 mmol, 1.0 eq) is dissolved in tetrahydrofuran (15 mL), and then tetrabutylammonium fluoride trihydrate (820 mg, 3.125 mmol, 10.0 eq) is added. The reaction solution is reacted at 90° C. for 18 hours. After the reaction is completed, the reaction solution is concentrated to remove tetrahydrofuran. The residue is diluted with ethyl acetate and washed with water three times, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is separated and purified by prep-HPLC (mobile phase: 0.1% FA / acetonitrile / water) to obtain compound A27 (46 mg, 30.8%) as a yellow solid. LCMS: [M+H] + =479.1.

[0182] 1 H NMR(400MHz,DMSO-d6)δ 11.13(s,1H),10.07(s,1H),8.49(d,J=8.4Hz,1H),8.22-8.11(m,2H),7.83(d,J=8.8Hz,1H),7.16(t,J=4.0 H,1H),6.74-6.71(m,2H),6.44(d,J=8.0Hz 1H),4.763(br s,4H),3.96(s,3H).

[0183] Examples 1-22. Preparation of Compound A28 [ka]

[0184] Step 1. Compound 92 Compound 91 (1.0 g, 4.975 mmol, 1.0 eq) is dissolved in DMF (10 mL), HATU (2.27 g, 5.97 mmol, 1.2 eq) is added, and after stirring for 10 min, compound 60 (963 mg, 7.462 mmol, 1.5 eq) and diisopropylethylamine (1.9 g, 14.925 mmol, 3.0 eq) are added, and the reaction mixture is stirred for 1 h at 25° C. After completion of the reaction by LCMS, water (30 mL) is added to the reaction mixture, and the suspension is filtered and dried to give compound 92 (1.1 g, 80%) as a white solid. LCMS: [M+H] + =296.1.

[0185] Step 2. Compound 93 Compound 92 (1.0 g, 3.610 mmol, 1.0 eq) is dissolved in triethylamine (20 mL), copper(I) iodide (137 mg, 0.722 mmol, 0.2 eq) and Pd(PPh3)2Cl2 (253 mg, 0.361 mmol, 0.1 eq) and compound 4 (1.0 g, 10.830 mmol, 3.0 eq) are added, and the reaction mixture is stirred at 90 °C for 1.5 h under nitrogen gas atmosphere. After monitoring the completion of the reaction by LCMS, water (50 mL) is added to the reaction solution, and then extracted with ethyl acetate (60 mL x 3), and the combined organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated, and the obtained residue is purified by silica gel column chromatography (silica gel, 0-15% EA / PE) to give compound 93 (900 mg, 84%) as a yellow solid. LCMS: [M+H] + =294.1.

[0186] Step 3. Compound 94 Compound 93 (850 mg, 2.897 mmol, 1.0 eq) is dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride trihydrate (970 mg, 3.476 mmol, 1.2 eq) is added, and the mixture is stirred at room temperature for 2 h. After monitoring the completion of the reaction by LCMS, water (30 mL) is added to the reaction solution, which is then extracted with ethyl acetate (50 mL x 3), and the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a residue, which is purified by silica gel column chromatography (silica gel, 0-30% EA / PE) to give compound 94 (380 mg, 60%) as a yellow solid. LCMS: [M+H] + =222.1.

[0187] Step 4. Compound A28 Compound 94 (300 mg, 1.357 mmol, 1.0 eq) and compound 7 (441 mg, 1.629 mmol, 1.2 eq) were dissolved in n-butanol (20 mL), and X-Phos (97 mg, 0.203 mmol, 0.15 eq) and potassium phosphate monohydrate (863 mg, 4.071 mmol, 3.0 eq) were added, and finally Pd2(dba)3 (124 mg, 0.136 mmol, 0.1 eq) was added. The reaction mixture was stirred at 90 °C for 16 h under nitrogen gas protection. After monitoring the reaction completion by LCMS, the reaction solution was directly concentrated and the resulting residue was purified by silica gel column chromatography (silica gel, 0-7% MeOH / DCM) to give the crude product, which was purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A28 (8.5 mg, 1%) as a yellow solid. LCMS: [M+H] + =457.2.

[0188] 1 H NMR(400MHz,DMSO-d6)δ 9.84(s,1H),8.29(d,J=5.6Hz,1H),8.02(s,2H),7.78(d,J=8.4Hz,2H),7.73(d,J=8.4Hz,2H),7.61(s,4H),6.79(d,J=6.0Hz,1H),4.82(br s,2H),4.50(br s,2H).

[0189] Examples 1-23. Preparation of Compound A29 [ka]

[0190] Step 1. Compound 96 Compound 95 (200 mg, 0.93 mmol, 1.0 eq) was dissolved in methanol / water (2 mL / 1 mL), lithium hydroxide (158 mg, 3.74 mmol, 4.0 eq) was then added and the reaction was allowed to react at room temperature for 1 h. The reaction was then spun down to give compound 96 (190 mg, 99%) as a white solid. LCMS: [M+H]+ =201.1.

[0191] Step 2. Compound 97 Compound 96 (200mg, 1.0mmol, 1.0eq) was dissolved in DMF (3mL), then compound 60 (154mg, 1.2mmol, 1.2eq) and HATU (575mg, 1.5mmol, 1.5eq) were added, the reaction was stirred at room temperature for 0.5h, then diisopropylethylamine (387mg, 3.0mmol, 3.0eq) was added, the reaction was stirred at room temperature for 1.5h, the reaction was slowly added to water, extracted twice with ethyl acetate, the combined organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=15 / 1) to give compound 97 (240mg, 87%) as a white solid. LCMS: [M+H] + =276.0.

[0192] Step 3. Compound 98 Compound 97 (150 mg, 0.55 mmol, 1.0 eq) is dissolved in triethylamine (3 mL), and then compound 5 (640 mg, 6.5 mmol, 12 eq), Pd(dppf)Cl2 (40 mg, 0.055 mmol, 0.1 eq) and copper(I) iodide (21 mg, 0.11 mmol, 0.2 eq) are added in sequence. After the addition is complete, the temperature is raised to 90° C. and stirred for 2 hours. The reaction solution is extracted with ethyl acetate / water, and the organic phase is purified by silica gel column chromatography (PE / EA=15 / 1) to give compound 98 (150 mg, 62%) as a white solid. LCMS: [M+H] + =294.1.

[0193] Step 4. Compound 99 Compound 98 (150 mg, 0.51 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), then tetrabutylammonium fluoride trihydrate (200 mg, 0.77 mmol, 1.5 eq) was added and the reaction was allowed to react at room temperature for 2 h. The reaction was spun to dryness and the residue was purified by silica gel column chromatography (PE / EA=15 / 1) to give compound 99 (100 mg, 89%) as a pale yellow solid. LCMS: [M+H] + =222.1.

[0194] Step 5. Compound 100 Compound 99 (320 mg, 0.90 mmol, 1.0 eq) is dissolved in dioxane (5 mL), then compound 8 (200 mg, 0.90 mmol, 1.0 eq), potassium phosphate (621 mg, 2.7 mmol, 3.0 eq), X-phos (86 mg, 0.18 mmol, 0.2 eq) and Pd2(dba)3 (23 mg, 0.031 mmol, 0.1 eq) are added and the reaction is stirred at 90° C. for 2 h after the addition is complete. Cooled to room temperature, the reaction is spun dry and the residue is purified by silica gel column chromatography (DCM / MeOH=10 / 1) to give compound 100 (120 mg, 25%) as a pale yellow solid. LCMS: [M+H] + =541.2.

[0195] Step 6. Compound A29 Compound 100 (100 mg, 0.18 mmol, 1.0 eq) is dissolved in dichloromethane (3 mL), then trifluoroacetic acid (3 mL) is added at 0° C. and reacted at room temperature for 2 hours. After the reaction is completed, the reaction solution is slowly added to saturated aqueous sodium bicarbonate solution, the mixture is extracted twice with ethyl acetate (100 mL), the organic phase is combined and then washed with water, the organic phase is concentrated, ethyl acetate (4 mL), methanol (1 mL) and dichloromethane (1 mL) are added to the residue, the mixture is stirred at room temperature for 0.5 minutes, and filtered to obtain compound A29 (80.3 mg, 79%) as a pale yellow solid. LCMS: [M+H] + =457.2.

[0196] 1 H NMR(400MHz,DMSO-d6)δ 9.79(s,1H),8.36-8.22(m,2H),7.94-7.87(m,2H),7.85-7.75(m,2H),7. 66-7.56(m,5H),6.79(d,J=6.0Hz,1H),5.40(dd,J=10.0,2.4Hz,1H),4.67 (d,J=127.6Hz,4H),3.94(d,J=12.0Hz,1H),3.71-3.55(m,1H),2.17-2.06 (m,1H),1.96(t,J=9.6Hz,2H),1.68(d,J=12.8Hz,1H),1.59-1.49(m,2H).

[0197] Examples 1-24. Preparation of Compound A30 [ka]

[0198] Step 1. Compound 103 Compound 100 (5.0 g, 24.51 mmol, 1.0 eq). Compound 102 (4.21 g, 49.01 mmol, 2.0 eq) and sodium carbonate (4.07 g, 49.01 mmol, 2.0 eq) are dissolved in 1,2-dichloroethane (130 mL), and then 2,2'-bipyridine (3.83 g, 24.51 mmol, 1.0 eq) and anhydrous copper acetate (4.45 g, 24.51 mmol, 1.0 eq) are added. The reaction solution is replaced with oxygen gas three times, and then stirred at 70 ° C under an oxygen gas atmosphere for 8 hours. The reaction solution is cooled to room temperature. The reaction solution is diluted with 1,2-dichloroethane, washed successively with ammonia water, water, and saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate=16 / 1) to give compound 103 (5.54 g, 92%) as a yellow oil. LCMS: [M+H] + =244.0.

[0199] Step 2. Compound 104 Compound 103 (5.54 g, 27.70 mmol, 1.0 eq) is dissolved in a mixture of tetrahydrofuran / methanol / water (1 / 1 / 2, 60 mL), and then lithium hydroxide (2.72 g, 113.48 mmol, 5.0 eq) is added. The reaction is allowed to react at 40° C. for 1 h. After completion of the reaction, the reaction is distilled under reduced pressure to remove most of the methanol and tetrahydrofuran. The remaining solution is adjusted to pH 5.0 by dropwise addition of saturated aqueous sodium citrate solution, and extracted with ethyl acetate (200 mL×3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 104 (5.05 g, 96%) as a white solid. LCMS: [M+H] + =230.0.

[0200] Step 3. Compound 105 Compound 104 (5.05 g, 24.08 mmol, 1.0 eq), compound 60 (3.74 g, 28.90 mmol, 1.2 eq) and HATU (10.99 g, 28.90 mmol, 1.2 eq) are dissolved in DMF (80 mL), the reaction solution is cooled to 0 °C, and diisopropylethylamine (12.45 g, 96.32 mmol, 4.0 eq) is slowly added. The reaction solution is reacted at room temperature for 2 hours. After the reaction is completed, water (200 mL) is added to the reaction solution and extracted with ethyl acetate (150 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give compound 105 (6.34 g, 94%) as a white solid. LCMS: [M+H] + =305.0.

[0201] Step 4. Compound 106 Compound 105 (1.0 g, 3.28 mmol, 1.0 eq) is dissolved in triethylamine (14.5 mL), followed by addition of compound 62 (966 mg, 9.83 mmol, 3.0 eq), bistriphenylphosphinepalladium(II) dichloride (230 mg, 0.328 mmol, 0.1 eq) and copper(I) iodide (187 mg, 0.983 mmol, 0.3 eq) and nitrogen gas replacement three times. The reaction solution is stirred at 90°C under nitrogen gas atmosphere for 2 hours. The reaction solution is combined, diluted with ethyl acetate and filtered. The filtrate is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate=13 / 1) to give compound 106 (625 mg, 59%) as a tan solid. LCMS: [M+H] + =323.2.

[0202] Step 5. Compound 107 Compound 106 (330 mg, 1.02 mmol, 1.0 eq) is dissolved in tetrahydrofuran (8 mL) and then tetrabutylammonium fluoride trihydrate (484 mg, 1.54 mmol, 1.5 eq) is added. The reaction is stirred at 25° C. for 30 min and concentrated. The residue is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate=19 / 1) to give compound 107 (240 mg, 93%) as a yellow solid. LCMS: [M+H] + =251.1.

[0203] Step 6. Compound 108 Compound 107 (200 mg, 0.799 mmol, 1.0 eq), compound 65 (357 mg, 0.959 mmol, 1.2 eq) and potassium phosphate monohydrate (552 mg, 2.400 mmol, 3.0 eq) are dissolved in dioxane (10 mL), and then X-phos (76 mg, 0.160 mmol, 0.2 eq) and Pd2(dba)3 (73 mg, 0.80 mmol, 0.1 eq) are quickly added. After replacing with nitrogen gas three times, the reaction solution is stirred at 100 °C under nitrogen gas atmosphere for 1 hour. The reaction solution is cooled to room temperature, water (20 mL) is added to the reaction solution, and then extracted with ethyl acetate (20 mL × 3). The combined organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by flash silica gel column chromatography (dichloromethane / methanol=16 / 1) to give compound 108 (193 mg, 41%) as a yellow solid. LCMS: [M+H] + =586.2.

[0204] Step 7. Compound A30 Compound 108 (188 mg, 0.321 mmol, 1.0 eq) and potassium carbonate (133 mg, 0.963 mmol, 3.0 eq) are dissolved in a mixed solvent (dioxane / water=5 / 1, 3.6 mL) and the reaction is stirred at 110° C. for 2.5 h. Cool to room temperature and concentrate the reaction. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give A30 (83.0 mg, 53%) as a yellow solid. LCMS: [M+H] + =486.1.

[0205] 1H NMR(400MHz,DMSO-d6)δ 12.90(br s,1H),9.77(s,1H),8.27(d,J=6.0Hz,1H),8.01(br s,2H),7.67(d,J=8.4Hz,2H),7.58(d,J=8.8Hz,2H),6.74(d,J=6.0Hz,1H),6.67-6.59(m,2H),4.62(br s,4H),3.52-3.44(m,1H),1.17-1.07(m,2H),1.05-0.96(m,2H).

[0206] Examples 1-25. Preparation of Compound A32 [ka]

[0207] Step 1. Compound 111 Compound 109 (1.0 g, 7.99 mmol, 1.0 eq) is dissolved in DMF (20 mL), then NaH (480 mg, 60% content in mineral oil, 11.99 mmol, 1.5 eq) is added under ice bath conditions, the reaction is stirred at 25° C. for 20 min, and then compound 110 (2.49 g, 15.98 mmol, 2.0 eq) is added. After the addition is complete, the reaction is stirred at room temperature for 1 h. After the reaction is complete, the reaction is poured into ice water and then extracted with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (PE / EA=20 / 1) to give compound 111 (1.0 g, 81%) as a brown oily liquid. LCMS: [M+H] + =154.1.

[0208] Step 2. Compound 112 Compound 111 (9.80 g, 63.98 mmol, 1.0 eq) is dissolved in DCM (10 mL), purged with nitrogen gas, cooled to 0° C., and then NBS (3.64 g, 63.89 mmol, 1.0 eq) is added. After the addition is complete, the reaction is stirred under ice bath conditions for 0.5 h. After the reaction is complete, the reaction is poured into water and then extracted with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product compound 112 (11.0 g, 74%) as a brown oily liquid. LCMS: [M+H] + =232.0.

[0209] Step 3. Compound 113 The crude product, compound 112 (11.0 g, 47.6 mmol, 1.0 eq) is dissolved in methanol (50 mL) and then sodium hydroxide (5.7 g, 142.2 mmol, 3.0 eq) is added to make a 1.0 M aqueous solution of sodium hydroxide. After the addition is complete, the reaction is stirred at 40 °C for 16 h. The reaction is cooled to room temperature and concentrated. The pH of the resulting aqueous solution is adjusted to about 4-5 with 1.0 M hydrochloric acid solution and extracted with ethyl acetate. The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (PE / EA=30 / 1) to give compound 113 (2.6 g, 25%) as a white solid. LCMS: [M+H] + =218.0.

[0210] Step 4. Compound 114 Compound 113 (850 mg, 3.86 mmol, 1.0 eq) is dissolved in DMF (5 mL), then HATU (1.93 g, 5.07 mmol, 1.3 eq) is added, and the reaction is stirred at room temperature for 10 min. Diisopropylethylamine (1.51 g, 11.69 mmol, 3.0 eq) and compound 60 (505 mg, 3.90 mmol, 1.0 eq) are added to the reaction in sequence. The reaction is stirred at room temperature for 1 h. The reaction is diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by silica gel column chromatography (PE / EA=30 / 1) to give compound 114 (1.0 g, 88%) as a yellow oily liquid. LCMS: [M+H] + =293.1.

[0211] Step 5. Compound 115 Compound 114 (600 mg, 2.04 mmol, 1.0 eq) is dissolved in DMF (5 mL), and then CuI (78 mg, 0.41 mmol, 0.2 eq), Pd(PPh3)2Cl2 (144 mg, 0.20 mmol, 0.1 eq) and compound 62 (603 mg, 12.2 mmol, 6.0 eq) are added successively under room temperature. The atmosphere is replaced with nitrogen gas, and the reaction solution is stirred at 90°C under nitrogen gas atmosphere for 2 hours. The reaction solution is cooled to room temperature, filtered, and the filtrate is concentrated. The residue is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is purified by silica gel column chromatography (PE / EA=20 / 1) to obtain compound 115 (400 mg, 63%) as a black oily liquid. LCMS: [M+H] + =311.2.

