Production and Use of Quinazolinone Derivatives as Kinase Inhibitors

Abstract

The present invention discloses a compound represented by formula I, its stereoisomers, deuterides or pharmaceutically acceptable salts, or a pharmaceutical composition containing them, and their use as BRAF regulators in the manufacture of drugs for treating related diseases, and each group represented by formula (I) is as defined in the specification. [Chemical formula 1] TIFF2025523998000103.tif38156

Description

Technical Field

[0001] The present invention relates to the field of drugs, and in particular to small molecule compounds related to the dysregulation of kinases (such as, but not limited to, BRAF kinase), their stereoisomers, deuterides or pharmaceutically acceptable salts, and their use in the manufacture of drugs for treating related diseases.

Background Art

[0002] Kinases are enzymes that can catalyze the transfer of phosphate groups from high-energy phosphate donor molecules to specific substrates. This process is called phosphorylation, where the substrate gains a phosphate group while the high-energy ATP molecule provides the phosphate group. Kinases are broadly classified into protein kinases, lipid kinases, and carbohydrate kinases depending on the substrate on which they act. Kinases are present in various species from bacteria to fungi, worms, and mammals. More than 500 different kinases have been identified in humans.

[0003] MAP kinase (MAPK) is a family of serine / threonine kinases that can respond to various extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all thought to be able to participate in the mitogenic stimulation of the MAPK pathway. At the receptor level, activation of this pathway induces a signal cascade, whereby the Ras GTPase exchanges GDP for GTP. Next, Ras activates MEK (MAPKK) by activating Raf kinase (also called MAPKKK).

[0004] The BRAF protein is a member of the RAF family of serine / threonine kinases, which is involved in the Ras Raf MEK extracellular signal-regulated kinase (ERK) pathway or the cascade of the mitogen-activated protein kinase (MAPK) / ERK signaling pathway that affects cell division and differentiation. Mutations in the BRAF gene can cause uncontrolled proliferation and subsequent tumor formation. BRAF is mutated and / or overactivated in common human cancers such as melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer and its metastatic cancers, and primary brain tumors. Although some BRAF inhibitors cause excellent extracranial responses, cancers may develop brain metastases during or after the use of BRAF inhibitor therapy. It is estimated that brain metastases occur in 20% of subjects with cancer, where the majority of brain metastases occur in subjects with melanoma, colorectal cancer, lung cancer and renal cell carcinoma. Brain metastases contribute significantly to the overall cancer mortality in subjects with progressive cancer, and the prognosis remains poor despite multiple treatment modalities and advances in systemic therapies, including surgery, radiotherapy, chemotherapy, immunotherapy, and / or combinations of targeted therapies.

[0005] In addition, BRAF has been identified as a potential target for treating primary brain tumors. The BRAF V600E mutation has been reported to be frequent in primary brain tumors: Schindler et al. analyzed 1,320 central nervous system (CNS) tumors, and Behling et al. analyzed 969 CNS tumors in pediatric and adult populations. These studies, combined with other studies, reported the presence of the BRAF V600E mutation in various cancers, including papillary craniopharyngioma, pleomorphic xanthoastrocytoma (PXA), ganglioglioma, astrocytoma, and the like.

[0006] The blood-brain barrier (BBB) is a highly selective physical transport and metabolic barrier that separates the CNS from the blood. The BBB can prevent some drugs from entering brain tissue and is a limiting factor for the delivery of many peripherally administered agents to the CNS. Usually, many drugs used in cancer treatment cannot pass through the blood-brain barrier. This means that these drugs cannot effectively kill cancer cells in the brain because they cannot penetrate the brain. Treatment for subjects with brain tumors includes surgical resection, radiation therapy, and / or chemotherapy using agents such as temozolomide and / or bevacizumab. However, surgical treatment of brain tumors is not always possible. For example, the tumor may be inaccessible or the subject may not be able to tolerate the trauma of neurosurgery. Also, treatment using radiation therapy and cytotoxic agents is known to have undesirable side effects. For example, the use of temozolomide itself causes mutations in a significant proportion of subjects and worsens the prognosis, and the fact that bevacizumab has a boxed warning for gastrointestinal perforation, complications of surgery and wound healing, and bleeding is increasingly proven by more and more evidence. Kinase inhibitors are used to treat many peripheral cancers. However, due to their structural characteristics, many kinase inhibitors such as BRAF inhibitors (e.g., vemurafenib and dabrafenib) are substrates of active transporters such as P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). For example, according to reports, dabrafenib has an MDR1 efflux ratio of 11.4, a BCRP efflux ratio of 21.0, and a total brain-to-plasma ratio of 0.023. On the other hand, according to reports, vemurafenib has an MDR1 efflux ratio of 83, a BCRP efflux ratio of 495, and a total brain-to-plasma ratio of 0.004.

[0007] Since both P-gp and BCRP are expressed in endothelial cells that cover the inside of blood and brain capillaries, the activities of both P-gp and BCRP in the BBB both play an important role in preventing most kinase inhibitors from being distributed in the brain parenchyma. Therefore, kinase inhibitors are generally not suitable for the treatment of tumors or cancers in the brain (protected by the BBB). Therefore, there is still a need for the treatment of tumors with BRAF mutations. Also, the treatment needs for CNS tumors (including CNS tumors with BRAF mutations) are still not met. Summary of the Invention Means for Solving the Problems

[0008] The present invention provides a small molecule compound having BRAF regulatory activity, its stereoisomer, deuteride or pharmaceutically acceptable salt, and the compound can penetrate the blood-brain barrier better, has a high brain / blood ratio, and further has high activity, small side effects, excellent pharmacokinetics and high bioavailability.

[0009] The present invention provides a compound of formula I below, its stereoisomer, deuteride or pharmaceutically acceptable salt,

Chemical formula

Chemical formula

Chemical formula

[0010] R6 is H, halogen, C 1-4 Alkyl group or haloC 1-4 Alkyl group, and in some embodiments, R6 is H, Alternatively, R5, R6, and the atoms to which they are attached together form a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocycle includes a heteroaryl group and a heterocycloalkyl group. In some embodiments, a 5-membered heterocycle is formed. In some embodiments, a 5-membered heterocycloalkyl group is formed. Optionally, it is substituted with 1 to 3 groups selected from halogen, OH, NH2, -NH C 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, and C 1-4 alkyl group, R7, R8, and R9 are independently H, halogen, OH, NH2, -NH C 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, or halo C 1-4 alkoxy group. In some embodiments, R7, R8, and R9 are independently H, halogen, -NH C 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, or halo C 1-4 alkoxy group. In some embodiments, R7 is H or halogen. In some embodiments, R8 is halogen, OH, NH2, -NH C 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, C 1-4 alkoxy group, or halo C 1-4 alkoxy group. In some embodiments, R8 is halogen, -NH C 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, C 1-4 alkoxy group, or halo C 1-4 alkoxy group. In some embodiments, R9 is H or halogen, Y is C1-2 an alkylene group, O or NR y and in some embodiments, Y is O, in some embodiments, Y is NH, in some embodiments, Y is a methylene group or an ethylene group, R y is H or C 1-4 alkyl group, and in some embodiments, R y is H, and in some embodiments, R y is a methyl group, an ethyl group, a propyl group or an isopropyl group, etc., M is O or NR m and in some embodiments, M is NH, in some embodiments, M is a methylimino group, an ethylimino group, a propylimino group or an isopropylimino group, W is a bond, O or NR w and in some embodiments, W is a bond, O, NH or NC 1-4 alkyl group, R m and R w are independently H or C 1-4 alkyl group, and in some embodiments, R m and R w are independently H, a methyl group, an ethyl group, a propyl group or an isopropyl group, R is C 1-4 alkyl group, C 3-8 cycloalkyl group, a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O or -O-C 3-6 cycloalkyl group, and the alkyl group, cycloalkyl group and heterocycle are optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, and in some embodiments, R is C 1-4 alkyl group, C3-8 Selected from a cycloalkyl group or a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, cycloalkyl group, and heterocycle are optionally substituted with a halogen, C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, and is substituted with 1 to 3 groups selected therefrom. In some embodiments, R is C 3-8 Selected from a cycloalkyl group or a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, and O, and is optionally substituted with a halogen, C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, and is substituted with 1 to 3 groups selected therefrom. In some embodiments, R is C 3-4 Selected from a cycloalkyl group or a 4-membered monocyclic heterocycloalkyl group, 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group, or 6- to 10-membered spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and is optionally substituted with a halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, and is substituted with 1 to 3 groups selected therefrom. In some embodiments, R is C 1-4 alkyl group, C 3-8Selected from a cycloalkyl group or a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally halogen, C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, and is substituted with 1 to 3 groups selected therefrom. In some embodiments, R is C 1-4 alkyl group, C 3-8 Selected from a cycloalkyl group or a 4- to 7-membered monocyclic heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group, or 6- to 10-membered spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, optionally halogen, C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, and is substituted with 1 to 3 groups selected therefrom. In some embodiments, R is a 4- to 7-membered saturated monocyclic heterocycloalkyl group, 5- to 10-membered saturated fused-ring heterocycloalkyl group, 5- to 10-membered saturated fused-ring heterocycloalkyl group, or 6- to 10-membered saturated spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, optionally halogen, C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4Substituted with 1 to 3 groups selected from alkyl groups, and in some embodiments, the cycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopentenyl group, a cyclohexenyl group, etc., the monocyclic heterocycloalkyl group is selected from an azacyclopropyl group, an azetidinyl group, a tetrahydropyrrolyl group, a piperidinyl group, a piperazinyl group, an oxiranyl group, an oxetanyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a morpholinyl group, etc., and the fused-ring heterocycloalkyl group is selected from [Chemical formula] etc., and the fused-ring heterocycloalkyl group is selected from [Chemical formula] etc., and the spiro-ring heterocycloalkyl group is selected from [Chemical formula] etc., and when Cy is P2, R is a 4- to 10-membered saturated heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, in some embodiments, when Cy is P3, the compound satisfies one of the following conditions, (1) R5 is a substituted or unsubstituted C 3-6 cycloalkyl group, a substituted or unsubstituted 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, a substituted or unsubstituted C 3-6 cycloalkyloxy group, a substituted or unsubstituted C 1-4 alkoxy group or a substituted or unsubstituted halo C 1-4 alkoxy group, and R is C3-8 a cycloalkyl group, a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, or -O-C 3-6 is a cycloalkyl group, optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and haloC 1-4 alkyl group, and is substituted with 1 to 3 groups selected from (2) R5 and R6 and the atoms linked thereto together form a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the heterocycle is optionally substituted with 1 to 3 groups selected from halogen, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, and C 1-4 alkyl group, and is substituted with 1 to 3 groups selected from (3) X2 is N or CR3, and R3 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, and W is O, (4) R 31 and R 32 , or R 32 and R 33 and the atoms linked thereto together form a carbocyclic ring or a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the carbocyclic ring or heterocycle is optionally substituted with 1 to 3 groups selected from halogen, C 3-6 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 halogenated alkoxy group, and CN, and is substituted with 1 to 3 groups selected from 1-4 ​(5) X2 is N or CR3, and R3 is C 1-4 an alkyl group, halo C 1-4 an alkyl group, C 1-4 an alkoxy group, halo C 1-4 an alkoxy group, C 2-4 an alkenyl group, C 2-4 an alkynyl group, -NHC 1-4 an alkyl group, -N(C 1-4 alkyl)2 or CN, and W is NR w where R is C 3-8 a cycloalkyl group or a 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with 1 to 3 groups selected from halogen, C 1-4 an alkyl group, C 1-4 an alkoxy group, C 1-4 a haloalkoxy group, OH, NH2, -NHC 1-4 an alkyl group, -N(C 1-4 alkyl)2, and halo C 1-4 an alkyl group (6) X2 is N or CR3, X6 is SO or SO2, W is a bond, and R3 is C 1-4 an alkyl group, halo C 1-4 an alkyl group, C 1-4 an alkoxy group, halo C 1-4 an alkoxy group, C 2-4 an alkenyl group, C 2-4 an alkynyl group, -NHC 1-4 an alkyl group, -N(C 1-4 alkyl)2 or CN, and R is C 3-4 a cycloalkyl group or a 4-membered monocyclic heterocycloalkyl group, 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group, or 6- to 10-membered spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, optionally substituted with halogen, C 1-4 an alkyl group, C 1-4 an alkoxy group, OH, NH2, -NHC 1-4 an alkyl group, -N(C 1-4 alkyl)2, and halo C1-4 substituted with 1 to 3 groups selected from alkyl groups, (7) X6 is CO, X2 is N or CR3, W is a bond, and R3 is C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, (8) At least one of X2, X3, X4, and X5 is N. When X2 is CR3, R3 is H, C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, (9) X2 is N or CR3, and R3 is H, C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, -NHC 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, -N(C 1-4 alkyl)2 or CN, and R8 is halogen, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, C 1-4 alkoxy group or halo C 1-4 alkoxy group.