[0212] Step 6. Compound 116 Compound 115 (400 mg, 1.68 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10 mL) and then tetrabutylammonium fluoride trihydrate (936 mg, 2.52 mmol, 1.5 eq) is added. After the addition is complete, the mixture is stirred at 25° C. for 0.5 h. The reaction is diluted with ethyl acetate and washed with water and saturated brine. The combined organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography (PE / EA=20 / 1) to give compound 116 (270 mg, 68%) as a red solid. LCMS: [M+H] + =239.1.

[0213] Step 7. Compound A32 Compound 116 (280 mg, 0.75 mmol, 1.0 eq) is dissolved in dioxane (10 mL), and then compound 10 (197 mg, 0.83 mmol, 1.1 eq), potassium phosphate monohydrate (607 mg, 2.64 mmol, 3.5 eq), X-Phos (72 mg, 0.15 mmol, 0.2 eq) and Pd2(dba)3 (69 mg, 0.08 mmol, 0.1 eq) are added in sequence. After replacing with nitrogen gas three times, the reaction solution is stirred at 110 °C for 5 h. The reaction solution is cooled to room temperature and concentrated. The residue is diluted with ethyl acetate (30 mL), then washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A32 (18.5 mg, 5%) as a yellow solid. LCMS: [M+H] + =474.0.

[0214] 1 H NMR(400MHz,DMSO-d6)δ 12.86(br s,1H),9.79(s,1H),8.25(d,J=6.0Hz,1H),8.15-7.85(m,2H),7.66-7.54(m,4H),6.74(d,J=6.0Hz,1H),6.72-6.68(m,2H),4.65(br s, 4H), 4.49-4.40 (m, 2H), 1.37 (t, J=6.8Hz, 3H).

[0215] Examples 1-26. Preparation of Compound A37 [ka]

[0216] Step 1. Compound 118 Add compound 117 (400 mg, 2.01 mmol, 1.2 eq), compound 21 (434.28 mg, 1.67 mmol, 1.0 eq) and diisopropylethylamine (649.37 mg, 5.01 mmol, 3.0 eq) to isopropanol (20 mL). Allow the reaction to react at 50° C. for 16 h with stirring. Cool the reaction and remove the solvent under reduced pressure. Purify by silica gel column chromatography (PE / EA=2 / 1) to give compound 118 (538 mg, 76%) as a pale yellow solid. LCMS: [M+H] + =422.0.

[0217] Step 2. Compound 119 Compound 117 (200 mg, 0.47 mmol, 1.0 eq) is dissolved in dioxane (6 mL), then compound 21 (106 mg, 0.47 mmol, 1.0 eq), potassium phosphate monohydrate (382 mg, 1.7 mmol, 3.5 eq), X-Phos (45 mg, 0.094 mmol, 0.2 eq) and Pd2(dba)3 (43 mg, 0.047 mmol, 0.1 eq) are added, and the reaction is reacted at 90 °C for 3 h under nitrogen gas atmosphere after the addition is complete. Cool to room temperature, evaporate the solvent under reduced pressure, and the resulting pale yellow solid crude product 119 is used directly in the next reaction. LCMS: [M+H] + =610.2.

[0218] Step 3. Compound A37 The crude product, compound 119 (289 mg, 474 mmol, 1.0 eq) is dissolved in a mixed solvent of dioxane / water (5 mL / 1 mL), then potassium carbonate (654 mg, 4.74 mmol, 10.0 eq) is added at 25° C., and the reaction solution is reacted at 110° C. for 2 hours. After the reaction is completed, the mixture is concentrated to obtain the crude product, which is separated and purified by prep-HPLC (mobile phase: 0.1% FA / acetonitrile / water) to obtain compound A37 (58 mg, 24%) as a yellow solid. LCMS: [M+H] + =510.2.

[0219] 1 H NMR(400MHz,DMSO-d6)δ 12.93(s,1H),9.93(s,1H),8.57(d,J=8.4Hz,1H),8.17(br s,1H),7.98(br s,1H),7.91-7.86(m,3H),7.80(d,J=8.4Hz,1H),7.68-7.66(m,3H),6.71(s,2H),4.62(br s,4H),3.97(s,3H).

[0220] Examples 1-27. Preparation of Compound A38 [ka]

[0221] Step 1. Compound 120 Compound 109 (20.0 g, 159.84 mmol, 1.0 eq) is dissolved in anhydrous DMF (100 mL), and then NaH (9.59 g, 60% content in mineral oil, 239.76 mmol, 1.5 eq) is added under ice bath conditions. The reaction is stirred under ice bath for 30 minutes, and then compound bromoacetonitrile (38.34 g, 319.68 mmol, 2.0 eq) is added. The reaction is stirred at 25° C. overnight. After the reaction is completed, the reaction is quenched by adding saturated aqueous ammonium chloride solution, and water (200 mL) is added to obtain a mixture. The mixture is extracted with ethyl acetate (300 mL×3). The organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain compound 120 (20.3 g, 77%) as a white solid. LCMS: [M+H] + =165.1.

[0222] Step 2. Compound 121 Compound 120 (20.3 g, 123.66 mmol, 1.0 eq) is dissolved in methanol (250 mL) and cobalt dichloride (9.63 g, 74.19 mmol, 0.6 eq) is added. The reaction is cooled in an ice bath for 10 min, then sodium borohydride (28.07 g, 741.94 mmol, 6.0 eq) is added slowly to the reaction while maintaining the ice bath. The reaction is stirred at 25 °C for 16 h. After monitoring the reaction completion by LCMS, the crude compound 121 reaction is used directly in the next reaction. LCMS: [M+H] + =169.1.

[0223] Step 3. Compound 122 To the reaction mixture of crude compound 121 (123.66 mmol, 1.0 eq) is added sodium methoxide (10.02 g, 185.50 mmol, 1.5 eq). The reaction mixture is stirred at 80° C. overnight. The reaction mixture is cooled to room temperature, filtered, the filter cake is washed with methanol, and the filtrate is concentrated under vacuum. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1-3 / 1, ethyl acetate) to give compound 122 (13.5 g, 80%, two steps) as a pale pink solid. LCMS: [M+H] + =137.2.

[0224] Step 4. Compound 124 Compound 122 (3.0 g, 22.03 mmol, 1.0 eq) is dissolved in anhydrous DMF (40 mL), then NaH (1.76 g, 60% content in mineral oil, 44.07 mmol, 2.0 eq) is added under ice bath conditions. The reaction is stirred under ice bath for 30 min, then compound 123 (7.67 g, 33.05 mmol, 1.5 eq) is added. The reaction is stirred at 25° C. for 30 min. After the reaction is completed, the reaction is quenched with saturated aqueous ammonium chloride solution, and water (60 mL) is added to obtain a mixture. The mixture is extracted with ethyl acetate (90 mL×3). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1-2 / 1) to obtain compound 124 (989 mg, 20%) as a white solid. LCMS: [M+H] + =219.1.

[0225] Step 5. Compound 125 Compound 124 (950 mg, 4.35 mmol, 1.0 eq) is dissolved in dichloromethane (10 mL), then cooled to 0° C. and NBS (697 mg, 3.92 mmol, 0.9 eq) is added while maintaining at 0° C. The reaction is allowed to react at 0° C. for 30 min. After completion of the reaction, the reaction is rotary evaporated to dryness and the residue is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give compound 125 (956 mg, 73%) as a white solid. LCMS: [M+H] + =297.0.

[0226] Step 6. Compound 126 Compound 125 (920 mg, 3.10 mmol, 1.0 eq) is dissolved in a mixed solvent (triethylamine / tetrahydrofuran = 1 / 1, 12 mL), and then compound 62 (3.04 g, 31.0 mmol, 10.0 eq), bistriphenylphosphinepalladium dichloride (217 mg, 0.310 mmol, 0.1 eq) and copper(I) iodide (118 mg, 0.620 mmol, 0.2 eq) are added. After replacing with nitrogen gas three times, the reaction solution is stirred at 90 ° C under nitrogen gas atmosphere for 3 hours. After cooling the reaction solution, it is diluted with ethyl acetate and filtered. The filtrate is washed with ammonia water and saturated saline, dried over anhydrous sodium sulfate, and concentrated to obtain crude product 126 (4.5 g). The crude product 126 is used directly in the next reaction. LCMS: [M+H] + =315.1.

[0227] Step 7. Compound 127 The crude product 126 obtained from the previous step (4.5 g, 3.10 mmol, 1.0 eq) is dissolved in ethyl acetate (20 mL) and then tetrabutylammonium fluoride trihydrate (1.40 g, 4.43 mmol, 1.4 eq) is added. The reaction is stirred at room temperature for 30 min. The reaction is concentrated and the residue is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to give compound 127 (711 mg, 92%, two steps) as a yellow solid. LCMS: [M+H] + =243.1.

[0228] Step 8. Compound 128 Compound 127 (100 mg, 0.413 mmol, 1.0 eq), compound 65 (161 mg, 0.413 mmol, 1.0 eq) and potassium phosphate monohydrate (285 mg, 1.239 mmol, 3.0 eq) are added to dioxane (5 mL), followed by the rapid addition of X-phos (39 mg, 0.083 mmol, 0.2 eq) and Pd2dba3 (38 mg, 0.041 mmol, 0.1 eq). After purging with nitrogen gas three times, the reaction mixture is stirred at 100 °C under nitrogen gas atmosphere for 2 h. The reaction is cooled to room temperature and concentrated. The residue is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 11) to give compound 128 (163 mg, 66%) as a brown solid. LCMS: [M+H] + =596.2.

[0229] Step 9. Compound A38 Compound 128 (160 mg, 0.269 mmol, 1.0 eq) and potassium carbonate (111 mg, 0.807 mmol, 3.0 eq) are dissolved in a mixed solvent (dioxane / water=5 / 1, 6 mL). The reaction is stirred at 110° C. for 3 h. Cool to room temperature and concentrate the reaction. The residue is purified by pre-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give A38 (62.5 mg, 46%) as a white solid. LCMS: [M+H] + =496.1.

[0230] 1H NMR(400MHz,DMSO-d6)δ 12.92(br.s,1H),9.78(s,1H),8.40(d,J=3.6Hz,1H),8.15(br.s,1H),7.91(br.s,1H),7.74(d,J=8.8Hz,2H ),7.62(d,J=8.8Hz,2H),6.82(d,J=4.0Hz,1H),6.74(d,J=4.0Hz,1H),4.38-4.25(m,4H),3.96-3.85(m,2H).

[0231] Examples 1-28. Preparation of Compound A40 [ka]

[0232] Step 1. Compound 131 Compound 129 (4.0 g, 14.38 mmol, 1.5 eq), compound 130 (2.0 g, 9.58 mmol, 1.0 eq), Pd(dppf)Cl2 (1.39 g, 1.92 mmol, 0.2 eq), potassium carbonate (4.0 g, 28.76 mmol, 3.0 eq) are added to dioxane / water (10 / 1, 100 mL). The reaction is reacted at 90 °C under nitrogen gas atmosphere for 16 hours. The reaction is cooled and the solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography (PE / EA=4 / 1) to give compound 131 (3.35 g, 76%) as a pale yellow solid. LCMS: [M+H] + =280.1.

[0233] Step 2. Compound 132 Compound 16 (1.2 g, 7.2 mmol, 5.0 eq) is dissolved in isopropanol (6 mL), then compound 131 (400 mg, 1.44 mmol, 1.0 eq) and diisopropylethylamine (743 mg, 5.8 mmol, 4.0 eq) are added. The reaction is stirred at 90° C. for 16 h. The reaction is cooled to room temperature and then concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give compound 132 (430 mg, 73%) as a yellow solid. LCMS: [M+H] + =410.1.

[0234] Step 3. Compound 133 Compound 132 (430 mg, 1.05 mmol, 1.0 eq) is dissolved in dichloromethane (5 mL) and then trifluoroacetic acid (5 mL) is added. The reaction is stirred at room temperature for 1 h. The reaction is concentrated, the pH value is adjusted to 7 with aqueous sodium carbonate solution, and then extracted with ethyl acetate (50 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 133 (340 mg, 100%) as a yellow solid. LCMS: [M+H] + =326.1.

[0235] Step 4. Compound 134 Compound 133 (340 mg, 1.04 mmol, 1.0 eq) is dissolved in tetrahydrofuran (6 mL), then Boc2O (228 mg, 1.04 mmol, 1.0 eq) and DMAP (26 mg, 0.21 mmol, 0.2 eq) are added. The reaction is stirred at 25° C. for 1 h. The reaction is concentrated and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give compound 134 (280 mg, 63%) as a white solid. LCMS: [M+H] + =426.1.

[0236] Step 5. Compound A40 Compound 134 (125 mg, 0.29 mmol, 1.0 eq) is dissolved in dioxane (5 mL), then compound 6 (70 mg, 0.29 mmol, 1.0 eq), potassium phosphate monohydrate (237 mg, 1.02 mmol, 3.5 eq), X-Phos (28 mg, 0.058 mmol, 0.2 eq) and Pd2(dba)3 (27 mg, 0.029 mmol, 0.1 eq) are added. After replacing the air with nitrogen gas three times, the reaction solution is stirred at 100 °C under nitrogen gas atmosphere for 4 hours. After cooling to room temperature, potassium carbonate (121 mg, 0.87 mmol, 3.0 eq) and water (1 mL) are added to the reaction solution. The reaction solution is subsequently stirred at 110 °C for 3 hours. The reaction is concentrated and the residue is purified by pre-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A40 (30.3 mg, 20%) as a yellow solid. LCMS: [M+H] + =528.1.

[0237] 1 H NMR(400MHz,DMSO-d6)δ 13.20(br.s,1H),10.13(s,1H),8.50(d,J=3.6Hz,1H),8.10(br.s,1H),7.87(br. s,1H),7.84-7.76(m,2H),6.59(s,1H),4.62(br.s,4H),3.91(s,3H),2.19(s,3H).

[0238] Examples 1-29. Preparation of Compound A41 [ka]

[0239] Step 1. Compound 136 Compound 135 (2.0 g, 10.47 mmol, 1.0 eq) is dissolved in a mixture of dioxane (40 mL) and water (6 mL), and then compound 129 (3.5 g, 12.57 mmol, 1.2 eq), potassium carbonate (4.3 g, 31.41 mmol, 3.0 eq) and Pd(dppf)Cl2 (760 mg, 1.047 mmol, 0.1 eq) are added in sequence. The atmosphere is purged with nitrogen gas and the reaction is stirred at 100 °C for 16 h. The reaction is cooled to room temperature and concentrated. The residue is purified by silica gel column chromatography (PE / EA=1 / 1) to give compound 136 (2.0 g, 73%) as a brown solid. LCMS: [M+H] + =263.2.

[0240] Step 2. Compound 137 Compound 16 (1.1 g, 6.7 mmol, 5.0 eq) and compound 136 (350 mg, 1.3 mmol, 1.0 eq) are dissolved in isopropanol (10 mL), then diisopropylethylamine (503 mg, 3.9 mmol, 3.0 eq) is added. The reaction is stirred at 80° C. for 36 h. The reaction is cooled to room temperature and concentrated. The residue is purified by silica gel column chromatography (PE / EA=1 / 1) to give compound 137 (400 mg, 78%) as a white solid. LCMS: [M+H] + =393.1.

[0241] Step 3. Compound 138 Compound 137 (400 mg, 1.0 mmol, 1.0 eq) is dissolved in dichloromethane (5 mL) and then trifluoroacetic acid (5 mL) is added. The reaction is stirred at 25° C. for 2 h. The reaction is concentrated, the residue is diluted with dichloromethane, and the pH is adjusted to alkaline with saturated aqueous sodium carbonate. The resulting reaction mixture is filtered and the solid is collected. The solid is lyophilized to give compound 138 (300 mg, 95%) as a white solid. LCMS: [M+H] + =309.1.

[0242] Step 4. Compound 139 Compound 138 (300 mg, 0.97 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10 mL), then DMAP (24 mg, 0.19 mmol, 0.2 eq) and Boc2O (211 mg, 0.97 mmol, 1.0 eq) are added sequentially. The reaction is stirred at room temperature for 2 h. The reaction is concentrated and the residue is purified by silica gel column chromatography (PE / EA=2 / 1) to give compound 5 (280 mg, 71%) as a white solid. LCMS:[M-55] + =409.1.

[0243] Step 5. Compound 140 Compound 139 (120 mg, 0.29 mmol, 1.0 eq) is dissolved in dioxane (8 mL) and then compound 6 (70 mg, 0.29 mmol, 1.0 eq), potassium phosphate monohydrate (200 mg, 0.87 mmol, 3.0 eq), X-Phos (29 mg, 0.06 mmol, 0.2 eq) and Pd2(dba)3 (28 mg, 0.03 mmol, 0.1 eq) are added sequentially. The atmosphere is flushed with nitrogen and the reaction is stirred at 100 °C for 2 h. The reaction is cooled to room temperature and concentrated. The crude product 140 is used directly in the next reaction. LCMS: [M+H] + =611.2.

[0244] Step 6. Compound A41 The crude product, compound 140, is dissolved in a mixture of dioxane (5 mL) and water (2 mL), and then potassium carbonate (120 mg, 0.87 mmol, 3.0 eq) is added. The reaction is stirred at 110° C. for 2 h. The reaction is cooled to room temperature and concentrated. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A41 (22.6 mg, yield for two steps: 15%) as a white solid. LCMS: [M+H] + =510.2.