[0011] As a specific technical solution 1 of the present invention, there is provided a compound represented by formula I, its stereoisomer, deuteride or pharmaceutically acceptable salt,

Chemical formula

[0012] As a specific technical solution 2 of the present invention, there is provided a compound represented by formula I, its stereoisomer, deuteride or pharmaceutically acceptable salt,

Chemical formula

Chemical formula

[0013] In some embodiments, in the compound of formula I, Cy is selected from P1, P2 or P3,

Chemical formula

[0014] As a specific technical solution 3 of the present invention, it is a compound, its stereoisomer, deuteride or pharmaceutically acceptable salt described in technical solution 1 or 2, Ring A is a 5-membered heteroaryl group, and the heteroaryl group is optionally substituted with 1 to 2 groups selected from halogen, C 1-4 alkoxy group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, C 1-4 alkyl group, haloC 1-4 alkoxy group and haloC 1-4 alkyl group, When Cy is P3, the compound satisfies at least one of the following conditions: (1) R5 is a substituted or unsubstituted C 3-6 cycloalkyl group, a substituted or unsubstituted 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, a substituted or unsubstituted C 3-6 cycloalkyloxy group, a substituted or unsubstituted C 1-4 alkoxy group or a substituted or unsubstituted haloC 1-4 alkoxy group, and R is a C 3-8 cycloalkyl group, a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O or -O-C 3-6 cycloalkyl group, optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and haloC 1-4 alkyl group, (2) R5 and R6 and the atoms linked thereto together form a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the heterocycle is optionally substituted with 1 to 3 groups selected from halogen, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2, CN and C 1-4 alkyl group, (3) X2 is N or CR3, and R3 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, and W is O (4) R 31 and R 32 , or R 32 and R 33 and the atoms linked thereto together form a carbocyclic ring or a 5- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 3 groups selected from halogen, C 3-6 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 halogenated alkoxy group, and CN 1-4 (5) X2 is N or CR3, and R3 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, and W is NR w wherein R is C 3-8 cycloalkyl group or a 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and is optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 halogenated alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2, and haloC 1-4 alkyl group (6) X2 is N or CR3, X6 is SO or SO2, W is a bond, and R3 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, and R is C 3-4 cycloalkyl group or a 4-membered monocyclic heterocycloalkyl group, 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group or 6- to 10-membered spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and haloC 1-4 alkyl group (7) X6 is CO, X2 is N or CR3, W is a bond, and R3 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN (8) At least one of X2, X3, X4, X5 is N. When X2 is CR3, R3 is H, C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4an alkyl group, -N(C 1-4 alkyl)2 or CN, and (9) X2 is N or CR3, and R3 is H, C 1-4 alkyl group, haloC 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, and R8 is halogen, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, C 1-4 alkoxy group or haloC 1-4 alkoxy group.

[0015] As a specific technical solution 4 of the present invention, it is a compound, a stereoisomer, a deuteride or a pharmaceutically acceptable salt described in technical solution 1 or 2, and when Cy is P3, the compound satisfies one of the following conditions: (1) R5 is a substituted or unsubstituted C 3-6 cycloalkyl group, a substituted or unsubstituted 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, a substituted or unsubstituted C 1-4 alkoxy group or a substituted or unsubstituted haloC 1-4 alkoxy group, and R is a C 3-8 cycloalkyl group or a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and optionally, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and haloC 1-4 alkyl group, and is substituted with 1 to 3 groups selected therefrom, (2) X2 is N or CR3, and R3 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4An alkoxy group, OH, NH2, -NHC 1-4 An alkyl group, -N(C 1-4 alkyl)2 or CN, W is O, (3)R 31 and R 32 , or R 32 and R 33 and the atoms linked thereto together form a carbocyclic ring or a 5- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, and the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 3 groups selected from halogen, C 3-6 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, and CN, 1-4 substituted, (4)X2 is N or CR3, R3 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, W is NR w and R is C 3-8 cycloalkyl group or a 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, O, optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and haloC 1-4 alkyl group, (5)X2 is N or CR3, X6 is SO or SO2, W is a bond, R3 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, and R is C 3-4A cycloalkyl group or a 4-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a 6- to 8-membered monocyclic heterocycloalkyl group, a 5- to 6-membered monocyclic heteroaryl group, a 5- to 10-membered fused-ring heterocycloalkyl group, a 5- to 10-membered fused-ring heterocycloalkyl group, or a 6- to 10-membered spiro-ring heterocycloalkyl group, optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, (6) X6 is CO, X2 is N or CR3, W is a bond, and R3 is C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, (7) At least one of X2, X3, X4, and X5 is N. When X2 is CR3, R3 is H, C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, (8) X2 is N or CR3, R3 is H, C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, and R8 is halogen, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2, CN, C 1-4 alkoxy group or halo C 1-4It is an alkoxy group.

[0016] As a specific technical solution 5 of the present invention, it is a compound, its stereoisomer, deuteride or pharmaceutically acceptable salt described in technical solution 3, R3, R 31 , R 32 , R 33 are independently H, halogen, C 1-4 alkyl group, haloC 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, haloC 1-4 alkoxy group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl) 2、 CN or C 3-6 cycloalkyl group, or R 31 and R 32 , or R 32 and R 33 and the atoms to which they are attached together form a C 3-6 cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group and the heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2 and CN, R5 is C 1-4 alkyl group, haloC 1-4 alkyl group, C 3-6 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, C 1-4 alkoxy group, haloC 1-4 alkoxy group or C 3-6 cycloalkyloxy group, and is optionally substituted with halogen, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2, C 1-4 alkoxy group, haloC 1-4 alkoxy group, haloC 1-4An alkyl group, CN, and C 1-4 substituted with 1 to 3 groups selected from an alkyl group or =O, R6 is H, halogen, C 1-4 an alkyl group or halo C 1-4 an alkyl group, or R5, R6, and the atoms linked thereto together form a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the heterocycloalkyl group is optionally substituted with halogen, OH, NH2, -NHC 1-4 an alkyl group, -N(C 1-4 alkyl)2, CN, and C 1-4 substituted with 1 to 3 groups selected from an alkyl group, R is C 1-4 an alkyl group, C 3-8 a cycloalkyl group or a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, or -O-C 3-6 selected from a cycloalkyl group, and the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with halogen, C 1-4 an alkyl group, C 1-4 an alkoxy group, halo C 1-4 an alkoxy group, OH, NH2, -NHC 1-4 an alkyl group, -N(C 1-4 alkyl)2, and halo C 1-4 substituted with 1 to 3 groups selected from an alkyl group.

[0017] As a specific technical solution 6 of the present invention, it is a compound, stereoisomer, deuteride, or pharmaceutically acceptable salt described in technical solution 5, and the compound has the structure of the following formula I-1,

Chemical formula

[0018] As a specific technical solution 7 of the present invention, it is a compound, a stereoisomer, a deuteride, or a pharmaceutically acceptable salt thereof described in technical solution 5, wherein the compound has the structure of formula I-2 below, [Chemical formula] Here, ring B is a 5-membered heteroaryl group or a 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, and optionally, =O, halogen, C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, OH, and halo C 1-4 alkoxy group, and is substituted with 1 to 3 groups selected therefrom, R is a 4- to 7-membered saturated monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a 5- to 10-membered saturated fused-ring heterocycloalkyl group, a 5- to 10-membered saturated fused-ring heterocycloalkyl group, or a 6- to 10-membered saturated spiro-ring heterocycloalkyl group, and optionally, halogen, C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4 alkyl group, and is substituted with 1 to 3 groups selected therefrom.

[0019] As a specific technical solution 8 of the present invention, it is a compound, a stereoisomer, a deuteride or a pharmaceutically acceptable salt described in technical solution 5, and the compound has the structure of the following formula I-3

Chemical formula

[0020] As a specific technical solution 9 of the present invention, it is a compound, a stereoisomer, a deuteride or a pharmaceutically acceptable salt described in technical solution 1 or 2, and the compound has the structure of the following formula I-4,

Chemical formula

[0021] As a specific technical solution 10 of the present invention, it is a compound, stereoisomer, deuteride or pharmaceutically acceptable salt described in technical solution 8, R6 and R9 are H, Y is O, M is NH, X2 is N or CR3, X6 is SO or SO2, W is a bond, R3 is C 1-4 alkyl group, halo C 1-4 alkyl group, C 1-4 alkoxy group, halo C 1-4 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 or CN, R is a 4-membered monocyclic heterocycloalkyl group, 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group or 6- to 10-membered spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O or -O-C 3-6 cycloalkyl group, and the 4-membered monocyclic heterocycloalkyl group is halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and halo C 1-4Substituted with 1 to 3 groups selected from alkyl groups, and the 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group or 6- to 10-membered spiro-ring heterocycloalkyl group is optionally halogen, C 1-4 alkyl group, C 1-4 alkoxy group, OH, NH2, -NHC 1-4 alkyl group, -N(C 1-4 alkyl)2 and haloC 1-4 alkyl group, and is substituted with 1 to 3 groups selected therefrom.

[0022] As a specific technical solution 11 of the present invention, it is a compound, stereoisomer, deuteride or pharmaceutically acceptable salt described in technical solution 9, and the compound has the structure of the following formula I-5, [Chemical formula] R3 is C 1-2 alkyl group, haloC 1-2 alkyl group, C 1-2 alkoxy group, haloC 1-2 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 or CN, R 31 、R 32 are each independently H, F, Cl, C 1-2 alkyl group, haloC 1-2 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-2 alkoxy group, haloC 1-2 alkoxy group, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 or CN, R5 is C 1-2 alkyl group, haloC 1-2 alkyl group, C 3-4A cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, C 1-2 An alkoxy group, halo C 1-2 An alkoxy group or C 3-4 Is a cycloalkyloxy group, R8 is H, F, Cl, CN, C 1-2 An alkyl group, C 2-4 An alkenyl group, C 2-4 An alkynyl group, halo C 1-2 An alkyl group, C 1-2 An alkoxy group or halo C 1-2 Is selected from an alkoxy group, R is a 4-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a 6- to 8-membered monocyclic heterocycloalkyl group, a 5- to 6-membered monocyclic heteroaryl group, a 5- to 10-membered fused-ring heterocycloalkyl group, a 5- to 10-membered fused-ring heterocycloalkyl group, or a 6- to 10-membered spiro-ring heterocycloalkyl group. The 4-membered monocyclic heterocycloalkyl group is substituted with 1 to 3 groups selected from F, Cl, C 1-2 An alkyl group, C 1-2 An alkoxy group, OH, NH2, -NHC 1-2 An alkyl group, -N(C 1-2 Alkyl)2 and halo C 1-2 An alkyl group. The 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group, or 6- to 10-membered spiro-ring heterocycloalkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, C 1-2 An alkyl group, C 1-2 An alkoxy group, OH, NH2, -NHC 1-2 An alkyl group, -N(C 1-2 Alkyl)2 and halo C 1-2 An alkyl group.

[0023] As a specific technical solution 12 of the present invention, it is a compound, its stereoisomer, deuteride, or pharmaceutically acceptable salt described in technical solution 8, technical solution 9, or technical solution 10, X2 is CR3, and X3 is CR 31 and X4 is CR 32 and X5 is CH, X6 is SO2, X7 is CH, R3 is C 1-2 alkyl group, halo C 1-2 alkyl group, C 1-2 alkoxy group, halo C 1-2 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 or CN, R 31 , R 32 are each independently H, F, Cl, C 1-2 alkyl group, halo C 1-2 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-2 alkoxy group, halo C 1-2 alkoxy group, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 or CN or C 3-6 cycloalkyl group, R5 is C 1-2 alkyl group, CN or C-substituted with =O 1-2 alkyl group, halo C 1-2 alkyl group, C 3-4 cycloalkyl group, 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, C 1-2 alkoxy group, halo C 1-2 alkoxy group or C 3-4 cycloalkyloxy group, R8 is H, F, Cl, CN, C 1-2 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, halo C 1-2 alkyl group, C 1-2 alkoxy group or halo C 1-2 alkoxy group, R is a 4- to 5-membered monocyclic heterocycloalkyl group, 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group or 6- to 10-membered spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, or -O-C 3-6 is a cycloalkyl group, and the 4-membered monocyclic heterocycloalkyl group is substituted with 1 to 3 groups selected from F, Cl, C 1-2 alkyl group, C 1-2 alkoxy group, OH, NH2, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 and halo C 1-2 alkyl group, and the 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group or 6- to 10-membered spiro-ring heterocycloalkyl group or C 3-6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, C 1-2 alkyl group, C 1-2 alkoxy group, OH, NH2, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 and halo C 1-2 alkyl group.

[0024] As a specific technical solution 13 of the present invention, it is a compound, stereoisomer, deuteride or pharmaceutically acceptable salt described in technical solution 12, wherein R3 is CN, R 31 , R 32 are each independently H, F or Cl or C 3-6 is a cycloalkyl group, wherein R5 is C 1-2 alkyl group, CN or C-substituted with =O 1-2 alkyl group, halo C 1-2 alkyl group or C 1-2 is selected from alkoxy group, wherein R8 is H, R is a 6- to 10-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, or a 4- to 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, or -O-C 3-6 cycloalkyl group, and the 6- to 10-membered spirocyclic heterocycloalkyl group, 4- to 5-membered monocyclic heterocycloalkyl group or C 3-6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, C 1-2 alkyl group or C 1-2 alkoxy group.

[0025] As a specific technical solution 14 of the present invention, it is a compound, a stereoisomer, a deuteride or a pharmaceutically acceptable salt thereof as described in technical solution 8, technical solution 9 or technical solution 10, X2 is CR3, X3 is CR 31 wherein, X4 is CR 32 wherein, X5 is CH, X6 is SO2, X7 is CH, R3 is C 1-2 alkyl group, halo C 1-2 alkyl group, C 1-2 alkoxy group, halo C 1-2 alkoxy group, C 2-4 alkenyl group, C 2-4 alkynyl group, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 or CN, R 31 、R 32 are each independently H, F, Cl, C 1-2 alkyl group, halo C 1-2 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-2 alkoxy group, halo C 1-2 alkoxy group, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 or CN, R5 is C 1-2 alkyl group, halo C 1-2 alkyl group, C 3-4A cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, C 1-2 An alkoxy group, halo C 1-2 An alkoxy group or C 3-4 A cycloalkyloxy group, and R8 is H, F, Cl, CN, C 1-2 An alkyl group, C 2-4 An alkenyl group, C 2-4 An alkynyl group, halo C 1-2 An alkyl group, C 1-2 An alkoxy group or halo C 1-2 Selected from an alkoxy group, and R is a 4-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a 6- to 8-membered monocyclic heterocycloalkyl group, a 5- to 6-membered monocyclic heteroaryl group, a 5- to 10-membered fused-ring heterocycloalkyl group, a 5- to 10-membered fused-ring heterocycloalkyl group, or a 6- to 10-membered spiro-ring heterocycloalkyl group. The 4-membered monocyclic heterocycloalkyl group is substituted with 1 to 3 groups selected from F, Cl, C 1-2 An alkyl group, C 1-2 An alkoxy group, OH, NH2, -NHC 1-2 An alkyl group, -N(C 1-2 Alkyl)2 and halo C 1-2 An alkyl group. The 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group, or 6- to 10-membered spiro-ring heterocycloalkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, C 1-2 An alkyl group, C 1-2 An alkoxy group, OH, NH2, -NHC 1-2 An alkyl group, -N(C 1-2 Alkyl)2 and halo C 1-2 An alkyl group.

[0026] As a specific technical solution 15 of the present invention, a compound, a stereoisomer, a deuteride, or a pharmaceutically acceptable salt thereof described in the present invention, wherein the compound has the structure of the following formula I-6: [Chemical formula] having

[0027] a compound according to the present invention, a stereoisomer thereof, a deuteride or a pharmaceutically acceptable salt thereof, R is selected from a 5- to 10-membered fused cyclic heterocycloalkyl group, a 5- to 10-membered fused cyclic heterocycloalkyl group or a 6- to 10-membered spirocyclic heterocycloalkyl group, and the 5- to 10-membered fused cyclic heterocycloalkyl group, the 5- to 10-membered fused cyclic heterocycloalkyl group or the 6- to 10-membered spirocyclic heterocycloalkyl group is optionally F, Cl, C 1-2 alkyl group, C 1-2 alkoxy group, OH, NH2, -NHC 1-2 alkyl group, -N(C 1-2 alkyl)2 and haloC 1-2 alkyl group and is substituted with 1 to 3 groups selected therefrom.

[0028] As a specific technical solution 16 of the present invention, a compound described in Technical Solution 11, Technical Solution 12 or Technical Solution 14, a compound according to the present invention, a stereoisomer thereof, a deuteride or a pharmaceutically acceptable salt thereof, R3 is CN, R 31 and R 32 are each independently H, F or Cl, R5 is C 1-2 alkyl group or C 1-2 alkoxy group or is selected from haloC 1-2 alkyl group, R8 is H, R is a 6- to 10-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O or a 4- to 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the 6- to 10-membered spirocyclic heterocycloalkyl group is optionally F, Cl, C 1-2 alkyl group or C 1-2Substituted with 1 to 3 groups selected from alkoxy groups, or the 4- to 5-membered monocyclic heterocycloalkyl group is optionally F, Cl, C 1-2 alkyl group or C 1-2 Substituted with 1 to 3 groups selected from alkoxy groups.

[0029] A compound according to the present invention, its stereoisomer, deuteride or pharmaceutically acceptable salt, R is

Chemical formula

[0030] Furthermore, a compound according to the present invention, its stereoisomer, deuteride or pharmaceutically acceptable salt, R is

Chemical formula

[0031] As a specific technical solution of the present invention, a compound according to the present invention, its stereoisomer, deuteride or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures in Table 1.

[0032]

Table 1-1

Table 1-2

Table 1-3

[0033] As a specific technical solution of the present invention, a compound according to the present invention, its stereoisomer, deuteride or pharmaceutically acceptable salt, wherein the compound is selected from one of the structures in Table 2.

[0034]

Table 2-1

Table 2-2

Table 2-3

[0035] The present invention further provides a composition or a pharmaceutical preparation, wherein the composition or the pharmaceutical preparation contains a compound, a stereoisomer, a deuteride or a pharmaceutically acceptable salt thereof described in any one of the foregoing technical solutions, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the unit dosage form is also referred to as a "formulation specification").

[0036] Furthermore, the composition or the pharmaceutical preparation of the present invention contains 1 to 1500 mg of a compound, a stereoisomer, a deuteride or a pharmaceutically acceptable salt thereof described in any one of the foregoing technical solutions, and a pharmaceutically acceptable carrier and / or excipient.

[0037]

[0038] The present invention further provides the use of a compound, a stereoisomer, a deuteride or a pharmaceutically acceptable salt thereof described in any one of the foregoing technical solutions in the manufacture of a drug for treating / preventing BRAF-mediated diseases.

[0039] Furthermore, the BRAF-mediated disease is a tumor, and a more preferred tumor is a brain tumor.

[0040]

[0041]

[0042] The present invention further provides a method for treating a mammalian disease, the method comprising administering to a subject a therapeutically effective amount of a compound, a stereoisomer, a deuteride or a pharmaceutically acceptable salt thereof shown in any one of the foregoing technical solutions.Preferably, the disease is a tumor.Preferably, the therapeutically effective amount is 1 to 1500 mg.In some embodiments, the mammals described in the present invention include humans.

[0043] As used herein, "effective amount" or "therapeutically effective amount" means administering a sufficient amount of a compound disclosed herein which will relieve to some extent one or more of the symptoms of the disease or disorder being treated.