[0245] 1H NMR(400MHz,DMSO-d6)δ 13.17(br s,1H),10.22(s,1H),8.79-8.72(m,1H),8.48(d,J=3.6Hz,1H),8.40(d,J=13.6Hz,1H),8.21(s,1H),8.02(s,1H),6.57(s,1H),4.61(br s,4H),3.88(s,3H),2.17(s,3H).

[0246] Examples 1-30. Preparation of Compound A42 [ka]

[0247] Step 1. Compound 142 Compound 141 (2.0 g, 9.58 mmol, 1.0 eq), compound 129 (4.39 g, 14.38 mmol, 1.5 eq), Pd(dppf)Cl2 (1.39 g, 1.91 mmol, 0.2 eq), potassium carbonate (4.0 g, 29.0 mmol, 3.0 eq) are added to dioxane / water (10 / 1, 100 mL). The reaction is stirred at 100 °C for 16 h under nitrogen gas atmosphere. The reaction is cooled and the solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography (PE / EA=4 / 1) to give compound 142 (3.35 g, 76%) as a pale yellow solid. LCMS: [M+H] + =262.13.

[0248] Step 2. Compound 143 Compound 142 (300 mg, 1.15 mmol, 1.0 eq), compound 16 (958 mg, 5.75 mmol, 5.0 eq) and diisopropylethylamine (445 mg, 3.45 mmol, 3.0 eq) are dissolved in isopropanol (15 mL). The reaction is stirred at 80° C. overnight. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is purified by flash silica gel column chromatography (PE / EA=18 / 7) to give compound 143 (388 mg, 86%) as a yellow solid. LCMS: [M+H] +=392.1.

[0249] Step 3. Compound 144 Compound 143 (384 mg, 0.980 mmol, 1.0 eq) is dissolved in dichloromethane (3 mL) and then trifluoroacetic acid (8 mL) is added. The reaction is stirred at 25° C. for 30 minutes. The reaction is concentrated under vacuum, water (10 mL) is added, the pH is adjusted to 8 by adding saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (20 mL×3). The organic phases are combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 144 (302 mg, 100%) as a yellow solid. LCMS: [M+H] + =308.1.

[0250] Step 4. Compound 145 Compound 144 (302 mg, 0.980 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10 mL), then 4-dimethylaminopyridine (12 mg, 0.098 mmol, 0.1 eq) and di-t-butyl dicarbonate (214 mg, 0.980 mmol, 1.0 eq) are added and the reaction is stirred at room temperature for 1 h. After completion of the reaction, the reaction is concentrated and the residue is purified by flash silica gel column chromatography (PE / EA=3 / 1) to give compound 145 (362 mg, 90%) as a pale yellow solid. LCMS: [M+H] + =408.1.

[0251] Step 5. Compound 146 Compound 145 (120 mg, 0.294 mmol, 1.0 eq), compound 6 (70 mg, 0.294 mmol, 1.0 eq) and potassium phosphate monohydrate (203 mg, 0.882 mmol, 3.0 eq) are dissolved in dioxane (5 ml) and then X-phos (28 mg, 0.059 mmol, 0.2 eq) and Pd2(dba)3 (27 mg, 0.029 mmol, 0.1 eq) are added quickly. After replacing with nitrogen gas three times, the reaction is stirred at 100 °C under nitrogen gas atmosphere for 2 h. The reaction is concentrated and the residue is purified by flash silica gel column chromatography (PE / EA=2 / 3) to give compound 146 (125 mg, 69%) as a tan solid. LCMS: [M+H] + =610.2.

[0252] Step 6. Compound A42 Compound 146 (120 mg, 0.197 mmol, 1.0 eq) and potassium carbonate (136 mg, 0.985 mmol, 5.0 eq) are dissolved in a mixed solvent (dioxane / water=2 / 1, 4.5 mL). The reaction is stirred at 110° C. for 3 h. Cool to room temperature and concentrate the reaction. The residue is purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to give A42 (25.0 mg, 24%) as a white solid. LCMS: [M+H] + =510.2.

[0253] 1 H NMR(400MHz,DMSO-d6)δ 13.05(br.s,1H),9.96(s,1H),8.45(d,J=3.6Hz,1H),8.12(br.s,1H),7.99(dd,J=14.0,2.0Hz,1H),7.92(br.s, 1H),7.72(t,J=8.8Hz,1H),7.61(dd,J=8.4,2.0Hz,1H),6.59(s,1H),4.61(br.s,4H),3.91(s,3H),2.19(s,3H).

[0254] Examples 1-31. Preparation of Compound A43 [ka]

[0255] Step 1. Compound 149 Compound 147 (400 mg, 1.92 mmol, 1.0 eq), compound 148 (660 mg, 2.30 mmol, 1.2 eq), Pd(dppf)Cl2 (139.38 mg, 0.192 mmol, 0.1 eq), potassium carbonate (3.0 g, 4.78 mmol, 3.0 eq) are added to dioxane / water (5 / 1, 10 mL). The reaction is reacted at 90 °C for 16 h under nitrogen gas atmosphere. The reaction is cooled and the solvent is removed under reduced pressure. Purification is performed by silica gel column chromatography (PE / EA=4 / 1) to obtain compound 149 (500 mg, 88%) as a pale yellow solid. LCMS: [M+H] + =294.1.

[0256] Step 2. Compound 150 Compound 149 (500 mg, 1.70 mmol, 1.0 eq) and compound 16 (370 mg, 2.22 mmol, 1.3 eq) are dissolved in isopropanol (10 mL), and then diisopropylethylamine (659.12 mg, 5.1 mmol, 3.0 eq) is added. After the addition is complete, the atmosphere is replaced with nitrogen gas, and the reaction solution is reacted at 90° C. for 16 hours under nitrogen gas atmosphere. The reaction solution is cooled to room temperature, and the solvent is removed under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate / petroleum ether=2 / 1) to give compound 150 (400 mg, 55.4%) as a yellow solid. LCMS: [M+H] + =424.1.

[0257] Step 3. Compound 151 Compound 150 (280 mg, 0.662 mmol, 1.0 eq) is dissolved in dichloromethane (5 mL) and then trifluoroacetic acid (5 mL) is added to the solution. After the addition is complete, the reaction is allowed to react at 25 °C for 2 h. The reaction is evaporated under reduced pressure. The residue is dissolved in a small amount of dichloromethane and the pH is adjusted to 9-10 with saturated sodium carbonate solution. The resulting reaction mixture is filtered and the solid is collected. The solid is dried on a rotary evaporator to give compound 151 (200 mg, 86.3%) as a white solid, which is used directly in the next reaction. LCMS: [M+H] + =339.1.

[0258] Step 4. Compound 152 Compound 151 (150 mg, 0.442 mmol, 1.0 eq) is dissolved in tetrahydrofuran (25 mL), then Boc2O (67.60 mg, 0.309 mmol, 0.7 eq) and DMAP (5.40 mg, 0.044 mmol, 0.1 eq) are added to the solution. After the addition is complete, the reaction is allowed to react at room temperature for 2 hours. The reaction is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 1) to give compound 152 (80 mg, 41%) as a white solid. LCMS: [M+H] + =440.1.

[0259] Step 5. Compound 153 Compound 152 (70 mg, 0.159 mmol, 1.0 eq), compound 6 (37.92 mg, 0.159 mmol, 1.0 eq), Pd2(dba)3 (29.15 mg, 0.032 mmol, 0.2 eq), X-Phos (15.16 mg, 0.032 mmol, 0.2 eq), potassium phosphate monohydrate (109.98 mg, 0.478 mmol, 3.0 eq) are added to 1,4-dioxane (5 mL). After the addition is complete, the atmosphere is replaced with nitrogen gas, and the reaction solution is reacted at 100 °C under nitrogen gas atmosphere for 3 hours. The reaction solution is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain compound 153 (90 mg, 89%) as a white solid. LCMS: [M+H] + =642.2.

[0260] Step 5. Compound A43 Compound 153 (80 mg, 0.125 mmol, 1.0 eq) and potassium carbonate (51.70 mg, 0.374 mmol, 3.0 eq) are added to a mixture of 1,4-dioxane (4 mL) and water (2 mL). After the addition is complete, the reaction is reacted at 110° C. for 1 h. The solvent is removed under reduced pressure, the residue is dissolved in DMF (4 mL) and filtered, and the filtrate is purified by prep-HPLC (mobile phase: 0.1% HCOOH / acetonitrile / water) to give compound A43 (18 mg, 26.6%) as a white solid. LCMS: [M+H] + =542.2.

[0261] 1 H NMR(400MHz,DMSO-d6)δ 12.84(br.s,1H),10.17(s,1H),8.51(d,J=3.6Hz,1H),7.78(d,J=10Hz,3H),6.59(s,1H),4.95-4.32(br.s,4H),3.89(s,3H),2.18(s,6H).

[0262] Examples 1-32. Preparation of Compound A44 [ka]

[0263] Step 1. Compound 155 Compound 154 (3.4 g, 19.8 mmol, 0.9 eq) and compound 148 (6.1 g, 20.8 mmol, 1.0 eq) are dissolved in 1,4-dioxane (20 mL), followed by the addition of potassium carbonate (8.6 g, 62.4 mmol, 3.0 eq) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (456 mg, 0.62 mmol, 0.03 eq). The mixture is purged with nitrogen gas and the reaction is stirred at 90° C. for 16 h under nitrogen gas atmosphere. The reaction is cooled to room temperature, passed through diatomaceous earth, and the filtrate is concentrated to give a residue. The residue is purified by silica gel column chromatography (PE / EA=4 / 1) to give compound 155 (3.3 g, 64%) as a yellow solid. LCMS: [M+H] + =258.1.

[0264] Step 2. Compound 156 Compound 155 (3.3 g, 12.8 mmol, 1.0 eq) is dissolved in isopropanol (30 mL), compound 16 (4.2 g, 25.6 mmol, 2.0 eq) and diisopropylethylamine (8.2 g, 64 mmol, 5.0 eq) are added, and the reaction mixture is stirred for 3 h at 45° C. After monitoring the reaction completion by LC-MS, the reaction mixture is concentrated to give a residue, which is purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give compound 156 (2.8 g, 56%) as a yellow solid. LCMS: [M+H] + =388.1.

[0265] Step 3. Compound 157 Compound 156 (2.8 g, 7.23 mmol, 1.0 eq) is dissolved in dichloromethane (20 mL) and then trifluoroacetic acid (120 mL) is added. The reaction is stirred at room temperature for 2 hours. The reaction is concentrated to give a residue, and after adjusting the pH of the residue to alkaline with saturated aqueous sodium carbonate solution, a large amount of solid precipitates, which is filtered, collected, and dried to give crude compound 157 (1.7 g) as a yellow solid. LCMS: [M+H] + =304.0.

[0266] Step 4. Compound 158 Compound 157 (1.7 g, 5.6 mmol, 1.0 eq) is added to tetrahydrofuran (25 mL), followed by DMAP (136 mg, 1.12 mmol, 0.2 eq) and Boc2O (977 mg, 4.48 mmol, 0.8 eq). The reaction is stirred at room temperature for 2 hours. The reaction is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give compound 158 (2.0 g, 88%) as a white solid. LCMS: [M+H] + =404.0.

[0267] Step 5. Compound 159 Compound 158 (510 mg, 1.26 mmol, 1.0 eq) was dissolved in dioxane (15 mL), then compound 6 (300 mg, 1.26 mmol, 1.0 eq), potassium phosphate monohydrate (870 mg, 3.78 mmol, 3.0 eq), X-Phos (119 mg, 0.25 mmol, 0.2 eq) and Pd2(dba)3 (164 mg, 0.18 mmol, 0.15 eq) were added, and the reaction was stirred at 90° C. for 3 hours under nitrogen gas after the addition was complete. Cooled to room temperature, the reaction was diluted with ethyl acetate, passed through diatomaceous earth and the filtrate was concentrated to give a residue, which was used directly in the next reaction as crude compound 159. LCMS: [M+H] + =606.2.

[0268] Step 6. Compound A44 The crude product, compound 159 (200 mg, 0.33 mmol, 1.0 eq) is dissolved in a mixture of dioxane (8 mL) and water (3 mL), and then potassium carbonate (182 mg, 1.32 mmol, 4.0 eq) is added. The reaction solution is stirred at 110° C. for 2 hours. The reaction solution is diluted with ethyl acetate, then washed with water and saturated saline solution in sequence, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue is separated and purified by pre-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A44 (104.5 mg, 62%) as a white solid. LCMS: [M+H] + =506.1.

[0269] 1 H NMR(400MHz,DMSO-d6)δ 12.62(s,1H),9.78(s,1H),8.39(d,J=4.0Hz,1H),7.79-7.78(m,3H),7.44(d,J= 8.4Hz, 2H), 6.57 (s, 1H), 4.61 (br.s, 4H), 3.88 (s, 3H), 2.37 (s, 3H), 2.16 (s, 3H).

[0270] Example 1-33. Preparation of Compound A45 [ka]

[0271] Step 1. Compound 161 Compound 142 (350 mg, 1.34 mmol, 1.0 eq), compound 160 (242 mg, 1.34 mmol, 1.0 eq) and diisopropylethylamine (519 mg, 4.02 mmol, 3.0 eq) are dissolved in isopropanol (10 mL). The reaction is stirred at 80° C. overnight. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue, crude compound 161, is used directly in the next reaction. LCMS: [M+H] + =406.1.

[0272] Step 2. Compound 162 The crude product of compound 161 obtained above is dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (10 mL) is added. The reaction solution is stirred at 25° C. for 30 minutes. The reaction solution is concentrated under vacuum, and water (15 mL) is added to the residue, and the pH is adjusted to 8 by adding saturated aqueous sodium carbonate solution, and the residue is extracted with ethyl acetate (20 mL×3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated residue is purified by flash silica gel column chromatography (PE / EA=3 / 7) to obtain compound 162 (200 mg, 46%, two steps) as a brown solid. LCMS: [M+H] + =322.1.

[0273] Step 3. Compound 163 Compound 162 (200 mg, 0.621 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10 mL), then 4-dimethylaminopyridine (7 mg, 0.062 mmol, 0.1 eq) and di-t-butyl dicarbonate (135 mg, 0.621 mmol, 1.0 eq) are added and the reaction is stirred for 1 h at 25° C. After completion of the reaction, the reaction is concentrated and the residue is purified by flash silica gel column chromatography (PE / EA=7 / 3) to give compound 163 (166 mg, 63%) as a white solid. LCMS: [M+H] + =422.1.

[0274] Step 4. Compound 164 Compound 163 (155 mg, 0.296 mmol, 1.0 eq), compound 6 (71 mg, 0.296 mmol, 1.0 eq) and potassium phosphate hydrate (204 mg, 0.888 mmol, 3.0 eq) are dissolved in dioxane (5 ml), and then X-phos (28 mg, 0.0296 mmol, 0.2 eq) and Pd2(dba)3 (23 mg, 0.0592 mmol, 0.1 eq) are added quickly. After replacing with nitrogen gas three times, the reaction is stirred at 100 °C under nitrogen gas atmosphere for 2 h. The reaction is concentrated and the residue is purified by flash silica gel column chromatography (PE / EA=2 / 3) to give compound 164 (162 mg, 87%) as a tan solid. LCMS: [M+H] + =624.2.

[0275] Step 5. Compound A45 Compound 164 (160 mg, 0.256 mmol, 1.0 eq) and potassium carbonate (213 mg, 1.536 mmol, 6.0 eq) are dissolved in a mixed solvent (dioxane / water=2 / 1, 6 mL). The reaction is stirred at 110° C. for 5 h. Cool to room temperature and concentrate the reaction. The residue is purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to give A45 (29.7 mg, 21%) as a yellow solid. LCMS: [M+H] + =524.2.

[0276] 1 H NMR(400MHz,DMSO-d6)δ 13.04(br.s,1H),9.81(s,1H),8.10(br.s,1H),8.02-7.85(m,2H),7.70(t,J=8.8Hz,1H),7.59(dd ,J=8.8,2.0Hz,1H),6.58(s,1H),4.62(br.s,4H),3.90(s,3H),2.38(d,J=2.8Hz,3H),2.18(s,3H).

[0277] Example 1-34. Preparation of Compound A46 [ka]

[0278] Step 1. Compound 166 Compound 129 (2.01 g, 7.3 mmol, 1.5 eq), compound 165 (1 g, 4.8 mmol, 1 eq), Pd(dppf)Cl2 (349 mg, 0.48 mmol, 0.1 eq), potassium carbonate (1.99 mg, 14.4 mmol, 3.0 eq) are added to a dioxane / water (20 mL / 5 mL) solution. After the addition is complete, the atmosphere is replaced with nitrogen gas, and the reaction mixture is reacted at 90° C. for 16 hours under nitrogen gas atmosphere. After monitoring the reaction completion by LC-MS, the reaction mixture is filtered through diatomaceous earth, and the solid is washed with ethyl acetate. The filtrate is directly evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain compound 166 (1.3 g, 97%) as a pale yellow solid. LCMS: [M+H] + =280.1.