[0044] In some embodiments, the result is a decrease and / or alleviation of a disease symptom, sign or cause, or any other desirable change in a biological system. For example, an "effective amount" for therapeutic use is an amount that includes a compound disclosed in this application necessary to provide a clinically significant reduction in disease symptoms. Examples of a therapeutically effective amount are 1 - 1500 mg, 1 - 1400 mg, 1 - 1300 mg, 1 - 1200 mg, 1 - 1000 mg, 1 - 900 mg, 1 - 800 mg, 1 - 700 mg, 1 - 600 mg, 1 - 500 mg, 1 - 400 mg, 1 - 300 mg, 1 - 250 mg, 1 - 200 mg, 1 - 150 mg, 1 - 125 mg, 1 - 100 mg, 1 - 80 mg, 1 - 60 mg, 1 - 50 mg, 1 - 40 mg, 1 - 25 mg, 1 - 20 mg, 5 - 1500 mg, 5 - 1000 mg, 5 - 900 mg, 5 - 800 mg, 5 - 700 mg, 5 - 600 mg, 5 - 500 mg, 5 - 400 mg, 5 - 300 mg, 5 - 250 mg, 5 - 200 mg, 5 - 150 mg, 5 - 125 mg, 5 - 100 mg, 5 - 90 mg, 5 - 70 mg, 5 - 80 mg, 5 - 60 mg, 5 - 50 mg, 5 - 40 mg, 5 - 30 mg, 5 - 25 mg, 5 - 20 mg, 10 - 1500 mg, 10 - 1000 mg, 10 - 900 mg, 10 - 800 mg, 10 - 700 mg, 10 - 600 mg, 10 - 500 mg, 10 - 450 mg, 10 - 400 mg, 10 - 300 mg, 10 - 250 mg, 10 - 200 mg, 10 - 150 mg, 10 - 125 mg, 10 - 100 mg, 10 - 90 mg, 10 - 80 mg, 10 - 70 mg, 10 - 60 mg, 10 - 50 mg, 10 - 40 mg, 10 - 30 mg, 10 - 20 mg, 20 - 1500 mg, 20 - 1000 mg, 20 - 900 mg, 20 - 800 mg, 20 - 700 mg, 20 - 600 mg, 20 - 500 mg, 20 - 400 mg, 20 - 350 mg, 20 - 300 mg, 20 - 250 mg, 20 - 200 mg, 20 - 150 mg, 20 - 125 mg, 20 - 100 mg, 20 - 90 mg, 20 - 80 mg, 20 - 70 mg, 20 - 60 mg, 20 - 50 mg, 20 - 40 mg, 20 - 30 mg, 50 - 1500 mg, 50 - 1000 mg, 50 - 900 mg, 50 - 800 mg, 50 - 700 mg, 50 - 600 mg, 50 - 500 mg, 50 - 400 mg, 50 - 300 mg, 50 - 250 mg, 50 - 200 mg, 50 - 150 mg,including, but not limited to, 50 - 125 mg, 50 - 100 mg, 100 - 1500 mg, 100 - 1000 mg, 100 - 900 mg, 100 - 800 mg, 100 - 700 mg, 100 - 600 mg, 100 - 500 mg, 100 - 400 mg, 100 - 300 mg, 100 - 250 mg, 100 - 200 mg In some embodiments, the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the compound of the present invention or its stereoisomer, deuteride, or pharmaceutically acceptable salt. The present invention relates to a pharmaceutical composition or pharmaceutical formulation, and the pharmaceutical composition or pharmaceutical formulation contains a therapeutically effective amount of the compound described in the present invention or its stereoisomer, deuteride, or pharmaceutically acceptable salt, and a carrier and / or excipient.

[0045] The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "formulation specification"). In some embodiments, the pharmaceutical composition contains 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound of the present invention or its stereoisomer, deuteride, or pharmaceutically acceptable salt, but not limited thereto.

[0046] A method for treating mammalian diseases, said method comprising administering to a subject a therapeutically effective amount of a compound of the present invention, its stereoisomers, deuterides or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient.

[0047] The therapeutically effective amount is preferably 1 to 1500 mg.

[0048] The disease is preferably a tumor, particularly a brain tumor.

[0049] A method for treating mammalian diseases, said method comprising administering to a subject a compound of the present invention, its stereoisomers, deuterides or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier and / or excipient in a daily dose of 1 to 1500 mg / day, said daily dose may be a single dose or divided doses.

[0050] In some embodiments, the daily dose includes, but is not limited to, 10 to 1500 mg / day, 20 to 1500 mg / day, 25 to 1500 mg / day, 50 to 1500 mg / day, 75 to 1500 mg / day, 100 to 1500 mg / day, 200 to 1500 mg / day, 10 to 1000 mg / day, 20 to 1000 mg / day, 25 to 1000 mg / day, 50 to 1000 mg / day, 75 to 1000 mg / day, 100 to 1000 mg / day, 200 to 1000 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 200 to 800 mg / day, 25 to 400 mg / day, 50 to 400 mg / day, 100 to 400 mg / day, 200 to 400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0051] The present invention relates to a kit, which may include a composition in the form of a single dose or multiple doses, and the kit includes a compound of the present invention, its stereoisomer, deuteride or pharmaceutically acceptable salt, and the amount of the compound of the present invention, its stereoisomer, deuteride or pharmaceutically acceptable salt is the same as its amount in the above pharmaceutical composition.

[0052] In the present invention, the amount of the compound of the present invention, its stereoisomer or pharmaceutically acceptable salt is, in each case, converted in the form of the free base.

[0053] "Formulation specification" refers to the weight of the active ingredient contained in one unit formulation, one tablet unit formulation, or each other unit formulation.

[0054] Synthetic route In patent documents such as WO 2021116050A1, the manufacturing method of the BRAF regulator is described. Those skilled in the art can combine this document with known organic synthesis techniques to manufacture the compounds of the present invention, and the starting materials thereof are commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are those obtained from regular commercial sources, and the suppliers include companies such as Titan Technology, Aladdin Chemistry, Shanghai Derm, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, Nanjing Pharmaceutical Stone, WuXi AppTec, and Bailingwei Technology.

[0055] Specific and similar reactants can be selectively identified by the index of known chemical substances created by the Chemical Information Retrieval Service of the American Chemical Society, and these indexes are available in many public libraries, university libraries, and online. For chemicals that are known but not available in the catalog, optionally, a custom chemical synthesis contractor can be requested to manufacture them, and many of the standard chemical suppliers (for example, the companies listed above) provide custom synthesis services.

[0056] Terms Unless otherwise specified in the present invention, the terms of the present invention have the following meanings.

[0057] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen in the groups and compounds according to the present invention includes any of their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen in the groups and compounds according to the present invention may optionally be further substituted by one or more corresponding isotopes thereof, where the isotopes of carbon are 12 C and 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called triple hydrogen), and the isotopes of oxygen are 16 O and 17 O and 18 O, and the isotopes of sulfur are 32 S and 33 S and 34 S and 36 S, and the isotopes of nitrogen are 14 N and 15 N, and the isotope of fluorine is 19 F, and the isotopes of chlorine are 35 Cl and 37 Cl, and the isotopes of bromine are 79 Br and 81 Br.

[0058] As used herein, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0059] "Halogenation" or "halogen substitution" refers to substitution by one or more selected from F, Cl, Br, I, or their isotopes, and the upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens of the group being substituted. Unless otherwise specifically limited, the number of halogen substituents is any integer between 1 and the upper limit, and when the number of halogen substituents is greater than 1, they may be substituted with the same or different halogens. Usually, cases of 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, and 1 halogen substitution are included.

[0060] "Deuterium" refers to deuterium, which is an isotope of hydrogen (H).

[0061] "Deuteration" or "deuteride" refers to the case where at least one hydrogen atom in a group such as an alkyl group, cycloalkyl group, alkylene group, aryl group, heteroaryl group, mercapto group, heterocycloalkyl group, alkenyl group, alkynyl group, etc. is substituted by at least one deuterium atom. The upper limit of the number of deuterations is equal to the sum of the number of replaceable hydrogens in the group to be substituted. Unless otherwise specifically limited, the number of deuterations is any integer between 1 and the upper limit. For example, it can be 1 to 20 deuterium atom substitutions, 1 to 10 deuterium atom substitutions, 1 to 6 deuterium atom substitutions, 1 to 3 deuterium atom substitutions, 1 to 2 deuterium atom substitutions, or 1 deuterium atom substitution.

[0062] The "C x-y " group refers to a group containing x to y carbon atoms. For example, the "C 1-6 alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms.

[0063] The "alkyl group" refers to a monovalent straight-chain or branched-chain saturated aliphatic hydrocarbon group. Usually, it is an alkyl group having 1 to 20 carbon atoms, or an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, etc. The alkyl group may be further substituted with substituents.

[0064] The "alkylene group" refers to a divalent straight-chain and branched-chain saturated alkyl group. Examples of the alkylene group include, but are not limited to, methylene group, ethylene group, etc.

[0065] "Haloalkyl group" refers to the case where one or more hydrogens in an alkyl group are substituted by one or more halogen atoms (for example, fluorine, chlorine, bromine, iodine or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens in the alkyl group. Unless otherwise specifically limited, the number of halogen substituents is any integer between 1 and the upper limit. Usually, the alkyl group is substituted with 1 to 5 halogens, or substituted with 1 to 3 halogens, or substituted with 1 to 2 halogens, or substituted with 1 halogen. When the number of halogen substituents is greater than 1, it may be substituted by the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0066] "Alkoxy group" or "alkyloxy group" refers to an -O-alkyl group. For example, -O-C 1-8 alkyl group, -O-C 1-6 alkyl group, -O-C 1-4 alkyl group or -O-C 1-2 alkyl group. Specific non-limiting examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, cyclopropoxy group and cyclobutoxy group, etc. The alkoxy group may optionally be substituted with a substituent.

[0067] "Haloalkoxy group" refers to an -O-haloalkyl group. For example, -O-haloC 1-8 alkyl group, -O-haloC 1-6 alkyl group, -O-haloC 1-4 alkyl group or -O-haloC 1-2It is an alkyl group, and the upper limit of the number of halogen substituents is equal to the sum of the replaceable hydrogens of the group to be substituted. Unless otherwise particularly limited, the number of halogen substituents is any integer between 1 and the upper limit. Preferably, it is 1 to 5 halogen substitutions, 1 to 3 halogen substitutions, 1 to 2 halogen substitutions, or 1 halogen substitution. When the number of halogen substituents is greater than 1, it may be substituted by the same or different halogens. Non-limiting examples include monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, difluoroethyloxy group, etc.

[0068] "Alkenyl group" refers to a straight-chain hydrocarbon group or a branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C). Usually, it contains 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, or for example, 2 to 6 carbon atoms, or further for example, 2 to 4 carbon atoms. Examples thereof include vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group, 2-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-methyl-1-pentenyl group, 2-methyl-1-pentenyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 1-octenyl group, 3-octenyl group, 1-nonenyl group, 3-nonenyl group, 1-decenyl group, 4-decenyl group, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc., but are not limited thereto. The alkenyl group may optionally be further substituted with a substituent.

[0069] "Alkenylene group" refers to a straight-chain or branched-chain divalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond (C=C). Unless otherwise specified, the alkylene group contains 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Non-limiting examples include ethynylene group. The alkenylene group may optionally be substituted with a substituent.

[0070] "Alkynyl group" refers to a linear or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), usually containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and even further containing 2 to 4 carbon atoms. Examples thereof include, but are not limited to, ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 4-pentynyl group, 3-pentynyl group, 1-methyl-2-butynyl group, 2-hexynyl group, 3-hexynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 3-octynyl group, 3-nonynyl group, and 4-decynyl group. The alkynyl group may optionally be substituted with a substituent.

[0071] "Alkynylene group" refers to a linear or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), usually containing 2 to 6 carbon atoms, further containing 2 to 4 carbon atoms. Non-limiting examples include ethynylene group, propynylene group, and butynylene group. The alkynylene group may optionally be substituted with a substituent.