[0279] Step 2. Compound 167 Compound 166 (600 mg, 2.15 mmol, 1.0 eq) and compound 16 (3.59 mg, 21.48 mmol, 10 eq) are dissolved in n-butanol (10 mL), followed by the addition of diisopropylethylamine (2.78 mg, 21.48 mmol, 10.0 eq). After the addition is complete, the reaction is reacted at 110° C. for 16 hours under nitrogen gas atmosphere. The reaction is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound 167 (280 mg, 32%) as a pale yellow solid. LCMS: [M+H] + =410.1.

[0280] Step 3. Compound 168 Compound 167 (278 mg, 0.682 mmol, 1.0 eq) is dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (3 mL) is added to the solution. After the addition is complete, the reaction is allowed to react at 25° C. for 2 hours. The reaction is concentrated by distillation under reduced pressure. The residue is dissolved in dichloromethane, adjusted to pH (8-9) with saturated sodium carbonate solution, and the aqueous phase is extracted with dichloromethane (10 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and dried under vacuum to give crude compound 168 (222 mg) as a pale yellow solid. LCMS: [M+H] + =326.0.

[0281] Step 4. Compound 169 The crude product, compound 168, is dissolved in tetrahydrofuran (4 mL) followed by the addition of di-t-butyl dicarbonate (118 mg, 0.541 mmol, 0.8 eq) and 4-dimethylaminopyridine (8 mg, 0.068 mmol, 0.1 eq). After the addition is complete, the reaction is allowed to react at room temperature for 2 h. After monitoring the reaction completion by LC-MS, the reaction is evaporated under reduced pressure and the residue is purified by flash column chromatography (silica gel, petroleum ether / ethyl acetate 0-10%) to give compound 169 (180 mg, 62%) as a yellow solid. LCMS: [M+H] + =426.1.

[0282] Step 5. Compound A46 Compound 169 (270 mg, 0.634 mmol, 1.0 eq) is dissolved in dioxane (10 mL), and then compound 79 (142 mg, 0.634 mmol, 1.0 eq), potassium phosphate monohydrate (511 mg, 2.22 mmol, 3.5 eq), X-Phos (60 mg, 0.127 mmol, 0.2 eq) and Pd2(dba)3 (58 mg, 0.063 mmol, 0.1 eq) are quickly added. After replacing the air with nitrogen gas three times, the reaction solution is stirred at 100 °C under nitrogen gas atmosphere for 4 hours. The reaction solution is cooled to room temperature and potassium carbonate (525 mg, 3.8 mmol, 6.0 eq) and water (2 mL) are added to the reaction solution. The reaction solution is subsequently stirred at 110 °C for 3 hours. The reaction is concentrated and the residue is purified by pre-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A46 (54.3 mg, 17%) as a yellow solid. LCMS: [M+H] + =512.1.

[0283] 1 H NMR(400MHz,DMSO-d6)δ 13.17(br.s,1H),9.83(br.s,1H),8.49(d,J=3.2Hz,1H),8.21(br.s,1H),8.09-7.98(m,3H),7.89- 7.86(m,1H),7.79-7.74(m,1H),7.59-7.54(m,1H),4.98(t,J=12.4Hz,2H),4.51(t,J=12.4Hz,2H).

[0284] Example 1-35. Preparation of Compound A47 [ka]

[0285] Step 1. Compound 170 Compound 165 (5.0 g, 24.04 mmol, 1.0 eq) and compound 148 (8.4 g, 28.85 mmol, 1.2 eq) are dissolved in a mixture of 1,4-dioxane (80 mL) and water (8 mL), then potassium carbonate (9.9 g, 72.12 mmol, 3.0 eq) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.63 g, 3.60 mmol, 0.15 eq) are added. The reaction is purged with nitrogen gas and stirred at 90° C. under nitrogen gas atmosphere for 8 hours. The reaction is monitored for completion by LCMS, cooled to room temperature, passed through diatomaceous earth, and the filtrate is concentrated to give a residue. The residue is purified by silica gel column chromatography (PE / EA=12 / 1) to give compound 170 (6.4 g, 90%) as a yellow solid. LCMS: [M+H] + =294.1.

[0286] Step 2. Compound 171 Compound 170 (6.0 g, 20.4 mmol, 1.0 eq) is added to dioxane (150 mL) followed by Boc2O (17.8 g, 81.6 mmol, 4.0 eq). The reaction is stirred at 110° C. for 16 h. The reaction is concentrated to give a residue, which is purified by silica gel column chromatography (petroleum ether / ethyl acetate=20 / 1) to give compound 171 (4.4 g, 54%) as a yellow solid. LCMS: [M+H] + =394.1.

[0287] Step 3. Compound 172 Compound 171 (330 mg, 0.83 mmol, 1.0 eq) is dissolved in tetrahydrofuran (5 mL), NaH (60% content in mineral oil, 79 mg, 3.32 mmol, 4.0 eq) is added, the mixture is stirred at 0° C. for 15 min, then compound 16 (413 mg, 2.49 mmol, 3.0 eq) is added, and the reaction mixture is stirred at room temperature for 2 h. After monitoring the reaction completion by LC-MS, the reaction mixture is adjusted to a weak acidic pH by adding aqueous ammonium chloride solution, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a residue, which is purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=80 / 20) to give compound 172 (400 mg, 90%) as a yellow solid. LCMS: [M+H] + =524.1.

[0288] Step 4. Compound 173 Compound 172 (400 mg, 0.76 mmol, 1.0 eq) is dissolved in dichloromethane (3 mL) and then trifluoroacetic acid (16 mL) is added. The reaction is stirred at 25° C. for 0.5 h. The reaction is concentrated to give a residue, and after adjusting the pH of the residue to alkaline with saturated aqueous sodium carbonate solution, a large amount of solid precipitates, which is filtered, collected, and dried to give crude compound 173 (227 mg) as a yellow solid. LCMS: [M+H] + =340.0.

[0289] Step 5. Compound 174 Compound 173 (227 mg, 0.67 mmol, 1.0 eq) is added to tetrahydrofuran (5 mL), followed by DMAP (15 mg, 0.13 mmol, 0.2 eq) and Boc2O (120 mg, 0.54 mmol, 0.8 eq). The reaction is stirred at room temperature for 2 h. The reaction is diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=81 / 19) to give compound 174 (200 mg, 67%) as a white solid. LCMS: [M+H] + =440.1.

[0290] Step 6. Compound 175 Compound 174 (200 mg, 0.45 mmol, 1.0 eq) is dissolved in dioxane (6 mL) and then compound 6 (128 mg, 0.54 mmol, 1.2 eq), potassium phosphate monohydrate (310 mg, 1.35 mmol, 3.0 eq), X-Phos (42 mg, 0.09 mmol, 0.2 eq) and Pd2(dba)3 (54 mg, 0.06 mmol, 0.15 eq) are added. The reaction is stirred at 90° C. for 2 h under nitrogen gas. Cooled to room temperature, the reaction is diluted with ethyl acetate, passed through diatomaceous earth and the filtrate is concentrated to give a residue which is purified by flash column silica gel chromatography (petroleum ether / ethyl acetate=62 / 38) to give compound 175 (120 mg, 40%) as a yellow solid. LCMS: [M+H] + =642.2.

[0291] Step 7. Compound A47 Compound 175 (120 mg, 0.18 mmol, 1.0 eq) is dissolved in a mixture of dioxane (4 mL) and water (4 mL), and then potassium carbonate (248 mg, 1.8 mmol, 10.0 eq) is added. The reaction solution is stirred at 110° C. for 1 h. The reaction solution is diluted with ethyl acetate, then washed with water and saturated saline solution in sequence, dried over anhydrous sodium sulfate, and concentrated. The residue is separated and purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A47 (43.2 mg, 44%) as a yellow solid. LCMS: [M+H] + =542.2.

[0292] 1 H NMR(400MHz,DMSO-d6)δ 12.84(br.s,1H),9.78(s,1H),8.45(d,J=3.6Hz,1H),7.61-7.58(m,2H),7.41-7 .36(m,1H),6.55(s,1H),4.59(br.s,4H),3.83(s,3H),2.32(s,3H),2.11(s,3H).

[0293] Example 1-36. Preparation of Compound A48 [ka]

[0294] Step 1. Compound 177 Compound 176 (2.50 g, 10.93 mmol, 1.0 eq) and 1,2-ethylenediamine (3.05 g, 26.24 mmol, 2.4 eq) are dissolved in ethyl ether (70 mL). The atmosphere is replaced with nitrogen gas, and the solution is cooled to -65°C under nitrogen gas protection, and then n-butyllithium in n-hexane (2.4 M, 15 mL, 36.0 mmol, 3.29 eq) is slowly added dropwise over about 30 minutes while maintaining the temperature between -50°C and -65°C. The reaction solution is then stirred at -60°C for 10 minutes under nitrogen gas protection, and then the reaction solution is slowly warmed to -15°C, and then stirred for 2 hours while maintaining the temperature at -10°C to -25°C. The reaction solution is cooled to -60°C under nitrogen gas protection, and then a solution of NFSI (11.72g, 37.17mmol, 3.4eq) in tetrahydrofuran (20mL) is slowly added dropwise while maintaining the temperature between -50°C and -65°C. After the addition is completed, the reaction solution is slowly warmed to 0°C under nitrogen gas protection and stirred at 0°C for 1 hour. After the reaction is completed, the reaction solution is quenched by adding a saturated aqueous ammonium chloride solution, and the aqueous phase is extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and then concentrated. The residue is purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound 177 (1.2g, 44%) as a pale yellow solid. LCMS: [M+H] + =247.1.

[0295] Step 2. Compound 178 Compound 177 (350 mg, 1.42 mmol, 1.0 eq) and compound 148 (456 mg, 1.56 mmol, 1.1 eq) are dissolved in a mixture of 1,4-dioxane (15 mL) and water (2 mL), and potassium carbonate (686 mg, 4.97 mmol, 3.5 eq) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (103 mg, 0.14 mmol, 0.1 eq) are added. The atmosphere is replaced with nitrogen gas, and the reaction solution is stirred at 100° C. under a nitrogen gas atmosphere for 16 hours. The reaction solution is cooled to room temperature and concentrated. The residue is purified by silica gel column chromatography (PE / EA=3 / 1) to obtain compound 178 (370 mg, 69%) as a red-brown solid. LCMS: [M+H] + =377.2.

[0296] Step 3. Compound 179 Compound 178 (370 mg, 0.98 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10 mL) under nitrogen gas protection, cooled to 0°C, and NaH (118 mg, 60% content in mineral oil, 2.95 mmol, 3.0 eq) is added while maintaining at 0°C. The reaction solution is stirred at 25°C for 15 minutes. Compound 148 (985 mg, 5.90 mmol, 6.0 eq) is then added to the reaction solution. The reaction solution is stirred at 25°C for 2 hours. The reaction solution is diluted with ethyl acetate, then washed with water and saturated saline in sequence, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound 179 (400 mg, 80%) as a red-brown solid. LCMS: [M+H] + =507.1.

[0297] Step 4. Compound 180 Compound 179 (390 mg, 0.77 mmol, 1.0 eq) is dissolved in dichloromethane (3 mL) and then trifluoroacetic acid (3 mL) is added. The reaction is stirred at 25° C. for 2 h. The reaction is concentrated and the residue is diluted with ethyl acetate. The pH is then adjusted to alkaline with saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and concentrated to give compound 180 (220 mg, 87%) as a yellow solid. LCMS: [M+H] + =323.1.

[0298] Step 5. Compound 181 Compound 180 (220 mg, 0.68 mmol, 1.0 eq) is added to tetrahydrofuran (8 mL), followed by DMAP (8 mg, 0.07 mmol, 0.1 eq) and Boc2O (149 mg, 0.68 mmol, 1.0 eq). The reaction is stirred at 25° C. for 16 h. The reaction is concentrated and the residue is purified by silica gel column chromatography (PE / EA=1 / 1) to give compound 181 (220 mg, 76%) as a yellow solid. LCMS: [M+H] + =423.1.

[0299] Step 6. Compound 182 Compound 181 (200 mg, 0.47 mmol, 1.0 eq) is dissolved in dioxane (10 mL), and then compound 6 (113 mg, 0.47 mmol, 1.0 eq), potassium phosphate monohydrate (327 mg, 1.42 mmol, 3.0 eq), X-Phos (45 mg, 0.09 mmol, 0.2 eq) and Pd2(dba)3 (43 mg, 0.05 mmol, 0.1 eq) are added in sequence. The atmosphere is replaced with nitrogen gas, and the reaction solution is stirred at 90 °C under nitrogen gas atmosphere for 5 hours. The reaction solution is cooled to room temperature and concentrated. The residue is purified by silica gel column chromatography (PE / EA=3 / 2) to give compound 182 (140 mg, 47%) as a red-brown solid. LCMS: [M+H] + =625.2.

[0300] Step 7. Compound A48 Compound 182 (140 mg, 0.22 mmol, 1.0 eq) is dissolved in a mixture of dioxane (5 mL) and water (2 mL), then potassium carbonate (155 mg, 1.12 mmol, 5.0 eq) is added. The reaction is stirred at 110° C. for 3 h. The reaction is cooled to room temperature and concentrated. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A48 (13.3 mg, 11%) as a yellow solid. LCMS: [M+H] + =525.1.

[0301] 1 H NMR(400MHz,DMSO-d6)δ 12.90-12.80(m,1H),9.85(s,1H),8.63(d,J=10.8Hz,1H),8.44(d,J=3.2 Hz,1H),8.36-7.90(m,1H),7.67(d,J=12.0Hz,1H),6.54(s,1H),4.59(br s,4H),3.80(s,3H),2.54(s,3H),2.08(s,3H).

[0302] Example 1-37. Preparation of Compound A49 [ka]

[0303] Step 1. Compound 183 Compound 129 (2.01 g, 7.3 mmol, 1.5 eq), compound 165 (1 g, 4.8 mmol, 1 eq), Pd(dppf)Cl2 (349 mg, 0.48 mmol, 0.1 eq), potassium carbonate (1.99 mg, 14.4 mmol, 3.0 eq) are added to a dioxane / water (20 mL / 5 mL) solution. After the addition is complete, the atmosphere is replaced with nitrogen gas, and the reaction mixture is reacted at 90° C. under nitrogen gas atmosphere for 16 hours. After monitoring the reaction completion by LC-MS, the reaction mixture is filtered through diatomaceous earth, and the solid is washed with ethyl acetate. The filtrate is directly evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain compound 183 (1.3 g, 97%) as a pale yellow solid. LCMS: [M+H] + =280.1.

[0304] Step 2. Compound 184 Compound 183 (600 mg, 2.15 mmol, 1.0 eq) and compound 16 (3.59 mg, 21.48 mmol, 10 eq) are dissolved in n-butanol (10 mL), followed by the addition of diisopropylethylamine (2.78 mg, 21.48 mmol, 10.0 eq). After the addition is complete, the reaction is reacted at 110° C. for 16 hours under nitrogen gas atmosphere. The reaction is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give compound 184 (280 mg, 32%) as a pale yellow solid. LCMS: [M+H] + =410.1.

[0305] Step 3. Compound 185 Compound 184 (278 mg, 0.682 mmol, 1.0 eq) is dissolved in dichloromethane (4 mL), and then trifluoroacetic acid (3 mL) is added to the solution. After the addition is complete, the reaction is allowed to react at room temperature for 2 hours. The reaction is concentrated by distillation under reduced pressure. The residue is dissolved in dichloromethane, adjusted to pH (8-9) with saturated sodium carbonate solution, and the aqueous phase is extracted with dichloromethane (10 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and dried under vacuum to give the crude product compound 185 (222 mg) as a pale yellow solid. LCMS: [M+H] + =326.0.

[0306] Step 4. Compound 186 The crude product, compound 185, is dissolved in tetrahydrofuran (4 mL) followed by the addition of di-t-butyl dicarbonate (118 mg, 0.541 mmol, 0.8 eq) and 4-dimethylaminopyridine (8 mg, 0.068 mmol, 0.1 eq). After the addition is complete, the reaction is allowed to react at room temperature for 2 h. After monitoring the reaction completion by LC-MS, the reaction is evaporated under reduced pressure and the residue is purified by high speed column equipment (silica gel, petroleum ether / ethyl acetate 0-10%) to give compound 186 (180 mg, 62%) as a yellow solid. LCMS: [M+H] + =426.1.

[0307] Step 4. Compound 187 Compound 186 (200 mg, 0.47 mmol, 1.0 eq) is dissolved in dioxane (8 mL) and then compound 6 (112 mg, 0.47 mmol, 1.0 eq), potassium phosphate monohydrate (324 mg, 1.41 mmol, 3.0 eq), X-Phos (45 mg, 0.09 mmol, 0.2 eq) and Pd2(dba)3 (46 mg, 0.05 mmol, 0.1 eq) are added sequentially. The atmosphere is flushed with nitrogen and the reaction is stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction is cooled to room temperature and concentrated. The crude product 187 is used directly in the next reaction. LCMS: [M+H] + =628.2.

[0308] Step 5. Compound A49 The crude product, compound 187, is dissolved in a mixture of dioxane (5 mL) and water (2 mL), and then potassium carbonate (195 mg, 1.41 mmol, 3.0 eq) is added. The reaction is stirred at 110° C. for 3 h. The reaction is cooled to room temperature and concentrated. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A49 (41.5 mg, yield for two steps: 16%) as a white solid. LCMS: [M+H] + =528.1.

[0309] 1 H NMR(400MHz,DMSO-d6)δ 13.15(br s,1H),9.73(s,1H),8.45(d,J=3.2Hz,1H),8.28-7.98(m,2H),7.77(dd,J=11.6,7.2Hz,1H),7.61(dd,J=12.0,6.8Hz,1H),6.55(s,1H),4.60(br s,4H),3.82(s,3H),2.11(s,3H).

[0310] Example 1-38. Preparation of Compound A50 [ka] Step 1. Compound 188 Compound 131 (400 mg, 1.43 mmol, 1.0 eq), compound 24 (383 mg, 2.01 mmol, 1.4 eq) and diisopropylethylamine (740 mg, 5.73 mmol, 4.0 eq) are dissolved in isopropanol (8 mL). The reaction is stirred at 80° C. for 72 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is purified by flash silica gel column chromatography (PE / EA=1 / 1) to give compound 188 (443 mg, 71%) as a yellow solid. LCMS: [M+H] + =434.1.

[0311] Step 2. Compound 189 Compound 188 (440 mg, 1.01 mmol, 1.0 eq) is dissolved in dichloromethane (5 mL) and then trifluoroacetic acid (10 mL) is added. The reaction is stirred at 25° C. for 30 min. The reaction is concentrated under vacuum, and then water (15 mL) is added to the residue, the pH is adjusted to 8 with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (20 mL×3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 189 (350 mg, 98%) as a yellow solid. LCMS: [M+H] + =350.1.

[0312] Step 3. Compound 190 Compound 189 (350 mg, 1.00 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10 mL), then 4-dimethylaminopyridine (12 mg, 0.100 mmol, 0.1 eq) and di-t-butyl dicarbonate (218 mg, 1.00 mmol, 1.0 eq) are added. The reaction is stirred at 25° C. for 2 h. After completion of the reaction, the reaction is concentrated. The residue is purified by flash silica gel column chromatography (PE / EA=3 / 2) to give compound 190 (315 mg, 69%) as a yellow solid. LCMS: [M+H] + =450.1.

[0313] Step 4. Compound 191 Compound 190 (300 mg, 0.689 mmol, 1.0 eq), compound 6 (164 mg, 0.689 mmol, 1.0 eq) and potassium phosphate monohydrate (476 mg, 2.07 mmol, 3.0 eq) are dissolved in dioxane (5 ml), then X-phos (66 mg, 0.138 mmol, 0.2 eq) and Pd2(dba)3 (63 mg, 0.069 mmol, 0.1 eq) are quickly added. After replacing with nitrogen gas three times, the reaction solution is stirred at 100 °C under nitrogen gas atmosphere for 2 h. The reaction solution is concentrated and the residue is purified by flash silica gel column chromatography (PE / EA = 1 / 1) to give compound 191 (200 mg, 44%) as a brown solid. LCMS: [M+H] + =652.2.

[0314] Step 5. Compound A50 Compound 191 (200 mg, 0.307 mmol, 1.0 eq) and potassium carbonate (127 mg, 0.921 mmol, 3.0 eq) are dissolved in a mixed solvent (dioxane / water=2 / 1, 12 mL). The reaction is stirred at 110° C. for 3 h. The reaction is cooled to room temperature and concentrated. The residue is purified by pre-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give A50 (16.4 mg, 9%) as a yellow solid. LCMS: [M+H] + =552.2.

[0315] 1 H NMR(400MHz,DMSO-d6)δ 13.19(br.s,1H),9.60(s,1H),8.20-7.82(m,2H),7.78-7.69(m,2H),6.60( s,1H),5.08(s,2H),4.91(s,2H),4.63(br.s,4H),3.92(s,3H),2.20(s,3H).

[0316] Examples 1-39. Preparation of Compound A51 [ka]

[0317] Step 1. Compound 194 Compound 192 (4.6 g, 24.21 mmol, 1.0 eq) and compound 193 (8.4 g, 29.05 mmol, 1.2 eq) are dissolved in a mixture of 1,4-dioxane (40 mL) and water (8 mL), and then potassium carbonate (10.0 g, 72.63 mmol, 3.0 eq) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (526 mg, 0.72 mmol, 0.03 eq) are added. The atmosphere is purged with nitrogen gas, and the reaction mixture is stirred at 90° C. under a nitrogen atmosphere for 16 hours. The reaction mixture is cooled to room temperature, passed through diatomaceous earth, and the filtrate is concentrated to obtain a residue. The residue is purified by silica gel column chromatography (PE / EA=4 / 1) to obtain compound 194 (5.69 g, 85%) as a yellow solid. LCMS: [M+H] + =276.1.

[0318] Step 2. Compound 195 Compound 194 (1.6 g, 5.81 mmol, 1.0 eq) is dissolved in isopropanol (20 mL), compound 16 (1.46 mg, 8.72 mmol, 1.5 eq) and diisopropylethylamine (3.74 g, 29.05 mmol, 5.0 eq) are added, and the reaction mixture is stirred for 14 h at 90° C. After monitoring the reaction completion by LC-MS, the reaction mixture is concentrated to give a residue, which is purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=80 / 20) to give compound 195 (2.27 g, 96%) as a yellow solid. LCMS: [M+H] + =406.1.

[0319] Step 3. Compound 196 Compound 195 (2.2 g, 5.43 mmol, 1.0 eq) is dissolved in dichloromethane (18 mL) and then trifluoroacetic acid (30 mL) is added. The reaction is stirred at room temperature for 2 hours. The reaction is concentrated to give a residue, and after adjusting the pH of the residue to alkaline with saturated aqueous sodium carbonate solution, a large amount of solid precipitates, which is filtered, collected, and dried to give crude compound 196 (1.34 g) as a yellow solid. LCMS: [M+H] + =322.2.

[0320] Step 4. Compound 197 Compound 196 (1.34 g, 4.2 mmol, 1.0 eq) is added to tetrahydrofuran (10 mL), followed by successive addition of DMAP (102 mg, 0.84 mmol, 0.2 eq) and Boc2O (916 mg, 4.2 mmol, 1.0 eq). The reaction is stirred at room temperature for 2 h. The reaction is diluted with ethyl acetate, then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give compound 197 (1.4 g, 79%) as a yellow solid. LCMS: [M+H] + =422.2.

[0321] Step 5. Compound 198 Compound 197 (500 mg, 1.18 mmol, 1.0 eq) was dissolved in dioxane (12 mL), followed by the addition of compound 6 (338 mg, 1.42 mmol, 1.2 eq), potassium phosphate monohydrate (819 mg, 3.56 mmol, 3.0 eq), X-Phos (109 mg, 0.23 mmol, 0.2 eq) and Pd2(dba)3 (155 mg, 0.17 mmol, 0.15 eq), and after the addition was complete, the reaction was stirred at 90° C. for 3 hours under a nitrogen atmosphere. Cooled to room temperature, the reaction was diluted with ethyl acetate, passed through diatomaceous earth, and the filtrate was concentrated to give a residue, and the crude product 198 was used directly in the next reaction. LCMS: [M+H] + =624.5.

[0322] Step 6. Compound A51 The crude product, compound 198 (150 mg, 0.24 mmol, 1.0 eq) is dissolved in a mixture of dioxane (6 mL) and water (2 mL), and then potassium carbonate (331 mg, 2.4 mmol, 10.0 eq) is added. The reaction solution is stirred at 110° C. for 2 hours. The reaction solution is diluted with ethyl acetate, then washed with water and saturated saline solution in succession, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give a crude product, which is purified by slurrying with a mixture of petroleum ether / ethyl acetate=4 / 1 to give compound A51 (100.5 mg, 80%) as a yellow solid. LCMS: [M+H] + =524.1.

[0323] 1 H NMR(400MHz,DMSO-d6)δ 12.73(s,1H),9.66(s,1H),8.40(d,J=3.6Hz,1H),7.75(br.s,1H),7.51(t,J=8.4Hz,1H),7.39(d,J=12 .0Hz,1H),7.32(d,J=8.0Hz,1H),6.54(s,1H),4.59(br.s,4H),3.81(s,3H),2.41(s,3H),2.09(s,3H).

[0324] Examples 1-40. Preparation of Compound A52 [ka]

[0325] Step 1. Compound 200 Compound 199 (500 mg, 1.82 mmol, 1.0 eq) is dissolved in dioxane (10 mL) and then Boc2O (1.98 g, 9.1 mmol, 5.0 eq) is added. The reaction is stirred at 110° C. for 5 h. The reaction is cooled to room temperature and concentrated. The residue is purified by silica gel column chromatography (PE / EA=10 / 1) to give compound 200 (650 mg, 95%) as a yellow solid. LCMS: [M+H] + =376.2.

[0326] Step 2. Compound 201 Compound 200 (650 mg, 1.58 mmol, 1.0 eq) is dissolved in tetrahydrofuran (10 mL), the solution is stirred in an ice-water bath under N2 protection for 5 min, and NaH (277 mg, 60% content in mineral oil, 6.93 mmol, 4.0 eq) is added. The mixture is further stirred in an ice-water bath for 1 h, and compound 3 (1.45 g, 8.7 mmol, 5.0 eq) is added. The reaction is stirred at room temperature for 2 h. The reaction is poured into water and extracted with ethyl acetate. The ethyl acetate phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated. The residue is purified by silica gel column chromatography (PE / EA=4 / 1) to give compound 201 (850 mg, 97%) as a yellow solid. LCMS: [M+H] + =506.1.

[0327] Step 3. Compound 202 Compound 201 (850 mg, 1.68 mmol, 1.0 eq) is dissolved in dichloromethane (5 mL) and then trifluoroacetic acid (5 mL) is added. The reaction is stirred at room temperature for 2 h. The reaction is concentrated, the residue is diluted with dichloromethane, and the pH is adjusted to alkaline with saturated aqueous sodium carbonate. The resulting reaction mixture is filtered and the solid is collected. The solid is lyophilized to give compound 202 (440 mg, 81%) as a yellow solid. LCMS: [M+H] + =321.9.

[0328] Step 4. Compound 203 Compound 202 (440 mg, 1.37 mmol, 1.0 eq) is added to tetrahydrofuran (10 mL), followed by DMAP (8 mg, 0.07 mmol, 0.05 eq) and Boc2O (299 mg, 1.37 mmol, 1.0 eq). The reaction is stirred at room temperature for 2 h. The reaction is concentrated and the residue is purified by silica gel column chromatography (PE / EA=5 / 1) to give compound 203 (550 mg, 95%) as a white solid. LCMS: [M+H] + =422.1.

[0329] Step 5. Compound 204 Compound 203 (500 mg, 1.18 mmol, 1.0 eq) was dissolved in dioxane (8 mL) and then compound 7 (282 mg, 1.18 mmol, 1.0 eq), potassium phosphate (750 mg, 3.54 mmol, 3.0 eq), X-Phos (115 mg, 0.24 mmol, 0.2 eq) and Pd2(dba)3 (108 mg, 0.12 mmol, 0.1 eq) were added sequentially. The atmosphere was replaced with nitrogen gas and the reaction was stirred at 100 °C under nitrogen gas atmosphere for 4 h. The reaction was cooled to room temperature, filtered and the filtrate was concentrated to give crude product 204, which was used directly in the next reaction. LCMS: [M+H] + =624.2.

[0330] Step 6. Compound A52 The crude product, compound 204, is dissolved in a mixture of dioxane (5 mL) and water (2 mL), and then potassium carbonate (489 mg, 3.54 mmol, 3.0 eq) is added. The reaction is stirred at 110° C. for 3 hours. The reaction is cooled to room temperature, the reaction is diluted with ethyl acetate, washed with water, and the aqueous phase is extracted with ethyl acetate. The ethyl acetate phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (PE / EA=3 / 1) to obtain the crude product. The crude product is dissolved in ethyl acetate (30 mL) and stirred for 14 hours, filtered, and the filter cake is collected. The filter cake is dissolved in acetonitrile / water (150 mL / 350 mL) and lyophilized to obtain compound A52 (237.5 mg, yield for two steps: 38%) as a yellow solid. LCMS: [M+H] + =524.2.

[0331] 1 H NMR(400MHz,DMSO-d6)δ 13.09(s,1H),9.41(s,1H),8.38(d,J=3.6Hz,1H),8.14(br.s,1H),7.96(br.s,1H),7.66(d,J=8.8H z,1H),7.35(d,J=12.4Hz,1H),6.54(s,1H),4.59(br.s,4H),3.81(s,3H),2.23(s,3H),2.09(s,3H).

[0332] Examples 1-41. Preparation of Compound A53 [ka]

[0333] Step 1. Compound 206 Compound 205 (500 mg, 1.69 mmol, 1.0 eq) is dissolved in dioxane (10 mL), then compound 16 (565 mg, 3.38 mmol, 2.0 eq), cesium carbonate (1.9 g, 3.38 mmol, 2.0 eq), Xant-Phos (196 mg, 0.338 mmol, 0.2 eq) and Pd2(dba)3 (155 mg, 0.169 mmol, 0.1 eq) are quickly added. After replacing the air with nitrogen gas three times, the reaction solution is stirred at 80 °C under nitrogen gas atmosphere for 16 h. After cooling the reaction solution to room temperature, it is concentrated and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 206 (600 mg, 83%) as a yellow solid. LCMS: [M+H] + =426.0.

[0334] Step 2. Compound 207 Compound 206 (300 mg, 0.66 mmol, 1.0 eq) is dissolved in dichloromethane (5 mL) and then TFA (5 mL) is added. The reaction is stirred at room temperature for 2 h. The reaction is concentrated, the residue is dissolved in ethyl acetate, the pH value of the resulting solution is adjusted to 7 with aqueous sodium carbonate, and the aqueous phase is extracted with ethyl acetate (50 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 207 (230 mg, 95%) as a yellow solid. LCMS: [M+H] + =342.1.

[0335] Step 3. Compound 208 Compound 207 (230 mg, 0.67 mmol, 1.0 eq) is dissolved in tetrahydrofuran (5 mL), then Boc2O (147 mg, 0.67 mmol, 1.0 eq) and DMAP (4 mg.0.034 mmol, 0.05 eq) are added. The reaction is stirred at room temperature for 2 hours. The reaction is diluted with ethyl acetate, then washed successively with water and saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give compound 208 (280 mg, 95%) as a yellow solid. LCMS: [M+H] + =442.0.

[0336] Step 4. Compound 209 Compound 208 (200 mg, 0.45 mmol, 1.0 eq) and compound 6 (107 mg, 0.45 mmol, 1.0 eq) are dissolved in dioxane (15 mL), followed by potassium phosphate monohydrate (364 mg, 1.6 mmol, 3.5 eq), X-Phos (43 mg, 0.09 mmol, 0.2 eq) and Pd2(dba)3 (41 mg, 0.045 mmol, 0.1 eq). The atmosphere is flushed with nitrogen and the reaction is stirred under nitrogen atmosphere at 100 °C for 5 h. The reaction is cooled to room temperature and concentrated. The crude product 209 is used directly in the next reaction. LCMS: [M+H] + =644.1.

[0337] Step 5. Compound A53 The crude product, compound 209, is dissolved in a mixture of dioxane (15 mL) and water (3 mL), and then potassium carbonate (187 mg, 1.4 mmol, 3.0 eq) is added. The reaction is stirred at 110° C. for 2 h. The reaction is cooled to room temperature and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 5) to give the crude product. The crude product is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A53 (10.1 mg, yield for two steps: 4%) as a yellow solid. LCMS: [M+H]+ =544.1.

[0338] 1 H NMR(400MHz,DMSO-d6)δ 13.19(br.s,1H),9.59(s,1H),8.44(d,J=3.2Hz,1H),8.27(br.s,1H),8.03(br.s,1H),7.99(d ,J=8.0Hz,1H),7.72(d,J=12.0Hz,1H),6.54(s,1H),4.59(br.s,4H),3.81(s,3H),2.10(s,3H).

[0339] Examples 1-42. Preparation of Compound A54 [ka]

[0340] Step 1. Compound 211 Compound 186 (200 mg, 0.47 mmol, 1.0 eq) was dissolved in dioxane (8 mL) and then compound 210 (124 mg, 0.47 mmol, 1.0 eq), potassium phosphate monohydrate (379 mg, 1.64 mmol, 3.5 eq), X-Phos (45 mg, 0.094 mmol, 0.2 eq) and Pd2(dba)3 (43 mg, 0.047 mmol, 0.1 eq) were added sequentially. The atmosphere was flushed with nitrogen and the reaction was stirred at 90 °C under nitrogen atmosphere for 5 h. The reaction was cooled to room temperature and concentrated. The crude product 211 was used directly in the next reaction. LCMS: [M+H] + =654.0.

[0341] Step 2. Compound A54 The crude product, compound 211, is dissolved in a mixture of dioxane (5 mL) and water (1 mL), and then potassium carbonate (195 mg, 1.4 mmol, 3.0 eq) is added. The reaction is stirred at 110° C. for 1 h. The reaction is cooled to room temperature and concentrated. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A54 (56.2 mg, yield for two steps: 22%) as a yellow solid. LCMS: [M+H] + =554.0.

[0342] 1 H NMR(400MHz,DMSO-d6)δ 13.16(br.s,1H),9.72(s,1H),8.44(d,J=3.6Hz,1H),8.22(br.s,1H),7.99(br.s,1H),7.79-7.72(m,1H),7.65- 7.57(m,1H),6.31(s,1H),4.58(br.s,4H),3.80(s,3H),1.87-1.71(m,1H),0.95-0.77(m,2H),0.72-0.62(m,2H).