[0072] The "cycloalkyl group" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain cycloheteroatoms. The cycloalkyl group may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic may be in the form of fused rings, spiro rings, bridged rings or a combination thereof, and the bicyclic or polycyclic may contain one or more aromatic rings, but the entire ring system is not aromatic, and the connecting site may be on the aromatic ring or the non-aromatic ring. Usually, the cycloalkyl group contains 3 to 20 carbon atoms, further contains 3 to 8 carbon atoms, still further contains 3 to 6 carbon atoms, and when it is a monocyclic cycloalkyl group, it contains 3 to 15 carbon atoms, or 3 to 10 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms, and when it is a bicyclic or polycyclic cycloalkyl group, it contains 5 to 12 carbon atoms, or 5 to 11 carbon atoms, or 6 to 10 carbon atoms. Non-limiting examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, butenyl group, cyclopentenyl group, cyclohexenyl group, [Chemical formula] etc., and the cycloalkyl group may optionally be substituted with substituents.

[0073] The "cycloalkylene group" is a divalent group of the cycloalkyl group.

[0074] The "aryl group" refers to an aromatic carbocyclic ring that does not contain heteroatoms, and includes monocyclic aryl groups and condensed ring aryl groups. Usually, it contains 6 to 13 carbon atoms, further contains 6 to 9 carbon atoms, and further is a phenyl group. Non-limiting examples include phenyl group, naphthyl group, anthryl group, phenanthryl group, and the aryl group may optionally be substituted with substituents.

[0075] "Carbon ring" or "carbocyclic group" refers to a saturated, partially unsaturated, or aromatic carbocyclic ring, the meaning of which includes aryl group and cycloalkyl group. The carbocyclic ring may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic rings include bridged rings, fused rings and spiro rings and combinations thereof. The carbocyclic ring usually has 3 to 12 carbon atoms, or 3 to 10 carbon atoms, or 3 to 6 carbon atoms. In non-limiting examples, the monocyclic carbocyclic ring includes cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or phenyl group, etc., and the bicyclic bridged ring includes

Chem.

Chem.

Chem.

[0076] "Heterocycloalkyl group" refers to a saturated or partially unsaturated non-aromatic carbocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, S, and O. The heterocycloalkyl group may be monocyclic, bicyclic, or polycyclic, and the bicyclic or polycyclic ring may be in the form of a bridged ring, a fused ring, a spiro ring, or a combination thereof. The bicyclic or polycyclic ring may contain one or more aromatic rings or heteroaromatic rings, but the entire ring system is not aromatic, and the linking site may be on an aromatic ring or a non-aromatic ring. Usually, the heterocycloalkyl group is a 3- to 20-membered ring. When it is a monocyclic heterocycloalkyl group, it is usually a 3- to 15-membered ring, or a 3- to 10-membered ring, or a 3- to 8-membered ring, or a 3- to 6-membered ring. When it is a bicyclic or polycyclic heterocycloalkyl group, it is usually a 5- to 12-membered ring, or a 5- to 11-membered ring, or a 6- to 9-membered ring. Here, the heteroatoms N and S include their oxidation states. Non-limiting examples of the heterocycloalkyl group include azetidinyl group, morpholinyl group, piperazinyl group, piperidinyl group, tetrahydropyranyl group, oxetanyl group, pyranyl group, azacyclopentenyl group, azacyclohexenyl group, oxolyl group, oxinyl group, etc. The heterocycloalkyl group may optionally be substituted with a substituent.

[0077] "Heteroaromatic ring" or "heteroaryl group" refers to a ring having aromaticity and containing 1 to 4 heteroatoms selected from N, O, or S and their oxidation states, unless otherwise specified. It may be monocyclic, bicyclic, or polycyclic, and the bicyclic or polycyclic ring may be in the form of a bridged ring, a fused ring, a spiro ring, or a combination thereof. When it is bicyclic or polycyclic, it may be a condensation of a heteroaryl group and an aryl group, or a condensation of a heteroaryl group and a heteroaryl group. Here, both the heteroaryl group and the aryl group can be the linking site. Non-limiting examples include furyl group, thienyl group, pyrrolyl group, oxazolyl group, thiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, indolyl group, purinyl group,

Chemical Structure

[0078] "Heterocycle" or "heterocyclic group" refers to a saturated or unsaturated aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states, which includes heteroaryl groups and heterocycloalkyl groups. Heterocycles include monocyclic heterocycles, bridged bicyclic heterocycles, fused bicyclic heterocycles and spiro bicyclic heterocycles or combinations thereof. Usually, it is a 3- to 12-membered heterocycle or a 5- to 12-membered heterocycle, or a 5- to 7-membered heterocycle. The heterocyclic group may be linked on a heteroatom or a carbon atom, and non-limiting examples include oxiranyl group, azacyclopropyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, piperazinyl group, azacycloheptyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyrazolyl group, pyridazinyl group, imidazolyl group, piperidinyl group, piperidyl group, morpholinyl group, thiomorpholinyl group, 1,3-dithianyl group, dihydrofuryl group, dihydropyranyl group, dithiolanyl group, tetrahydrofuryl group, tetrahydropyrrolyl group, tetrahydroimidazolyl group, oxazolyl group, dihydrooxazolyl group, tetrahydrooxazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azadamantyl group and oxaspiro[3.3]heptyl group,

Chemical Structure

[0079] "Heterocyclylene group" refers to a divalent heterocyclic group which is substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic. Non-limiting examples include

Chem.

[0080] "Spiro ring" refers to a polycyclic group in which rings share one carbon atom (referred to as a spiro atom), which may contain 0 or one or more double bonds or triple bonds, and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states. Usually, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Usually, the spiro ring is 3 spiro 3 (representing a 3-membered ring spiro 3-membered ring), 3 spiro 4, 3 spiro 5, 3 spiro 6, 4 spiro 4, 4 spiro 5, 4 spiro 6, 5 spiro 5 or 5 spiro 6. Non-limiting examples of spiro rings include

Chem.

[0081] "Fused ring" refers to a polycyclic group in which rings share two adjacent ring atoms and one chemical bond, which may contain one or more double bonds or triple bonds, and the fused ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Usually, the fused ring is a 5- to 20-membered ring, or a 5- to 14-membered ring, or a 5- to 12-membered ring, or a 5- to 10-membered ring. Usually, the fused ring is 3 fused 4 ring (representing a fused ring formed by a 3-membered ring and a 4-membered ring. Based on the IUPC nomenclature rules, a fused ring with a 3-membered ring as the basic ring is possible, and a fused ring with a 4-membered ring as the basic ring is also possible, and the same applies hereinafter), 3 fused 5 ring, 3 fused 6 ring, 4 fused 4 ring, 4 fused 5 ring, 4 fused 6 ring, 5 fused 5 ring, 5 fused 6 ring, 6 fused 6 ring. Non-limiting examples of fused rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene,

Chem.

[0082] "Bridged ring" refers to a structure where two rings share two non-adjacent ring atoms and may contain one or more double or triple bonds. A bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si, and their oxidation states. Usually, the ring atoms of a bridged ring are 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings are adamantane, [Chemical formula] including.

[0083] "Substituted" or "substituent" means that, unless otherwise specified, any substitution occurs at chemically acceptable positions and the number of substituents satisfies the laws of chemical bonding. Exemplary substituents are C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 heteroalkyl group, C 5-12 aryl group, 5- to 12-membered heteroaryl group, hydroxy group, C 1-6 alkoxy group, C 5-12 aryloxy group, thiol group, C 1-6 alkylthio group, cyano group, halogen, C 1-6 alkylthiocarbonyl group, C 1-6 alkylcarbamoyl group, N-carbamoyl group, nitro group, silyl group, sulfinyl group, sulfonyl group, sulfoxide, haloC 1-6 alkyl group, haloC 1-6 alkoxy group, amino group, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C1-6 (alkyl), -NHCO2(C 1-6 (alkyl), -NHC(=O)N(C 1-6 (alkyl)2, -HC(=O)NH(C 1-6 (alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 (alkyl), -SO2N(C 1-6 (alkyl)2, -SO2NH(C 1-6 (alkyl), -SO2NH2, -SO2C 1-6 including, but not limited to, an alkyl group, etc.

[0084] "Optional" or "optionally" means that the event or circumstance described thereafter may occur, but does not necessarily occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "an alkyl group optionally substituted by F" means that the alkyl group may be substituted by F, but does not necessarily have to be substituted by F, indicating that it includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

[0085] "Pharmaceutically acceptable salt" refers to a salt obtained by reacting the compound of the present invention with a non-toxic inorganic base or organic base when the compound is a free acid or with a non-toxic inorganic acid or organic acid when the compound is a free base, while maintaining the biological effectiveness and properties of the free acid or free base.

[0086] "Pharmaceutical composition" represents one or more of the compounds of the present specification or their stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals, mixtures with other components, where the other components include a physiologically / pharmaceutically acceptable carrier and / or excipient.

[0087] The "carrier" refers to a system that does not significantly stimulate the living body, does not eliminate the biological activity and properties of the given compound, changes the administration form and in-vivo distribution of the drug in the human body, controls the drug release rate, and can deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0088] "Excipient" refers to a substance that is not a therapeutic agent in itself but is added to a pharmaceutical composition as a diluent, excipient, adhesive, and / or vehicle to thereby improve its handling and storage properties or to permit or facilitate the compound or pharmaceutical composition to form a dosage form for administration. As is known to those skilled in the art, pharmaceutical excipients can provide various functions and may be described as wetting agents, buffering agents, suspending aids, lubricants, emulsifying agents, disintegrating agents, absorbents, preservatives, surfactants, coloring agents, flavoring agents, and sweetening agents. Examples of pharmaceutical excipients include, but are not limited to, the following: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethyl cellulose (e.g., sodium cross-linked carboxymethyl cellulose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter, suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, castor oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) water for endotoxin test; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic and compatible substances used in pharmaceutical formulations.

[0089] "Stereoisomer" refers to an isomer that results from a different spatial arrangement of atoms in a molecule and includes cis-trans isomers, enantiomers, and conformational isomers.

[0090] The compounds of the present invention further include their tautomers. For example, when the left compound with a pyrimidine ring substituted by OH is described in the present invention, the right tautomer compound is also included.

Chemical formula

[0091] "Solvate" refers to a substance formed by the intermolecular non-covalent binding of a compound of the present invention or its salt with a stoichiometric or non-stoichiometric solvent. When the solvent is water, it becomes a hydrate.

[0092] "Co-crystal" refers to a crystal formed by the binding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonding or other non-covalent bonds. Here, the pure states of the API and the CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the components. Co-crystals are multi-component crystals, including not only binary co-crystals formed between two neutral solids, but also multi-component co-crystals formed between a neutral solid and a salt or a solvate.

Modes for Carrying Out the Invention

[0093] Hereinafter, the technical solutions of the present invention will be described in detail in conjunction with examples. However, the protection scope of the present invention includes but is not limited to them.