[0343] Example 1-43. Preparation of Compound A55 [ka]

[0344] Step 1. Compound 213 Compound 186 (200 mg, 0.47 mmol, 1.0 eq) was dissolved in dioxane (8 mL) and then compound 212 (156 mg, 0.47 mmol, 1.0 eq), potassium phosphate monohydrate (299 mg, 1.41 mmol, 3.0 eq), X-Phos (48 mg, 0.1 mmol, 0.2 eq) and Pd2(dba)3 (46 mg, 0.05 mmol, 0.1 eq) were added sequentially. The atmosphere was flushed with nitrogen and the reaction was stirred at 90 °C under nitrogen atmosphere for 5 h. The reaction was cooled to room temperature and concentrated. The crude product 213 was used directly in the next reaction. LCMS: [M+H] + =656.2.

[0345] Step 2. Compound A55 The crude product, compound 213, is dissolved in a mixture of dioxane (5 mL) and water (2 mL), and then potassium carbonate (195 mg, 1.41 mmol, 3.0 eq) is added. The reaction is stirred at 110° C. for 2 h. The reaction is cooled to room temperature and concentrated. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A55 (104.4 mg, yield for two steps: 40%) as a white solid. LCMS: [M+H] + =556.2.

[0346] 1 H NMR(400MHz,DMSO-d6)δ 13.18(br.s,1H),9.73(s,1H),8.47(d,J=3.2Hz,1H),8.24(br.s,1H),8.04(br.s,1H),7.78(dd,J=11.6,6.8Hz,1H) ,7.66(dd,J=12.0,6.8Hz,1H),6.59(s,1H),4.63(br.s,4H),3.84(s,3H),3.00-2.88(m,1H),1.21(d,J=6.8Hz,6H).

[0347] Example 1-44. Preparation of Compound A56 [ka]

[0348] Step 1. Compound 215 Compound 186 (1.0 g, 2.35 mmol, 1.0 eq), compound 214 (384 mg, 2.35 mmol, 1.0 eq) and potassium phosphate (1.49 g, 7.1 mmol, 3.0 eq) are added to dioxane (15 mL), followed by the rapid addition of X-phos (42 mg, 0.24 mmol, 0.1 eq) and Pd2(dba)3 (114 mg, 0.24 mmol, 0.1 eq). After flushing with nitrogen gas three times, the reaction mixture is stirred at 100 °C under nitrogen gas atmosphere for 3 h. The reaction is cooled to room temperature and concentrated. The residue is purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 215 (900 mg, 66%) as a tan solid. LCMS: [M+H] + =581.2.

[0349] Step 2. Compound 216 Compound 215 (900 mg, 1.55 mmol, 1.0 eq) is dissolved in a mixed solvent (tetrahydrofuran / methanol / water = 1 / 1 / 2, 20 mL), and then lithium hydroxide (372 mg, 15.5 mmol, 10.0 eq) is added. The reaction is reacted at 40 °C for 30 min. After the reaction is complete, the pH of the reaction is adjusted to 3 with saturated aqueous citric acid and extracted with ethyl acetate (100 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 216 (520 mg, 74%) as a yellow solid. LCMS: [M+H] + =453.1.

[0350] Step 3. Compound A56 Compound 216 (150 mg, 0.33 mmol, 1.0 eq), compound 218 (44 mg, 0.40 mmol, 1.2 eq) and HATU (152 mg, 0.40 mmol, 1.2 eq) are dissolved in anhydrous DMF (10 mL) and then diisopropylethylamine (170 mg, 1.32 mmol, 4.0 eq) is added at 0 °C. The reaction is stirred at room temperature for 20 min. The reaction is diluted with ethyl acetate, washed with water and the aqueous phase is extracted with ethyl acetate (20 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give A56 (63.8 mg, 38%) as a yellow solid. LCMS: [M+H] + =508.1.

[0351] 1 H NMR(400MHz,DMSO-d6)δ 13.19(br.s,1H),9.70(s,1H),8.44(d,J=3.6Hz,1H),8.14(br.s,2H),7.76(dd,J=11.6,6.8Hz,1H),7.61(dd,J=12.0,6.8Hz,1 H),6.41(s,1H),5.73(br.s,1H),4.47(br.s,2H),4.18(br.s,1H),4.00(br.s,1H),3.81(s,3H),3.71(br.s,1H),2.10(s,3H).

[0352] Examples 1-45. Preparation of Compound A57 [ka]

[0353] Step 1. Compound A57 Compound 216 (150 mg, 0.33 mmol, 1.0 eq), compound 219 (49 mg, 0.40 mmol, 1.2 eq) and HATU (152 mg, 0.40 mmol, 1.2 eq) are dissolved in anhydrous DMF (10 mL) and then diisopropylethylamine (170 mg, 1.32 mmol, 4.0 eq) is added at 0 °C. The reaction is stirred at 25 °C for 20 min. The reaction is diluted with ethyl acetate, washed with water and the aqueous phase is extracted with ethyl acetate (20 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give A57 (50.1 mg, 29%) as a yellow solid. LCMS: [M+H] + =522.1.

[0354] 1 H NMR(400MHz,DMSO-d6)δ 9.70(s,1H),8.44(d,J=3.6Hz,1H),8.12(br.s,2H),7.76(dd,J=11.6,7.2Hz,1H),7.61(dd,J=12.0, 6.8Hz,1H),6.45(s,1H),4.44(br.s,1H),4.27-4.15(m,4H),3.81(s,3H),3.22(s,3H),2.10(s,3H).

[0355] Example 1-46. Preparation of Compound A58 [ka]

[0356] Step 1. Compound 221 Compound 220 (350 mg, 1.06 mmol, 1.0 eq) is dissolved in tetrahydrofuran (5 mL), then cooled to 0° C. under nitrogen gas protection, and NaH (255 mg, 60% content in mineral oil, 6.38 mmol, 6.0 eq) is added at 0° C. The reaction solution is warmed to room temperature and stirred at room temperature for 15 minutes. Compound 2 (1.77 g, 10.63 mmol, 10.0 eq) is added to the reaction solution. The reaction solution is stirred at room temperature for 48 hours. The reaction solution is diluted with ethyl acetate, then washed with water and saturated saline in sequence, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography (PE / EA=3 / 1) to obtain compound 221 (300 mg, 61%) as a yellow solid. LCMS: [M+H] + =460.0.

[0357] Step 2. Compound 222 Compound 221 (300 mg, 0.65 mmol, 1.0 eq) is dissolved in dichloromethane (5 mL) and then trifluoroacetic acid (5 mL) is added. The reaction is stirred at 25° C. for 2 h. The reaction is concentrated, the residue is diluted with ethyl acetate, and the pH is adjusted to alkaline with saturated aqueous sodium carbonate, followed by extraction with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and concentrated to give compound 222 (230 mg, 94%) as a red-brown solid. LCMS: [M+H] + =376.1.

[0358] Step 3. Compound 223 Compound 222 (230 mg, 0.61 mmol, 1.0 eq) is added to tetrahydrofuran (5 mL), followed by DMAP (7 mg, 0.06 mmol, 0.1 eq) and Boc2O (134 mg, 0.61 mmol, 1.0 eq). The reaction is stirred at 25° C. for 1 h. The reaction is concentrated and the residue is purified by silica gel column chromatography (PE / EA=3 / 1) to give compound 223 (210 mg, 72%) as a white solid. LCMS: [M+H] + =475.2.

[0359] Step 4. Compound 224 Compound 223 (200 mg, 0.42 mmol, 1.0 eq) was dissolved in dioxane (8 mL), followed by the addition of compound 6 (100 mg, 0.42 mmol, 1.0 eq), potassium phosphate monohydrate (290 mg, 1.26 mmol, 3.0 eq), X-Phos (40 mg, 0.08 mmol, 0.2 eq) and Pd2(dba)3 (38 mg, 0.04 mmol, 0.1 eq). The atmosphere was replaced with nitrogen gas and the reaction mixture was stirred under nitrogen gas atmosphere at 100 °C for 5 h. After completion of the reaction, the crude product 224 was used directly in the next reaction. LCMS: [M+H] + =678.0.

[0360] Step 5. Compound A58 To the reaction mixture of 224 from the previous step, add water (2.5 mL) followed by potassium carbonate (580 mg, 4.2 mmol, 10.0 eq). Stir the reaction mixture at 110 °C for 2 h. Cool the reaction mixture to room temperature and concentrate. Pre-purify the residue by silica gel column chromatography (PE / EA=1 / 1) to obtain crude product (110 mg). Slurry the crude product with a mixture of (PE / EA=1 / 1, 10 mL) for 16 h. Filter the mixture to obtain compound A58 (62 mg, 26%) as a yellow solid. LCMS: [M+H] + =578.1.

[0361] 1 H NMR(400MHz,DMSO-d6)δ 13.25(br.s,1H),9.69(s,1H),8.42(d,J=3.6Hz,1H),8.36(br.s,1H),8.14(d,J=7.6Hz,1H),8 .10(br.s,1H),7.67(d,J=11.6Hz,1H),6.53(s,1H),4.58(br.s,4H),3.78(s,3H),2.07(s,3H).

[0362] Examples 1-47. Preparation of Compound A59 [ka]

[0363] Step 1. Compound A59 Compound A42 (250 mg, 0.508 mmol, 1.0 eq) and compound 225 (210 mg, 0.814 mmol, 1.6 eq) are dissolved in DMF (6 mL), then cesium carbonate (496 mg, 1.524 mmol, 3.0 eq) is added, and the reaction solution is stirred under nitrogen gas atmosphere at 25 ° C for 24 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture is diluted with water and extracted with ethyl acetate, the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1: 2) to obtain the crude product of compound, and the crude product is purified by pre-HPLC (mobile phase: 0.1% NH4HCO3 / water / acetonitrile) to obtain compound A59 (50.4 mg, 14%) as a white solid. LCMS: [M+H] + =714.2.

[0364] 1 H NMR(400MHz,DMSO-d6)δ 9.80(s,1H),8.40(d,J=3.6Hz,1H),8.31(s,1H),8.06(s,1H),7.82(d,J=8.8Hz,2H),7.61(d,J=8.8H z,2H),6.58(s,1H),5.84(d,J=10.8Hz,2H),4.62(br.s,4H),3.89(s,3H),2.17(s,3H),1.39(s,18H).

[0365] Examples 1-48. Preparation of Compound A60 [ka]

[0366] Step 1. Compound A60 Compound A49 (300 mg, 0.568 mmol, 1.0 eq) and compound 225 (235 mg, 0.909 mmol, 1.6 eq) are dissolved in DMF (7 mL), then cesium carbonate (554 mg, 1.704 mmol, 3.0 eq) is added, and the reaction mixture is stirred under nitrogen gas atmosphere at 25 ° C for 16 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture is diluted with water and extracted with ethyl acetate, the organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and the residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1: 2) to obtain the crude product of compound, and the crude product is purified by pre-HPLC (mobile phase: 0.1% NH4HCO3 / water / acetonitrile) to obtain compound A60 (13.0 mg, 3%) as a white solid. LCMS: [M+H] + =750.2.

[0367] 1 H NMR(400MHz,DMSO-d6)δ 9.75(s,1H),8.46(d,J=3.6Hz,1H),8.37(s,1H),8.17(s,1H),7.82(dd,J=11.6,7.2Hz,1H),7.67(dd,J=11. 6,6.4Hz,1H),6.55(s,1H),5.89(d,J=11.0Hz,2H),4.59(br.s,4H),3.82(s,3H),2.11(s,3H),1.39(s,18H).

[0368] Examples 1-49. Preparation of Compound A61 and Compound A62 [ka]

[0369] Step 1. Compound 227 Compound 226 (5.0 g, 22.916 mmol, 1.0 eq) is dissolved in 30% sodium hydroxide solution (25 mL), purged with nitrogen gas, and the reaction is stirred under nitrogen gas atmosphere at 100° C. for 30 min. The reaction is cooled to room temperature, neutralized with concentrated hydrochloric acid to about pH=2, and the mixture is extracted three times with ethyl ether, and the combined organic phase is dried over anhydrous sodium sulfate and concentrated to give compound 227 (3.8 g, 93%) as a yellow oil.

[0370] Step 2. Compound 229 Compound 227 (2.0 g, 11.236 mmol, 1.0 eq), sodium bicarbonate (3.8 g, 44.944 mmol, 1.0 eq) and tetrabutylammonium bisulfate (381 mg, 1.124 mmol, 0.1 eq) are dissolved in dichloromethane / water (30 mL / 30 mL), the reaction mixture is cooled to 0° C. and stirred for 10 min, then compound 228 (2.78 g, 16.854 mmol, 1.5 eq) is added. The reaction is stirred at 25° C. for 16 h. The reaction is washed with saturated brine, the separated organic phase is dried over anhydrous sodium sulfate and concentrated to give compound 229 (900 mg, 36%) as a pale yellow oil.

[0371] Step 3. Compound 230 Compound A42 (900 mg, 01.765 mmol, 1.0 eq) is dissolved in DMF (10 mL), and then compound 229 (800 mg, 3.530 mmol, 2.0 eq) and cesium carbonate (1.7 g, 5.295 mmol, 3.0 eq) are added to the reaction solution. The reaction solution is stirred at 25° C. for 4 hours. The reaction solution is diluted with a large amount of ethyl acetate, then washed with water and saturated brine in succession, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography (DCM / MeOH=15 / 1) to give compound 230 (1.2 g, 100%, containing a small amount of DMF) as a brown oil. LCMS: [M+H] + =700.2.

[0372] Step 4. Compound A61 Compound 230 (1.2 g, 1.714 mmol, 1.0 eq) is dissolved in DCM (60 mL), followed by the addition of morpholine (1.49 g, 17.143 mmol, 10.0 eq) and Pd(PPh3)4 (396 mg, 0.343 mmol, 0.2 eq) in sequence. The atmosphere is replaced with nitrogen gas, and the reaction is stirred at 25° C. under nitrogen gas atmosphere for 30 min. After completion of the reaction, the reaction is concentrated, and the residue is purified by prep-HPLC (mobile phase: 0.1% aqueous ammonia / acetonitrile / water) to give compound A61 (210 mg, 20%) as a yellow solid. LCMS: [M+H] + =620.5.

[0373] 1 H NMR(400MHz,DMSO-d6)δ 8.43(d,J=3.6Hz,1H),8.26(s,1H),8.00(dd,J=14.0,2.0Hz,1H),7.89(s,1H),7.68(t,J=8.8Hz,1H),7 .61(dd,J=8.8,2.0Hz,1H),6.57(s,1H),5.59(d,J=9.5Hz,2H),4.62(s,4H),3.90(s,3H),2.19(s,3H).

[0374] Step 5. Compound A62 Compound A61 (31.0 mg, 0.05 mmol, 1.0 eq) was added to distilled water (4 mL), followed by sodium bicarbonate (8.4 mg, 0.10 mmol, 2.0 eq). The reaction was stirred at 25° C. for 15 min. After the reaction became completely clear, the reaction was directly lyophilized to give compound A62 (31 mg, 94%) as a yellow solid. LCMS: [M+H] + =620.1.

[0375] 1H NMR(400MHz,CD3OD-d4)δ 8.33(s,1H),8.24(d,J=4.0Hz,1H),7.98(dd,J=13.6,2.0Hz,1H),7.90(d,J=1.0Hz,1H),7.64(t,J=8.6Hz,1 H),7.51(dd,J=8.6,2.0Hz,1H),6.50(s,1H),5.81(d,J=8.8Hz,2H),4.60(s,4H),3.99(s,3H),2.25(s,3H). 31 P NMR (162MHz, CD3OD-d4) δ 1.18 ppm.

[0376] Examples 1-50. Preparation of Compound A64 [ka]

[0377] Step 1. Compound 232 Compound 231 (2.0 g, 9.21 mmol, 1.0 eq) is dissolved in DCM / H2O (80 mL, 1 / 1). The reaction is cooled to 0°C. NaHCO3 (3.09 g, 36.84 mmol, 4.0 eq) and Bu4NHSO4 (313 mg, 0.921 mmol, 0.1 eq) are added to the reaction. The reaction is stirred at 0°C for 10 min. At 0°C, compound 2 (3.04 g, 18.42 mmol, 2.0 eq) is added dropwise to the reaction and the temperature is controlled at 0-5°C. The reaction is stirred at room temperature for 18 h. After the completion of the reaction is detected by LCMS, it is quenched with ice water and the reaction is extracted with DCM (50 mL x 3). The combined organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (DCM / EA=1 / 1) to give compound 232 (2.4 g, 97%) as a colorless oil. LCMS: [M+Na] + =288.2.

[0378] Step 2. Compound 233 Compound A42 (1.0 g, 1.96 mmol, 1.0 eq) and compound 232 (1.04 g, 3.92 mmol, 2.0 eq) are dissolved in anhydrous DMF (10 mL) and Cs2CO3 (1.28 g, 3.92 mmol, 2.0 eq) is added. The reaction is stirred at 25 °C for 16 h. The reaction mixture is filtered and the solid is washed with ethyl acetate. The filtrate is diluted with ethyl acetate (30 mL), water (30 mL) is added to the reaction, and the aqueous phase is extracted with ethyl acetate (30 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by flash silica gel column chromatography (DCM / EA = 3 / 1) to give compound 233 (1.4 g, 96%) as a yellow solid. LCMS: [M+H] + =739.2.