[0094] Detection Method The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is performed using a nuclear magnetic spectrometer (Bruker Avance III 400 and Bruker Avance 300). The measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard is tetramethylsilane (TMS). The MS measurement is performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)). HPLC measurements were performed using an Agilent 1260 DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM). For thin-layer chromatography, silica gel plates from Yantai Huanghai HSGF254 or Qingdao GF254 were used. The specifications of the silica gel plates employed in thin-layer chromatography (TLC) were 0.15 mm - 0.20 mm, and the specifications adopted for the separation and purification of the finished product by thin-layer chromatography were 0.4 mm - 0.5 mm. Column chromatography generally used silica gel with a particle size of 200 - 300 mesh from Yantai Huanghai as the carrier. Example 1

Chemical formula

[0095] Step 1: In a 50 mL reaction flask, 1A (800 mg, 5.99 mmol), triethylamine (1.82 g, 17.97 mmol), and dichloromethane (10 mL) were sequentially added. After addition, the mixture was stirred at 0 °C for 20 minutes, and then a dichloromethane (7 mL) solution of sulfamic acid chloride (692 mg, 5.99 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 1 h. The reaction solution was diluted with dichloromethane (50 mL) and washed successively with water (30 mL × 1) and saturated brine (30 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM / MeOH = 15 / 1) to obtain 1B (180 mg, yield 17%).

[0096] Step 2: Add 1C (250 mg, 0.8 mmol, refer to WO 2021116050A1 for the production method), 1B (160 mg, 0.9 mmol), cesium carbonate (310 mg, 0.96 mmol), and N,N-dimethylformamide (10 mL) sequentially into a 50 mL reaction flask. After the addition is complete, stir at 80 °C for 18 hours for reaction. Add ethyl acetate (50 mL) to the reaction solution, and wash with water (40 mL × 2). Dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain Compound 1 (86 mg, yield 23%). LCMS m / z = 470.5 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.36 (s, 1H), 7.90 - 7.84 (m, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.53 (dd, 1H), 7.39 (d, 1H), 3.84 (s, 4H), 3.48 (s, 3H), 2.10 (t, 4H), 1.78 - 1.69 (m, 2H). Example 2

Chemical Structure

[0097] Step 1: Add 2A (520 mg, 4.34 mmol), triethylamine (2.19 g, 21.64 mmol), and dichloromethane (10 mL) to a 50 mL reaction flask in sequence. After addition, stir at 0 °C for 20 minutes, and then slowly dropwise add a solution of chlorosulfamic acid (500 mg, 4.34 mmol) in dichloromethane (7 mL). Stir at room temperature for 1 h to allow the reaction to proceed. Dilute the reaction solution with dichloromethane (50 mL), wash it successively with water (50 mL×1) and saturated brine (50 mL×1), dry the organic layer over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by column chromatography (DCM / MeOH = 15 / 1) to obtain 2B (450 mg, yield 32%).

[0098] Step 2: Add 1C (250 mg, 0.8 mmol), 2B (250 mg, 1.54 mmol), cesium carbonate (520 mg, 1.60 mmol), and N,N-dimethylformamide (10 mL) to a 50 mL reaction flask in sequence. After addition, stir at 100 °C for 16 h to allow the reaction to proceed. Add ethyl acetate (50 mL) to the reaction solution, and wash it with water (40 mL×2). Dry the organic layer over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by preparative liquid chromatography (equipment: waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 2 (60 mg, yield 16%). LCMS m / z = 456.2[M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.35 (s, 1H), 7.89 - 7.84 (m, 1H), 7.78 (d, 1H), 7.67 (dd, 1H), 7.50 (dd, 1H), 7.39 (d, 1H), 3.47 (s, 3H), 3.37 - 3.34 (m, 4H), 1.59 - 1.56 (m, 2H), 0.65 - 0.59 (m, 1H), 0.19 - 0.16 (m, 1H). Example 3 [Chemical formula]

[0099] Step 1: To a 50 mL reaction flask, sulfamic acid chloride (1.0 g, 8.68 mmol), triethylamine (2.63 g, 26.04 mmol) and dichloromethane (10 mL) were added sequentially. After the addition, the mixture was stirred at 0 °C for 20 minutes, and cyclopropanol (1.11 g, 17.36 mmol) was slowly added dropwise. Then the mixture was stirred at room temperature for 1 h for reaction. The reaction solution was concentrated under reduced pressure to obtain 3B, which was directly used in the next step without purification.

[0100] Step 2: To a 50 mL reaction flask, 1C (500 mg, 1.6 mmol), 3B (1.0 g crude product), cesium carbonate (620 mg, 1.92 mmol) and N,N-dimethylformamide (15 mL) were added sequentially. After the addition, the mixture was stirred at 100 °C for 18 h for reaction. Ethyl acetate (50 mL) was added to the reaction solution, and then the mixture was washed with water (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (equipment: waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 18 minutes) to obtain compound 3 (100 mg, yield 14.5%). LCMS m / z = 431.1 [M + H] + ; 1 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.77 (d, 1H), 7.67 - 7.54 (m, 3H), 7.48 (dd, 1H), 4.24 - 4.13 (m, 1H), 3.58 (s, 3H), 0.94 - 0.83 (m, 2H), 0.79 - 0.68 (m, 2H). Example 4 [Chemical formula]

[0101] Step 1: In a 250 mL three-necked flask under nitrogen gas protection, 4A (4.0 g, 26.08 mmol) was dissolved in dry tetrahydrofuran (80 mL), and triphosgene (2.94 g, 9.91 mmol) was slowly added under an ice bath. After the addition was complete, the mixture was stirred at 70 °C for 4 h for reaction. After complete reaction, the reaction solution was concentrated under reduced pressure, the residue was triturated with petroleum ether for purification, the solid was filtered and dried to obtain 4B (3.86 g, yield 83%).

[0102] 1 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.84 (s, 1H), 7.24 - 7.18 (m, 2H), 7.03 (dd, 1H).

[0103] Step 2: In a 250 mL single-necked flask, 4B (3.85 g, 21.51 mmol) was dissolved in an aqueous solution (60 mL) of sodium hydroxide (1.03 g, 25.75 mmol), methoxyamine hydrochloride (2.69 g, 32.27 mmol) was added, and the mixture was stirred at room temperature overnight for reaction. After complete reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in a mixed solvent of dichloromethane (200 mL) and methanol (10 mL), dried over anhydrous sodium sulfate, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain 4C (2.8 g, yield 71%). LCMS m / z = 183.1 [M + H] + ;

[0104] Step 3: In a 50 mL single-neck flask, 4C (2.6 g, 14.27 mmol) was dissolved in trimethyl orthoformate (54 mL). After addition was complete, the mixture was stirred at 105 °C for 4 h for reaction. After complete reaction, the reaction solution was concentrated under reduced pressure, and the residue was triturated and purified with petroleum ether. The solid was filtered and dried to obtain 4D (2.4 g, yield 88%). LCMS m / z = 193.1 [M+H] + ;

[0105] Step 4: In a 100 mL single-neck flask, 4D (2.4 g, 12.49 mmol) was dissolved in dry N,N-dimethylformamide (40 mL). Under an ice bath, cesium carbonate (4.88 g, 14.99 mmol) was slowly added. After addition was complete, the mixture was stirred at room temperature for 0.5 h for reaction. Under an ice bath, a solution of 2,3,6-trifluorobenzonitrile (2.32 g, 14.99 mmol) in N,N-dimethylformamide (10 mL) was slowly added dropwise. After addition was complete, the mixture was stirred at room temperature for 1 h for reaction. After complete reaction, the reaction solution was poured into ice water (250 mL), stirred for 30 min, filtered, and the obtained solid was dried and then triturated and purified with a mixed solvent of petroleum ether (100 mL) and ethyl acetate (10 mL). The solid was filtered and dried to obtain 4E (3.6 g, yield 88%). LCMS m / z = 330.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.98 (m, 1H), 7.83 (d, 1H), 7.75 (dd, 1H), 7.64 ‐ 7.53 (m, 2H), 4.06 (s, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -107.70 (s), -128.37 (s).

[0106] Step 5: In a 100 mL single-necked flask, dissolve 4E (0.33 g, 1.00 mmol) in dry N,N-dimethylformamide (4 mL). Under an ice bath, slowly add cesium carbonate (0.39 g, 1.20 mmol). After addition, stir at 50 °C for 0.5 h for reaction. Under an ice bath, slowly dropwise add a solution of (3R)-3-fluoropyrrolidine-1-sulfonamide (0.20 g, 1.19 mmol) in N,N-dimethylformamide (1 mL). After addition, stir at 100 °C for 6 h for reaction. After complete reaction, pour the reaction solution into ice water (50 mL), stir for 30 min, filter, and dry the obtained solid. Then separate and purify it by preparative liquid (instrument: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 min) to obtain compound 4 (32 mg, yield 7%). LCMS m / z = 478.1 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.63 (s, 1H), 7.91 - 7.81 (m, 2H), 7.71 (dd, 1H), 7.56 (d, 1H), 7.41 (d, 1H), 5.40 (m, 0.5H), 5.27 (m, 0.5H), 4.05 (s, 3H), 3.58 - 3.32 (m, 4H), 2.17 (m, 2H).

[0107] 19 F NMR (377 MHz, DMSO-d6) δ -127.22 (s), -172.76 (s). Example 5

Chemical Structure

[0108] Step 1: To a 50 mL reaction flask, 5A (720 mg, 6.04 mmol), triethylamine (1.83 g, 18.12 mmol) and dichloromethane (10 mL) were sequentially added. After the addition was complete, the mixture was stirred at 0 °C for 20 minutes, and a dichloromethane (7 mL) solution of sulfamic acid chloride (700 mg, 6.04 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 - 2 h to react. The reaction solution was diluted with dichloromethane (100 mL), washed successively with water (40 mL×1) and saturated brine (40 mL×1), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM / MeOH = 12 / 1) to obtain 5B (600 mg, yield 61%).

[0109] Step 2: To a 100 mL reaction flask, 1C (0.72 g, 2.30 mmol), 5B (0.41 g, 2.53 mmol), cesium carbonate (0.90 g, 2.76 mmol) and N,N-dimethylformamide (20 mL) were sequentially added. After the addition was complete, the mixture was stirred at 80 °C for 18 h to react. Ethyl acetate (100 mL) was added to the reaction solution, and it was washed with water (40 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 5 (12 mg, yield 1%). LCMS m / z = 456.30[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s,1H), 7.76 (d,1H), 7.63 (dd,2H), 7.48 (dd,1H), 7.38 (d,1H), 7.08 (s,1H), 3.83 (s,4H), 3.47 (s,3H), 0.56 (s,4H).

[0110] 19 19F NMR (377 MHz, DMSO-d6) δ -134.36 (s). Example 6

Chemical formula

[0111] Step 1: In a 50 mL reaction flask, 6A (synthesis method refer to WO2017 / 1660,2017,A1) (620 mg, 5.38 mmol), triethylamine (1633.21 mg, 16.14 mmol) and dichloromethane (20 mL) were added sequentially. After addition, the mixture was stirred at 0 °C for 20 minutes, and a dichloromethane (10 mL) solution of sulfamic acid chloride (622 mg, 5.38 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 - 2 h for reaction. The reaction solution was diluted with dichloromethane (100 mL), washed successively with water (40 mL×1) and saturated brine (40 mL×1), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain 6B (500 mg, yield 48%).