[0379] Step 3. Compound A64 Compound 233 (500 mg, 0.676 mmol, 1.0 eq) is dissolved in EA (15 mL) and HCl (2.0 M in EA, 15 mL) is added. The reaction is stirred at room temperature for 5 min, during which a solid precipitates. The reaction mixture is quickly diluted with petroleum ether (1 L), filtered, and the solid is washed with petroleum ether. The residual solid is purified by pre-HPLC (mobile phase: 0.1% trifluoroacetic acid / acetonitrile / water) to give A64 (111.3 mg, 24%) as a yellow solid. LCMS: [M+H] + =639.2.

[0380] 1H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),8.47(d,J=3.6Hz,1H),8.39(br.s,3H),8.35(d,J=2.0Hz,1H),8.12(s,1H) ),8.05(dd,J=14.4,2.0Hz,1H),7.76(t,J=8.8Hz,1H),7.64(dd,J=8.4,2.0Hz,1H),6.59 (s,1H),6.36(d,J=10.8Hz,1H),6.25(d,J=10.8Hz,1H),4.62(br.s,4H),4.03(s,1H),3. 91(s,3H),2.19(s,3H),2.15-2.06(m,1H),0.91(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H).

[0381] Example 1-51. Preparation of Compound A65 [ka]

[0382] Step 1. Compound 236 Compound 234 (5.0 g, 38.12 mmol, 1.0 eq) and compound 235 (8.0 g, 38.12 mmol, 1.0 eq) are dissolved in dichloromethane (50 mL), the solution is cooled to -70°C, and then a solution of triethylamine (4.2 g, 41.93 mmol, 1.1 eq) in dichloromethane (30 mL) is added dropwise. After addition is complete, the reaction is allowed to react at -70°C for 2 hours. After monitoring the reaction completion by LC-MS, the reaction is allowed to warm to room temperature and the crude product 236 is used directly in the next reaction. LCMS: [M+H] + =306.0.

[0383] Step 2. Compound 237 To the above reaction mixture containing compound 236, add Na2CO3 (12.1 g, 114.3 mmol, 3.0 eq) in water (30 mL). After the addition is complete, the reaction mixture is allowed to react at 25° C. for 16 h. After monitoring the reaction completion by LC-MS, the reaction mixture is diluted with dichloromethane, separated, and the aqueous phase is extracted with dichloromethane (100 mL×3). The dichloromethane phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 237 (3.6 g, 28%). LCMS: [M+H] + =288.1.

[0384] Step 3. Compound 238 The crude product, compound 237 (3.6 g, 12.53 mmol, 1.0 eq) is dissolved in dichloromethane / water (70 mL / 70 mL), sodium bicarbonate (4.2 g, 50.13 mmol, 4.0 eq) and Bu4NHSO4 (426 mg, 1.25 mmol, 0.1 eq) are added, the reaction is cooled to 0° C., and compound 5 (3.1 g, 18.80 mmol, 1.5 eq) is added. The reaction is stirred at 25° C. for 16 h. After monitoring the reaction completion by LC-MS, the reaction is diluted with dichloromethane, separated, and the aqueous phase is extracted with dichloromethane (100 mL×3). The dichloromethane phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (dichloromethane / ethyl acetate=15 / 1) to give compound 238 (1.3 g, 31%) as a colorless oil. LCMS: [M+H] + =336.0.

[0385] Step 4. Compound A65 Compound A42 (400 mg, 0.79 mmol, 1.0 eq) is dissolved in DMF (10 mL) and then compound 238 (527 mg, 1.57 mmol, 2.0 eq) is added. The reaction is stirred at 25° C. for 16 h. After completion of the reaction, the reaction is diluted with ethyl acetate, separated, and the aqueous phase is extracted with ethyl acetate (100 mL×3). The ethyl acetate phases are combined and concentrated under reduced pressure to remove the solvent. The residue is purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A65 (61.5 mg, 10%) as a yellow solid. LCMS: [M+H] + =809.2.

[0386] 1 H NMR(400MHz,DMSO-d6)δ 10.01(s,1H),8.46(d,J=4.0Hz,1H),8.31(dd,J=12.4,1.6Hz,1H),8.10-7.99(m,2H),7 .74(t,J=8.8Hz,1H),7.63(dd,J=8.4,1.6Hz,1H),7.35(t,J=8.0Hz,1H),7.22-7.12(m, 3H),6.59(s,1H),6.24-6.12(m,1H),6.10-5.88(m,2H),4.91-4.80(m,1H),4.62(br.s, 4H), 3.91 (s, 3H), 3.85-3.71 (m, 1H), 2.19 (s, 3H), 1.26-1.16 (m, 3H), 1.17-1.11 (m, 6H).

[0387] Examples 1-52. Preparation of Compound A68 [ka]

[0388] Step 1. Compound 240 Compound 239 (2.0 g, 8.1 mmol, 1.0 eq) is dissolved in a mixture of dichloromethane (30 mL) and water (30 mL). Tetrabutylammonium bisulfate (275 mg, 0.8 mmol, 0.1 eq) is added at 0° C., followed by sodium bicarbonate (2.72 g, 32.4 mmol, 4.0 eq). The reaction is stirred at 0° C. for 20 min. Compound 228 (2.67 g, 16.2 mmol, 2.0 eq) is slowly added to the reaction. After the addition is complete, the reaction is reacted at 25° C. for 16 h. The reaction is diluted with dichloromethane (50 mL), washed with water, and the organic phase is dried over anhydrous sodium sulfate and then concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=4:1) to give compound 240 (2.1 g, 88%) as a white solid. LCMS: [M+H] + =296.1.

[0389] Step 2. Compound 241 Compound A42 (400 mg, 0.79 mmol, 1.0 eq) and Cs2CO3 (767 mg, 2.36 mmol, 3.0 eq) are dissolved in DMF (7 mL), and then compound 240 (697 mg, 2.36 mmol, 3.0 eq) is added. The reaction is stirred at 25 °C for 16 h. After monitoring the reaction completion by LC-MS, the reaction is diluted with ethyl acetate (50 mL), then washed successively with water (20 mL x 3) and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 241 (550 mg, 91%) as a yellow solid. LCMS: [M+H] + =769.1.

[0390] Step 3. Compound A68 Compound 241 (300 mg, 0.39 mmol, 1.0 eq) is dissolved in ethyl acetate (5 mL), and then hydrochloric acid (4.0 Min EA) solution (5 mL) is added. The reaction is stirred at 25° C. for 5 min. A large amount of yellow solid precipitates in the reaction, and 30 mL of petroleum ether is added to the reaction to dilute the reaction and precipitate more yellow solid. The mixture is filtered and the yellow solid is washed with petroleum ether (10 mL×3). The yellow solid is separated and purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A68 (43.8 mg, 17%) as a yellow solid. LCMS: [M+H] + =669.2.

[0391] 1 H NMR(400MHz,DMSO-d6)δ 10.01(s,1H),8.46(d,J=3.6Hz,1H),8.28(d,J=2.0Hz,1H),8.12-7.98(m,2H),7.75(t,J=8.8Hz,1H),7.63(dd,J=8.4,2.0Hz,1 H),6.59(s,1H),6.19-6.11(m,2H),4.62(s,4H),3.91(s,3H),3.89-3.82(m,1H),3.54(s,3H),2.71-2.64(m,2H),2.19(s,3H).

[0392] Example 1-53. Preparation of Compound A69 [ka]

[0393] Step 1. Compound 243 Compound 242 (150 mg, 0.648 mmol, 1.0 eq) is dissolved in DCM / H2O (4 mL, 1 / 1). The reaction is cooled to 0°C. NaHCO3 (218 mg, 2.592 mmol, 4.0 eq) and Bu4NHSO4 (22 mg, 0.065 mmol, 0.1 eq) are added to the reaction. The reaction is stirred at 0°C for 10 min. At 0°C, compound 228 (214 mg, 1.296 mmol, 2.0 eq) is added dropwise to the reaction and the temperature is controlled at 0-5°C. The reaction is stirred at 25°C for 18 h. After the completion of the reaction is detected by LCMS, the reaction is quenched with ice water and the aqueous phase is extracted with dichloromethane (20 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting colorless oily residue, crude product 243 (180 mg, 99%), is used directly in the next reaction. LCMS: [M+Na] + =302.1.

[0394] Step 2. Compound 244 Compound A42 (150 mg, 0.294 mmol, 1.0 eq) and compound 243 (165 mg, 0.588 mmol, 2.0 eq) are dissolved in anhydrous DMF (4 mL) and Cs2CO3 (192 mg, 0.588 mmol, 2.0 eq) is added. The reaction is stirred at 25 °C for 16 h. The reaction mixture is filtered and the solid is washed with ethyl acetate. The filtrate is washed with water (20 mL) and the aqueous phase is extracted with ethyl acetate (20 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash silica gel column chromatography (DCM / MeOH = 93 / 7) to give compound 244 (210 mg, 94%) as a yellow solid. LCMS: [M+H] + =753.2.

[0395] Step 3. Compound A69 Compound 244 (200 mg, 0.265 mmol, 1.0 eq) is dissolved in ethyl acetate (3 mL) and HCl (2.0 M in ethyl acetate, 3 mL) is added. The reaction is stirred at 25 °C for 5 min and a solid precipitates. Petroleum ether (100 mL) is added quickly to the reaction mixture to precipitate more solid. The reaction mixture is filtered and the solid is washed with copious amounts of petroleum ether. The solid is purified by pre-HPLC (mobile phase: 0.1% trifluoroacetic acid / acetonitrile / water) to give A69 (73.2 mg, 42%) as a yellow solid. LCMS: [M+H] + =653.3.

[0396] 1 H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),8.47(d,J=4.0Hz,1H),8.39-8.29(m,4H),8.13(s,1H),8.05(dd,J=14.0,2.0Hz,1H),7.75(t,J=8.8Hz,1H),7.63(dd,J=8. 8,2.0Hz,1H),6.59(s,1H),6.36(d,J=10.8Hz,1H),6.26(d,J=10.8Hz,1H),4.62(br.s,4H),3.96-3.86(m,4H),2.19(s,3H),0.93(s,9H)

[0397] Example 1-54. Preparation of Compound A70 [ka]

[0398] Step 1. Compound 246 Compound 245 (2.0 g, 9.8 mmol, 1.0 eq) is dissolved in DCM / H2O (70 mL, 1 / 1). The reaction is cooled to 0°C. NaHCO3 (3.3 g, 39.4 mmol, 4.0 eq) and Bu4NHSO4 (334 mg, 0.98 mmol, 0.1 eq) are added to the reaction. The reaction is stirred at 0°C for 10 min. At 0°C, compound 228 (3.2 g, 19.7 mmol, 2.0 eq) is added dropwise to the reaction and the temperature is controlled at 0-5°C. The reaction is stirred at 25°C for 18 h. After the completion of the reaction is detected by LCMS, the reaction is quenched with ice water and extracted with dichloromethane (60 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 246 (2.0 g, 81%) as a white solid. LCMS: [M+H] + =252.1.

[0399] Step 2. Compound 247 Compound A42 (304 mg, 0.597 mmol, 1.0 eq) and compound 246 (600 mg, 2.4 mmol, 4.0 eq) are dissolved in DMF (10 mL) and Cs2CO3 (583 mg, 1.8 mmol, 3.0 eq) is added. The reaction is stirred at 25 °C for 16 h. The reaction is diluted with ethyl acetate (100 mL), then washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by flash silica gel column chromatography (DCM / MeOH=12 / 1) to give compound 247 (400 mg, 92%) as a yellow solid. LCMS: [M+H] + =725.3.

[0400] Step 3. Compound A70 Compound 247 (260 mg, 0.36 mmol, 1.0 eq) is dissolved in ethyl acetate (20 mL) and HCl (2.0 M in ethyl acetate, 3 mL) is added. The reaction is stirred at 25 °C for 5 min and a solid precipitates. Petroleum ether (50 mL) is added to the reaction mixture to precipitate more solid. The reaction mixture is filtered and the solid is washed with petroleum ether. The solid is purified by pre-HPLC (mobile phase: 0.1% trifluoroacetic acid / acetonitrile / water) to give A70 (95.8 mg, 35%) as a yellow solid. LCMS: [M+H] + =625.2.

[0401] 1 H NMR(400MHz,DMSO-d6)δ 10.04(s,1H),8.54(s,3H),8.47(d,J=4.0Hz,1H),8.36(d,J=2.0Hz,1H),8.12(s,1H),8.07(dd,J=14.4,2.0Hz,1H),7.79 -7.74(m,1H),7.64(dd,J=8.8,2.0Hz,1H),6.59(s,1H),6.28(s,2H),4.62(s,4H),3.91(s,3H),2.19(s,3H),1.44(s,6H).

[0402] Example 1-55. Preparation of Compound A71 [ka]

[0403] Step 1. Compound 249 Compound 248 (2.0 g, 11.42 mmol, 1.0 eq) is dissolved in DCM / H2O (45 mL / 45 mL). The reaction is cooled to 0° C. under N2 protection, Bu4NHSO4 (387.63 mg, 1.14 mmol, 0.1 eq) and NaHCO3 (5.75 g, 68.50 mmol, 6.0 eq) are added to the reaction, and the reaction is stirred at 0° C. for 5 min. Compound 228 (5.65 g, 34.25 mmol, 3.0 eq) is slowly added to the reaction and stirred at 25° C. for 16 h. After monitoring the completion of the reaction by LCMS, the reaction is quenched with ice water and extracted with ethyl acetate. The ethyl acetate phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 249 (2.3 g, 90%) as a colorless oily solid. 1 H NMR (400MHz, CDCl3) δ 5.75 (s, 2H), 5.09 (br.s, 2H), 3.94-4.09 (m, 2H), 1.44 (s, 9H).

[0404] Step 2. Compound 250 Compound A42 (300 mg, 0.58 mmol, 1.0 eq) and Cs2CO3 (575.57 mg, 1.77 mmol, 3.0 eq) are dissolved in DMF (5 mL), the reaction mixture is stirred at room temperature for 5 min, then compound 249 (329.24 mg, 1.47 mmol, 2.5 eq) is added to the reaction mixture, and the reaction mixture is stirred at 25 °C for 1 h. After monitoring the completion of the reaction by LCMS, the reaction mixture is diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH=7 / 93) to give compound 250 (350 mg, 85%) as a pale yellow solid. LCMS: [M+H] + =697.3.

[0405] Step 3. Compound A71 Compound 250 (200 mg, 0.23 mmol, 1.0 eq) is dissolved in ethyl acetate (3 mL), ethyl acetate hydrochloride (3 mL, 4 M) is added to the reaction mixture, and the reaction mixture is stirred at 25° C. for 5 min. After monitoring the completion of the reaction by LCMS, the reaction is filtered to obtain a solid, and the solid is washed with petroleum ether. The obtained solid is purified by prep-HPLC (mobile phase: 0.1% CF3COOH / acetonitrile / water) to obtain compound A71 (96 mg, 52%) as a yellow solid. LCMS: [M+H] + =597.2.

[0406] 1 H NMR(400MHz,CDCl3)δ 10.49(s,1H),8.94(d,J=3.6Hz,1H),8.81(s,1H),8.71(s,3H),8.60-8.48(m,2H),8.22(d,J=8.8Hz ,1H),8.10(d,J=8.8Hz,1H),7.06(s,1H),6.73(s,2H),5.08(s,4H),4.37-4.26(m,5H),2.65(s,3H).

[0407] Example 1-56. Preparation of Compound A72 [ka]

[0408] Step 1. Compound 252 Compound 251 (1.0 g, 3.76 mmol, 1.0 eq) is dissolved in a mixture of dichloromethane (15 mL) and water (15 mL), and tetrabutylammonium bisulfate (1.29 g, 34.05 mmol, 3.0 eq) and sodium bicarbonate (1.89 g, 22.56 mmol, 6.0 eq) are added to the reaction solution at 0 ° C. The reaction solution is stirred at 0 ° C for 20 minutes. Compound 2 (1.24 g, 7.52 mmol, 2.0 eq) is slowly added to the reaction solution, and then the reaction solution is transferred to room temperature and reacted at room temperature for 18 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution is diluted with dichloromethane (25 mL), then washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1-15: 1) to give compound 252 (960 mg, 81%). LCMS: [M-Boc+H] + =214.0.

[0409] Step 2. Compound 253 Compound A42 (330 mg, 0.64 mmol, 1.0 eq) and compound 252 (502 mg, 1.6 mmol, 2.5 eq) are dissolved in DMF (14 mL), and then Cs2CO3 (625 mg, 1.92 mmol, 3.0 eq) is added. The reaction is stirred at 25 °C under nitrogen gas atmosphere for 2 h. After monitoring the reaction completion by LC-MS, the reaction is diluted with ethyl acetate (30 mL), then washed successively with water (20 mL × 3) and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 95 / 5) to give compound 253 (490 mg, 97%). LCMS: [M+H] + =787.2.

[0410] Step 3. Compound A72 Compound 253 (280 mg, 0.35 mmol, 1.0 eq) is dissolved in ethyl acetate (8 mL), and then a solution of hydrochloric acid in ethyl acetate (4 M, 2 mL) is added. The reaction is stirred at 25° C. for 5 min. A large amount of yellow solid precipitates in the reaction solution, which is filtered and washed with petroleum ether (30 mL×3). The resulting yellow solid is separated and purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound A72 (38.7 mg, 15%) as a yellow solid. LCMS: [M+H] + =687.2.