[0112] Step 2: In a 100 mL reaction flask, 1C (600 mg, 1.92 mmol), 6B (410 mg, 2.11 mmol), cesium carbonate (751 mg, 2.30 mmol) and N,N-dimethylformamide (20 mL) were added sequentially. After addition, the mixture was stirred at 80 °C for 18 h for reaction. Ethyl acetate (100 mL) was added to the reaction solution, and it was washed with water (40 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 80% acetonitrile, gradient elution, cycle time: 20 minutes) to obtain Compound 6 (8 mg, yield 1%). LCMS m / z = 488.20 [M+H]+ ; 1 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.34 (s, 1H), 7.77 (d, 2H), 7.66 (dd, 1H), 7.47 (dd, 1H), 7.38 (d, 1H), 5.01 (s, 0.5H), 4.87 (s, 0.5H), 3.81 (d, 4H), 3.47 (s, 3H), 2.56 (m, 2H), 2.37 ‐ 2.18 (m, 2H). Example 7

Chemical Structure

[0113] Step 1: In a 100 mL single-necked flask, 1B (281 mg, 1.60 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Under an ice bath, cesium carbonate (594 mg, 1.82 mmol) was slowly added. After addition, the mixture was stirred at 50 °C for 0.5 h for reaction. Under an ice bath, a solution of 4E (500 mg, 1.52 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise. After addition, the mixture was stirred at 100 °C for 2 h for reaction. After complete reaction, the reaction solution was poured into ice water (60 mL), stirred for 30 min, filtered, and the obtained solid was dried and then separated and purified by preparative liquid (equipment: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 7 (58 mg, yield: 8%). LCMS m / z = 486.1 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.63 (s, 1H), 7.93 ‐ 7.85 (t, 1H), 7.84 (d, 1H), 7.72 (dd, 1H), 7.54 (dd, 1H), 7.41 (d, 1H), 4.04 (s, 3H), 3.84 (s, 4H), 2.10 (t, 4H), 1.81 ‐ 1.66 (m, 2H).

[0114] 19 19F NMR (377 MHz, DMSO-d6) δ -127.26 (s). Example 8

Chemical Structure

[0115] Step 1: In a 100 mL single-neck flask, 5B (0.27 g, 1.52 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Under an ice bath, cesium carbonate (0.74 g, 2.28 mmol) was slowly added. After addition, the mixture was stirred at 50 °C for 0.5 h for reaction. Under an ice bath, a solution of 4E (0.5 mg, 1.52 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise. After addition, the mixture was stirred at 100 °C for 2 h for reaction. After complete reaction, the reaction solution was filtered, and the filtrate was concentrated. The resulting oily liquid was separated and purified by preparative liquid chromatography (equipment: Waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 80% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 8 (0.3 g, yield: 42%). LCMS m / z = 472.1 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.63 (s, 1H), 7.93 ‐ 7.86 (t, 1H), 7.84 (d, 1H), 7.72 (dd, 1H), 7.60 (dd, 1H), 7.43 (d, 1H), 4.05 (s, 3H), 3.98 (s, 4H), 0.62 (s, 4H).

[0116] 19 19F NMR (377 MHz, DMSO-d6) δ -127.15 (s). Example 9

Chemical Structure

[0117] Step 1: 9A (25 g, 184.46 mmol) and sodium formate (15.55 g, 21.51 mmol) were added to a 250 mL single-necked flask and reacted at 130 °C for 2 h. After complete reaction, it was cooled to room temperature, filtered, and 9B (22.0 g, yield 94%) was obtained from the filtrate. LCMS m / z = 128.2 [M+H] + ;

[0118] Step 2: In a 250 mL single-necked flask, 2-amino-5-hydroxybenzoic acid (1.0 g, 6.52 mmol) was added to 9B (6 mL, 36.2 mmol) and reacted at 150 °C for 21 h. After complete reaction, it was cooled to room temperature, filtered, the filter cake was washed twice with ethyl acetate (1 mL), and the filter cake was concentrated to obtain 9C (1.3 g, yield 82%). LCMS m / z = 245.2 [M+H] + ;

[0119] Step 3: In a 25 mL single-neck flask, 9C (0.60 g, 2.46 mmol) was dissolved in dry N,N-dimethylformamide (6 mL). Under an ice bath, cesium carbonate (1.6 g, 4.91 mmol) was slowly added. After the addition, the mixture was stirred at room temperature for 0.5 h for reaction. Under the ice bath, 2,3,6-trifluorobenzonitrile (0.41 g, 2.61 mmol) was slowly added dropwise. After the addition, the mixture was stirred at room temperature overnight for reaction. After complete reaction, ethyl acetate (10 mL) was added to the reaction system to dilute the reaction, then water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with water (20 mL × 2). After concentrating the organic phase, it was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 9E (0.75 g, yield 80%). LCMS m / z = 382.0 [M+H] + ;

[0120] Step 4: In a 25 mL single-neck flask, 9E (0.50 g, 1.31 mmol) was dissolved in dry N,N-dimethylformamide (5 mL). Under an ice bath, cesium carbonate (0.85 g, 2.61 mmol) and 1B (0.23 g, 1.31 mmol) were slowly added dropwise. After the addition, the mixture was stirred at 100 °C for 4 h for reaction. After complete reaction, the reaction was filtered. The filtrate was separated and purified by preparative liquid purification (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain 100 mg of solid. The solid was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 9 (22 mg, yield 3%). LCMS m / z = 538.1 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.39 (s, 1H), 7.89 - 7.82 (dd, 2H), 7.75 - 7.72 (dd, 1H), 7.55 - 7.52 (dd, 1H), 7.44 - 7.43 (d, 1H), 4.98 - 4.91 (q, 2H), 3.83 (s, 4H), 2.11 - 2.07 (t, 4H), 1.77 ‐ 1.70 (m, 2H).

[0121] 19 19F NMR (377 MHz, DMSO-d6) δ -127.30 (s), -67.08 (s). Example 10

Chemical formula

[0122] Step 1: 10A (20 g, 184.46 mmol) was added to ethyl formate (20 mL), and the reaction was carried out at 55 °C overnight. After the reaction was complete, it was cooled to room temperature, and the reaction solution was concentrated to obtain residue 10B (3.1 g, yield 12%). LCMS m / z = 100.2 [M + H] + ; 1 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 6.32 (s, 1H), 6.01 ‐ 5.67 (m, 1H), 3.71 - 3.60 (m, 2H).

[0123] Step 2: In a 25 mL single-neck flask, 2-amino-5-hydroxybenzoic acid (0.5 g, 3.31 mmol) was added to 10B (3.1 mL, 28.4 mmol), and the reaction was carried out at 150 °C for 21 hrs. After the reaction was complete, it was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (0.5 mL × 2), and the filter cake was concentrated to obtain 10C (0.70 g, yield 94%). LCMS m / z = 227.2 [M + H] + ;

[0124] Step 3: In a 25 mL single-neck flask, 10C (0.70 g, 3.09 mmol) was dissolved in dry N,N-dimethylformamide (6 mL). Under an ice bath, cesium carbonate (2.01 g, 6.17 mmol) was slowly added. After the addition, the mixture was stirred at room temperature for 0.5 h for reaction. Under the ice bath, 2,3,6-trifluorobenzonitrile (0.51 g, 3.20 mmol) was slowly added dropwise. After the addition, the mixture was stirred at room temperature overnight for reaction. After complete reaction, ethyl acetate (5 mL) was added to the reaction system to dilute the reaction. Then, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with water (20 mL × 2). After concentrating the organic phase, it was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 10E (1.1 g, yield 98%). LCMS m / z = 364.2 [M+H] + ;

[0125] Step 4: In a 25 mL single-neck flask, 10E (0.50 g, 1.38 mmol) was dissolved in dry N,N-dimethylformamide (5 mL). Under an ice bath, cesium carbonate (0.90 g, 2.76 mmol) and 1B (0.24 g, 1.38 mmol) were slowly added dropwise. After the addition, the mixture was stirred at 100 °C for 4 h for reaction. After complete reaction, the reaction was filtered. The filtrate was separated and purified by preparative liquid purification (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 10 (150 mg, yield 21%). LCMS m / z = 520.0 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.34 (s, 1H), 7.87 - 7.80 (m, 2H), 7.74 - 7.71 (dd, 1H), 7.54 - 7.50 (dd, 1H), 7.41 - 7.40 (d, 1H), 6.51 ‐ 6.22 (m, 1H), 4.51 - 4.43 (m, 2H), 3.82 (s, 4H), 2.11 - 2.07 (t, 4H), 1.78 ‐ 1.70 (m, 2H).

[0126] 19 19F NMR (377 MHz, DMSO-d6) δ -127.22 (s), -120.46 (s). Example 11

Chem.

[0127] Step 1: To a 100 mL reaction flask, 11A (5.0 g, 87.62 mmol) and ethyl formate (40 mL) were sequentially added. After addition, the mixture was stirred at 55 °C for 12 h. After completion of the reaction, it was concentrated under reduced pressure to obtain 11B (7.0 g, yield 93%). LCMS m / z = 86.20 [M+H] + ;

[0128] Step 2: To a 100 mL reaction flask, 11B (7.0 g, 82.26 mmol) and 4A (1.5 g, 9.83 mmol) were sequentially added. After addition, the mixture was stirred at 145 °C for 10 h. After completion of the reaction, it was filtered. The obtained solid was triturated and purified with ethyl acetate, and then the solid was filtered and dried to obtain 11C (1.5 g, yield 75%). LCMS m / z = 203.10 [M+H] + ;

[0129] Step 3: In a 100 mL reaction flask, 11C (1.5 g, 7.42 mmol) was dissolved in dry N,N-dimethylformamide (20 mL). Cesium carbonate (3.63 g, 11.13 mmol) was added under an ice bath. After addition, the mixture was reacted at room temperature for 0.5 h. A solution of 2,3,6-trifluorobenzonitrile (1.28 g, 8.16 mmol) in N,N-dimethylformamide (15 mL) was slowly added dropwise under an ice bath. After addition, the mixture was reacted at room temperature for 2 h. The reaction solution was diluted with ethyl acetate (50 mL), washed successively with water (50 mL×1) and saturated brine (50 mL×1). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE / EA = 2 / 1) to obtain 11D (1.4 g, yield 56%). LCMS m / z=340.10[M+H] + ;

[0130] Step 4: In a 100 mL reaction flask, 11D (0.2 g, 0.59 mmol), 1B (0.2 g, 1.12 mmol), cesium carbonate (0.38 g, 1.18 mmol) and N,N-dimethylformamide (10 mL) were added successively. After addition, the mixture was stirred at 100 °C for 12 h. Ethyl acetate (30 mL) was added to the reaction solution, and the mixture was washed with water (30 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 min) to obtain compound 11 (150 mg, yield 52%). LCMS m / z=496.20[M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.27 (s, 1H), 7.91 - 7.85 (m, 1H), 7.76 (d, 1H), 7.67 (dd, 1H), 7.53 (dd, 1H), 7.37 (d, 1H), 3.84 (s, 4H), 3.28 - 3.14 (m, 1H), 2.13 - 2.06 (m, 4H), 1.79 - 1.70 (m, 2H), 1.06 - 0.90 (m, 4H). Example 12

Chemical formula

[0131] Step 1: To a 50 mL reaction flask, 12A (100 mg, 0.75 mmol), triethylamine (150 mg, 1.50 mmol) and dichloromethane (10 mL) were sequentially added. After addition, the mixture was stirred at 0 °C for 20 minutes, and a dichloromethane (5 mL) solution of sulfamic acid chloride (92 mg, 0.80 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 2 h for reaction. The reaction solution was diluted with dichloromethane (40 mL) and washed successively with water (30 mL × 1) and saturated brine (30 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM / MeOH = 15 / 1) to obtain 12B (80 mg, yield 55%).