[0411] 1 H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),8.50-8.39(m,4H),8.24(d,J=2.0Hz,1H),8.14(s,1H),8.07 (dd,J=14.4,2.0Hz,1H),7.78(t,J=8.8Hz,1H),7.66-7.63(m,1H),7.22-7 .20(m,3H),7.08(dd,J=3.6,2.0Hz,2H),6.59(s,1H),6.24(q,J=10.8Hz,2 H),4.61(s,4H),4.44(s,1H),3.91(s,3H),3.12-3.00(m,2H),2.19(s,3H).

[0412] Example 1-57. Preparation of Compound A73 [ka]

[0413] Step 1. Compound 254 Compound A49 (500 mg, 0.948 mmol, 1.0 eq) is dissolved in DMF (30 mL), and then compound 2 (537 mg, 2.370 mmol, 2.0 eq) and cesium carbonate (772 mg, 2.370 mmol, 2.5 eq) are added to the reaction solution. The reaction solution is stirred at 25° C. for 16 hours. The reaction solution is diluted with a large amount of ethyl acetate, then washed with water and saturated brine in succession, dried over anhydrous sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography (DCM / MeOH=19 / 1) to give compound 254 (497 mg, 73%) as a yellow solid. LCMS: [M+H] + =718.2.

[0414] Step 2. Compound 255 Compound 254 (300 mg, 0.418 mmol, 1.0 eq) is dissolved in DCM (5 mL), followed by the addition of morpholine (109 mg, 1.254 mmol, 3.0 eq) and Pd(PPh3)4 (48 mg, 0.042 mmol, 0.1 eq) in sequence. The atmosphere is replaced with nitrogen gas, and the reaction is stirred at 25° C. under nitrogen gas atmosphere for 30 min. After completion of the reaction, the reaction is concentrated, and the residue is purified by prep-HPLC (mobile phase: 0.1% aqueous ammonia / acetonitrile / water) to give compound 255 (145 mg, 54%) as a white solid. LCMS: [M+H] + =638.2.

[0415] 1 H NMR(400MHz,DMSO-d6)δ 8.42(d,J=3.2Hz,1H),8.35(d,J=2.0Hz,1H),7.97(s,1H),7.72(dd,J=11.6,6.8Hz,1H),7.64(dd, J=12.0,6.8Hz,1H),6.54(s,1H),5.59(d,J=9.2Hz,2H),4.59(br.s,4H),3.82(s,3H),2.11(s,3H).

[0416] Step 3. Compound A73 Compound 255 (50.6 mg, 0.079 mmol, 1.0 eq) was added to distilled water (20 mL), followed by sodium bicarbonate (13.4 mg, 0.158 mmol, 2.0 eq). The reaction was stirred at 25° C. for 20 min. After the reaction became completely clear, the reaction was directly lyophilized to give compound A73 (51.6 mg, 95%) as a white solid. LCMS: [M+H] + =638.2.

[0417] 1 H NMR(400MHz,MeOD-d4)δ 8.46(s,1H),8.27(d,J=3.6Hz,1H),7.95-7.85(m,2H),7.58(dd,J=11.6,6.8Hz,1 H),6.48(s,1H),5.80(d,J=8.0Hz,2H),4.59(br.s,4H),3.95(s,3H),2.21(s,3H). 31 P NMR(162MHz,CD3OD-d4)δ 4.19 ppm.

[0418] Example 2-1. In vitro kinase activity evaluation Kinase detection kit: Kinase IC using HTRF kinEASE STK S2 kit (Cat#62ST2PEC, Cisbio) 50 The kinases ROCK1 (Cat#PV3691) and ROCK2 (Cat#PV3759) are all purchased from Invitrogen. Prepare the working solutions required for detection using the corresponding reagents as described in the kinase detection kit instructions.

[0419] [Table A]

[0420] 1X Kinase Buffer 1 mL of 1X kinase buffer contains 200 μL of 5X enzyme buffer, 5 μL of 1M MgCl2 (Cat. M8266, Sigma), 1 μL of 1M DTT (Cat. D5545, Sigma), 794 μL of ddH2O.

[0421] 2.5X Substrate and ATP Working Solution Specific concentrations of STK-biotin substrate and ATP are shown in Table A. Dilute STK-biotin substrate and ATP to 2.5x reaction concentrations using 1× kinase buffer.

[0422] 5X ROCK1 / ROCK2 Kinase Working Solution The concentrations of ROCK1 / ROCK2 are shown in Table A. Prepare 5X ROCK1 / ROCK2 kinase working solution using 1X kinase buffer.

[0423] 2X Streptavidin-XL665 and STK Antibody-Cryptate Working Solution For the concentrations of Streptavidin-XL665 and STK Antibody-Cryptate in the reaction, see Table A. 5 minutes prior to the end of the kinase reaction, prepare 2X Streptavidin-XL665 and STK Antibody-Cryptate working solutions using the detection buffer provided in the kit.

[0424] Prepare 100 μM compound stock solutions using 1X kinase buffer containing 2.5% DMSO, and dilute the stock solutions 4-fold using the above DMSO-containing kinase buffer to obtain nine test compound solutions with different concentrations. In addition to the wells for the test compounds, set up positive control wells (containing all reagents except compounds) and negative control wells (containing all reagents except compounds and kinase). Add 4 μL of test compound solution to all reaction wells except the control wells, and add 4 μL of 2.5% DMSO solution to the control wells. Add 4 μL of the previously prepared substrate and ATP working solution to all wells and mix thoroughly and evenly. Then add 2 μL / well of 5X ROCK1 / ROCK2 kinase working solution (containing 2.5 ng of ROCK1 / ROCK2 kinase) to all reaction wells except the negative control wells, and supplement the volume of the negative control wells with 2 μL of 1X kinase buffer. Mix thoroughly and evenly, and incubate at room temperature for 2 hours after sealing with plastic film. Start preparing the detection solution 5 minutes before the end of the kinase reaction. After the kinase reaction was completed, 10 μL of the prepared streptavidin-XL665 and STK antibody-cryptate working solution was added to all reaction wells, the plate was sealed and mixed evenly, then incubated at room temperature for 1 h, and finally the fluorescent signal (excitation wavelength is 320 nm, emission wavelength is 665 nm and 615 nm) was detected using a SpectraMax i3x Multi-Mode Reader (Molecular Devices) instrument.

[0425] The inhibition rate of each well is calculated through the fluorescence intensity value of each well. Inhibition rate=(ER 溶媒 -ER 化合物 ) / (ER 溶媒 -ER 空白 )×100% ER (emission ratio, emission ratio) = fluorescence intensity at 665 nm / fluorescence intensity at 615 nm, ER 化合物 is the ER of the test compound well, and ER 溶媒 is the ER of the vehicle (positive) control wells, and ER 空白 is the ER of blank (negative) control wells. The software GraphPad Prism 6.0 was used to plot the curves, and the half inhibitory concentration (IC) of each test compound was calculated by fitting with Prism 6.0. 50 ) is obtained.

[0426] According to the above test methods, the inhibitory activities of the compounds of the present invention against ROCK2 and ROCK1 are as shown in the following table. [Table 1-1] [Table 1-2]

[0427] From the above results, it is found that all the compounds of the present invention have good inhibitory activity against ROCK2 kinase, and furthermore, the compounds of the present invention have good selectivity for the inhibition of ROCK2 and ROCK1.

[0428] Example 3-1: Pharmacokinetic studies 1) Study objective: To obtain the in vivo pharmacokinetic characteristics of the compounds of the present invention in male SD rats. 2) Experimental content For each compound, six healthy male SD rats (weight range 200-250 g) were divided into two groups, three in each group, group 1 was administered a single intravenous dose (see Table 2 for doses) and group 2 was administered a single intragastric dose (see Table 2 for doses, fasted overnight before administration). Blood was collected via jugular vein or cardiac puncture at 0.083 (group 1 only), 0.25, 0.5, 1, 2, 4, 6 (group 2 only), 8 and 24 hours after administration, respectively, and at least 0.2 mL of whole blood was collected from each sample into EDTA-K2 anticoagulant tubes, mixed homogeneously and placed on wet ice after sample collection, plasma was centrifuged (6800 g, 6 min, 2-8 °C) within 1 hour, and plasma samples were stored in an ultra-low temperature refrigerator before analysis.

[0429] Experimental results: Based on the blood drug concentration data detected by LC-MS / MS, the pharmacokinetic parameters after administration were calculated using the non-compartmental model of WinNonlinR 7.0 software (Pharsight, USA), and are shown in the table below. [Table 2]

[0430] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, 【Chemistry 1】 Where: X is 【Chemistry 2】 is selected from the group consisting of R ２１ , R ２２ are each independently H, C １－６ Alkyl group, C ３－１０ cycloalkyl groups, Y is none, C(=O), O, S(=O) ｉ , C.R. ２３ R ２４ , NR; R is H, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl groups, saturated or partially unsaturated C ３－１０ a cyclic hydrocarbon group, a saturated or unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ an aryl group, a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１２ aralkyl groups, wherein up to two ring members of the cyclic hydrocarbon and heterocyclic groups are C(=O); R ２３ , R ２４ are each independently H, a halogen, or C １－６ Alkyl group, C ３－１０ selected from the group consisting of cyclic hydrocarbon groups; Ring A is a saturated or partially unsaturated C ３－１０ a cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); Ring C is a saturated or partially unsaturated C ３－１０ a cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); Ring D is absent or is a saturated or partially unsaturated C ３－１０ a cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); Ring E is 【Chemistry 3】 is selected from the group consisting of Ring G is a saturated or partially unsaturated C ３－１０ a cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); R １ is H, halogen, -CN, -NH ２ , C １－６ Alkyl group, C ６－１０ an aryl group, a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; an N-methyltetrahydropyrrolyl group, an N-methylpiperidinyl group, an acetyl group, -C(=O)-(C １－６ Alkylene) ｎ -CF ３ , -(C １－６ Alkylene) ｎ -CF ３ , -C(=O)-(C １－６ Alkylene) ｎ -CN, -C(=O)-(saturated or partially unsaturated C ３－１０ Cyclic hydrocarbon group) ｎ , —NH—C(═O)—(saturated or partially unsaturated C ３－１０ -C(═O)-(a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S), -C(═O)-C １－６ alkylene-(a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S), -C(=O)-(a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S), -C(=O)-C １－６ Alkylene-NH-(C １－６ alkyl), -C(=O)-C １－６ Alkylene-N(C １－６ Alkyl) ２ , N-methylpiperazine substituted acetyl group, -S(=O) ２ R １ａ , -P(=O)R １ａ R １ｂ , 【Chemistry 4】 is selected from the group consisting of R １ａ and R １ｂ are each independently H, a halogen atom, an amino group, a cyano group, a nitro group, or C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０ a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ an aryl group, a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１２ Aralkyl group, -C(=O)R ５ , -OC(=O)R ５ , -C(=O)OR ５ , -OR ５ , -SR ５ , -S(=O)R ５ , -S(=O) ２ R ５ , -S(=O) ２ N.R. ５ R ６ , -NR ５ R ６ , -C(=O)NR ５ R ６ , -NR ５ -C(=O)R ６ , -NR ５ -C(=O)OR ６ , -NR ５ -S(=O) ２ -R ６ , -NR ５ -C(=O)-NR ５ R ６ , -C １－６ Alkylene -NR ５ R ６ , -C １－６ Alkylene-OR ５ , -O-C １－６ Alkylene -NR ５ R ６ or R １ａ and R １ｂ together with the atoms to which they are attached form a 3-12 membered heterocyclic or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; R ３ , R ４ , R ７ , R ８ , R ９ and R １０ each occurrence independently represents H, a halogen atom, an amino group, a cyano group, a nitro group, C １－６ Alkyl groups, deuterated C １－６ Alkyl groups, halogenated C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０ a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ an aryl group, a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１２ Aralkyl group, -C(=O)R ５ , -OC(=O)R ５ , -C(=O)OR ５ , -OR ５ , -SR ５ , -S(=O)R ５ , -S(=O) ２ R ５ , -S(=O) ２ N.R. ５ R ６ , -NR ５ R ６ , -C(=O)NR ５ R ６ , -NR ５ -C(=O)R ６ , -NR ５ -C(=O)OR ６ , -NR ５ -S(=O) ２ -R ６ , -NR ５ -C(=O)-NR ５ R ６ , -C １－６ Alkylene -NR ５ R ６ , -C １－６ Alkylene-OR ５ , -O-C １－６ Alkylene -NR ５ R ６ , -C １－６ Alkylene-O-(P=O)(OH) ２ is selected from the group consisting of R ２ is H, halogen, amino group, cyano group, nitro group, C １－６ Alkyl groups, deuterated C １－６ Alkyl groups, halogenated C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０ a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ an aryl group, a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１２ Aralkyl group, -C(=O)R ５ , -OC(=O)R ５ , -C(=O)OR ５ , -OR ５ , -SR ５ , -S(=O)R ５ , -S(=O) ２ R ５ , -S(=O) ２ N.R. ５ R ６ , -NR ５ R ６ , -C(=O)NR ５ R ６ , -NR ５ -C(=O)R ６ , -NR ５ -C(=O)OR ６ , -NR ５ -S(=O) ２ -R ６ , -NR ５ -C(=O)-NR ５ R ６ , -C １－６ Alkylene -NR ５ R ６ , -C １－６ Alkylene-OR ５ , -O-C １－６ Alkylene -NR ５ R ６ , -C １－６ Alkylene-O-(P=O)(OH) ２ , -C １－６ Alkylene-O(C=O)R １１ , -C １－６ Alkylene-O(P=O)(OR １２ ) (NR １３ R １４ ), -C １－６ Alkylene-O(P=O)(OR １２ ) (OR １３ ) selected from the group consisting of R １１ , R １２ , R １３ , R １４ Each occurrence of represents independently H, C １－６ Alkyl group, C ３－６ a cycloalkyl group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ an aryl group, a 3- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and a cation; The cation is Na ＋ , K ＋ , Ca ２＋ , Mg ２＋ , N.H. ４ ＋ is selected from the group consisting of Each occurrence of the alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbon, heterocyclic, aryl, heteroaryl and aralkyl groups may optionally be selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１０ a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ an aryl group, a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１２ Aralkyl group, =N-OR ５ , -C(=NH)NH ２ , -C(=O)R ５ , -OC(=O)R ５ , -C(=O)OR ５ , -OR ５ , -SR ５ , -S(=O)R ５ , -S(=O) ２ R ５ , -S(=O) ２ N.R. ５ R ６ , -NR ５ R ６ , -C(=O)NR ５ R ６ , -NR ５ -C(=O)R ６ , -NR ５ -C(=O)OR ６ , -NR ５ -S(=O) ２ -R ６ , -NR ５ -C(=O)-NR ５ R ６ , -C １－６ Alkylene -NR ５ R ６ , -C １－６ Alkylene-OR ５ , -O-C １－６ Alkylene -NR ５ R ６ and is substituted by one or more substituents independently selected from the group consisting of: R ５ and R ６ Each occurrence of represents independently H, C １－６ Alkyl group, C ３－１０ a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ an aryl group, a 5- to 14-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１２ aralkyl groups; each occurrence of m is independently selected from the group consisting of 0, 1, 2, and 3; each occurrence of n is independently selected from the group consisting of 0, 1 and 2; i is selected from the group consisting of 1 and 2; The compound of formula I, or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein g is selected from the group consisting of 0, 1, 2, 3, and 4.

2. X is 【Chemistry 5】 is selected from the group consisting of Y is NH, NCH ３ The compound is selected from the group consisting of 2. The compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

3. Ring C is 【Chemistry 6】 and Ring E is 【Chemistry 7】 The compound is selected from the group consisting of 2. The compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

4. Ring A is a saturated or partially unsaturated C ３－１０ a cyclic hydrocarbon group, a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S; ６－１０ aryl groups, 5-14 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein up to two ring members of said cyclic hydrocarbon groups and heterocyclic groups are C(=O); Ring D is absent or is a saturated or partially unsaturated C ３－１０ a cyclic hydrocarbon group, and a saturated or partially unsaturated 3- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S.

2. The compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

5. The compound has a structure of any of the following formulas: 【Chemistry 8】 【Chemistry 9】 wherein each radical is as defined in claim 1.

2. A compound according to claim 1 or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

6. The compound is as follows: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 The compound is selected from the group consisting of 2. The compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

7. 1. A pharmaceutical composition comprising:

10. The pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers and a prophylactically and / or therapeutically effective amount of one or more compounds of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof.

8. 13. Use of a compound of claim 1 or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, comprising: The above use, characterized in that the medicament is used for the preparation of a medicament for preventing and / or treating a Rho-associated protein kinase-mediated disease.

9. The Rho-associated protein kinase-mediated disease is selected from the group consisting of autoimmune diseases, cardiovascular diseases, inflammation, central nervous system diseases, arterial thrombotic diseases, fibrotic diseases, tumor diseases, metabolic syndrome, insulin resistance, hyperinsulinemia, type 2 diabetes, impaired glucose tolerance, osteoporosis, and eye diseases.

9. The use according to claim 8.

10. The Rho-associated protein kinase-mediated disease is selected from the group consisting of lupus nephritis, atherosclerosis, rheumatoid arthritis (RA), hemangioma, angiofibroma, pulmonary fibrosis, hepatic fibrosis, psoriasis, corneal graft rejection, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, foreign body rejection, allergic inflammation, contact dermatitis, delayed hypersensitivity reaction, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, neuroinflammation, Osler-Weber syndrome, restenosis, fungal infection, parasitic infection, and viral infection.

9. The use according to claim 8.

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