[0132] Step 2: Add 1C (100 mg, 0.32 mmol), 12B (80 mg, 0.45 mmol), cesium carbonate (200 mg, 0.61 mmol), and N,N-dimethylformamide (10 mL) sequentially into a 50 mL reaction flask. After the addition is complete, stir at 100 °C for 12 hours for reaction. Add ethyl acetate (40 mL) to the reaction solution, wash it with water (40 mL × 2), dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by preparative liquid (equipment: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 12 (35 mg, yield 23%). LCMS m / z = 470.50[M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.35 (s, 1H), 7.92‐7.84 (m, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.54 (dd, 1H), 7.36 (d, 1H), 3.56 - 3.50 (m, 2H), 3.47 (s, 3H), 1.94 - 1.84 (m, 2H), 1.80‐1.72 (m, 2H), 1.08 - 0.98 (m, 2H), 0.57 - 0.51 (m, 2H). Example 13

Chemical Structure

[0133] Step 1: Add 13A (500 mg, 3.21 mmol), triethylamine (0.97 g, 9.59 mmol), and dichloromethane (10 mL) to a 50 mL reaction flask in sequence. After addition, stir at 0 °C for 20 minutes, and then slowly dropwise add a dichloromethane (7 mL) solution of sulfamic acid chloride (740 mg, 6.40 mmol). Stir at room temperature for 12 h to react. Concentrate the reaction solution under reduced pressure to obtain 13B (500 mg, crude product).

[0134] Step 2: Add 1C (1.58 g, 5.04 mmol), 13B (500 mg, 2.52 mmol), cesium carbonate (2.46 g, 7.62 mmol), and N,N-dimethylformamide (15 mL) to a 50 mL reaction flask in sequence. After addition, stir at 100 °C for 12 h to react. Filter the reaction solution, concentrate the filtrate under reduced pressure, and separate and purify the residue by preparative liquid (equipment: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 13 (46.76 mg, yield 3.78%). LCMS m / z = 492.4 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.83 (dd, 1H), 7.63 - 7.58 (m, 3H), 7.47 (t, 1H), 6.86 (s, 1H), 4.20 - 4.14 (m, 4H), 3.63 (s, 3H), 1.52 (t, 2H). Example 14

Chemical formula

[0135] Step 1: To a 50 mL reaction flask, sulfamic acid chloride (0.18 g, 1.59 mmol), triethylamine (0.48 g, 4.74 mmol) and dichloromethane (5 mL) were sequentially added. After the addition was complete, the mixture was stirred at 0 °C for 20 minutes, and 14A (0.20 g, 1.59 mmol) was slowly added dropwise. The mixture was then stirred at room temperature for 1 h to allow the reaction to proceed. The reaction solution was concentrated under reduced pressure and used directly in the next step without purification of the crude product.

[0136] Step 2: To a 50 mL reaction flask, 1C (490 mg, 1.56 mmol), 14B (0.30 g of crude product), cesium carbonate (1.52 mg, 4.67 mmol) and N,N-dimethylformamide (5 mL) were sequentially added. After the addition was complete, the mixture was stirred at 100 °C for 18 h to allow the reaction to proceed. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with water (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by medium-pressure preparative chromatography (equipment: Biotage Isolera One, chromatography column: C18 spherical 20 - 35um 100A 80 g (Agela Technologies), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water, gradient: 5% - 90% acetonitrile, gradient elution, cycle time: 20 minutes, retention time: 7 minutes) to obtain compound 14 (28 mg, yield 3.89%). LCMS m / z = 462.1 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.75 - 7.70 (m, 1H), 7.57 (dd, 2H), 7.47 (dd, 1H), 7.33 - 7.25 (m, 1H), 4.59 (d, 1H), 4.47 (d, 1H), 3.88 (t, 2H), 3.64 (dd, 2H), 3.57 (s, 3H), 2.88 - 2.76 (m, 1H).

[0137] 19 F NMR (377 MHz, DMSO-d6) δ -146.12 (s), -220.65 (s). Example 15

Chem.

[0138] Step 1: In a 100 mL single-neck flask, 15A (0.25 g, 1.74 mmol) was dissolved in dry acetonitrile (15 mL), 15B (0.53 g, 1.74 mmol) was added, and after the addition, the mixture was stirred at 30 °C for 1 h for reaction. After complete reaction, the reaction solution was concentrated, and the solid obtained was the crude product of compound 15C. Without purification, the reaction of the next step was carried out directly.

[0139] Step 2: Compound 15C (crude product) and dichloromethane (12 ml) were added to a single-neck flask, trifluoroacetic acid (3 ml) was added, and the reaction was carried out at room temperature for 2 h. After concentration, compound 15D was obtained. Without purification, the reaction of the next step was carried out directly.

[0140] Step 3: In a 100 mL single-neck flask, 15D (crude product) was dissolved in dry N,N-dimethylformamide (10 mL). Under an ice bath, cesium carbonate (2.27 g, 6.97 mmol) and 1C (300 mg, 0.96 mmol) were slowly added. After the addition, the mixture was stirred at 100 °C for 6 h for reaction. After complete reaction, the reaction solution was filtered, and after the filtrate was concentrated, an oily liquid was obtained. The residue was separated and purified by medium-pressure preparative chromatography (equipment: Biotage Isolera One, chromatography column: C18 spherical 20 - 35um 100A 80 g (Agela Technologies), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water, gradient: 5% - 90% acetonitrile, gradient elution, cycle time: 20 minutes, retention time: 7 minutes) to obtain compound 15 (120 mg, total yield of 3 steps: 14.4%). LCMS m / z = 480.4 [M + H] + ; 11H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.77 ‐ 7.72 (m, 1H), 7.59 (dd, 2H), 7.46 (dd, 1H), 7.30 (t, 1H), 6.11 (td, 1H), 3.91 (t, 2H), 3.82 ‐ 3.75 (m, 2H), 3.59 (s, 3H), 2.98 ‐ 2.84 (m, 1H).

[0141] 19 19F NMR (377 MHz, DMSO-d6) δ -121.73 (s), -145.77 (s). Example 16 [Chemical Formula]

[0142] Step 1: In a 100 mL single-neck flask, dissolve 3-(trifluoromethyl)azetidine hydrochloride (16A) (0.25 g, 1.55 mmol) in dry acetonitrile (15 mL), add 15B (0.47 g, 1.55 mmol), and stir at 30 °C for 1 h to react. After complete reaction, the reaction solution was concentrated, and the obtained solid was the crude compound 16C. Without purification, the reaction of the next step was directly carried out.

[0143] Step 2: Add the crude compound 16C and dichloromethane (12 ml) to a single-neck flask, add trifluoroacetic acid (3 ml), and react at room temperature for 2 h. After concentration, compound 16D was obtained. Without purification, the reaction of the next step was directly carried out.

[0144] Step 3: In a 100 mL single-neck flask, dissolve 16D (crude product) in dry N,N-dimethylformamide (10 mL). Under an ice bath, slowly add cesium carbonate (2.02 g, 6.20 mmol) and 1C (300 mg, 0.96 mmol). After addition, stir at 100 °C for 6 h to react. After complete reaction, filter the reaction solution, concentrate the filtrate to obtain an oily liquid, and separate and purify the residue by medium-pressure preparative chromatography (equipment: Biotage Isolera One, chromatography column: C18 spherical 20 - 35um 100A 80 g (Agela Technologies), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water, gradient: 5% - 90% acetonitrile, gradient elution, cycle time: 20 minutes, retention time: 8 minutes) to obtain compound 16 (100 mg, total yield of 3 steps 12.9%). LCMS m / z = 498.5 [M + H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.75 - 7.70 (m, 1H), 7.57 (dd, 2H), 7.45 (dd, 1H), 7.34 - 7.26 (m, 1H), 3.96 (t, 2H), 3.89 - 3.82 (m, 2H), 3.57 (s, 3H), 3.33 - 3.24 (m, 1H).

[0145] 19 F NMR (377 MHz, DMSO-d6) δ -70.81 (s), -145.19 (s). Example 17

Chemical Structure

[0146] Step 1: In a 100 mL single-necked flask, 2-azabicyclo[3.1.0]hexane hydrochloride (17A) (0.47 g, 3.97 mmol) was dissolved in dry acetonitrile (25 mL), 15B (1.2 g, 3.97 mmol) was added, and after addition, the mixture was stirred at 70 °C for 4 h to react. After complete reaction, the reaction solution was concentrated, and the solid obtained was the crude product of compound 17B. Without purification, the reaction of the next step was carried out directly.

[0147] Step 2: Compound 17B (680 mg, 2.59 mmol) and dichloromethane (12 ml) were added to a single-necked flask, trifluoroacetic acid (3 ml) was added, and the mixture was reacted at room temperature for 2 h. After concentration, the residue was separated by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:0 - 0:1) to obtain compound 17C (420 mg, yield: 99%).

[0148] Step 3: In a 100 mL single-necked flask, 17C (217 mg, 1.34 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Under an ice bath, cesium carbonate (655 mg, 2.01 mmol) was slowly added. After addition, the mixture was stirred at 50 °C for 0.5 h to react. Under an ice bath, a solution of 1C (420 mg, 1.34 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise. After addition, the mixture was stirred at 100 °C for 2 h to react. After complete reaction, the reaction solution was filtered, and the oily liquid obtained after concentrating the filtrate was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 80% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 17 (56 mg, yield: 9%). LCMS m / z = 456.5 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.36 (s, 1H), 7.86 (t, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.63 (dd, 1H), 7.38 (d, 1H), 3.48 (s, 3H), 3.39 (t, 1H), 3.18 (m, 1H), 2.93 (m, 1H), 2.05 (m, 1H), 1.98 (m, 1H), 1.61 (m, 1H), 0.78 (m, 1H), 0.52 (m, 1H).

[0149] 19 19F NMR (377 MHz, DMSO-d6) δ -128.22 (s). Example 18

Chemical formula

[0150] Step 1: To a 50 mL reaction flask, 18A (500 mg, 5.08 mmol), triethylamine (1.54 g, 15.24 mmol) and dichloromethane (10 mL) were sequentially added. After the addition was complete, the mixture was stirred at 0 °C for 20 minutes, and a solution of chlorosulfamic acid (1.17 g, 10.16 mmol) in dichloromethane (7 mL) was slowly added dropwise. The reaction was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure to obtain 18B (500 mg, crude product).

[0151] Step 2: 1C (1.76 g, 5.62 mmol), 18B (500 mg, 2.81 mmol), cesium carbonate (2.75 g, 8.37 mmol) and N,N-dimethylformamide (15 mL) were sequentially added to a 50 mL reaction flask. After the addition was complete, the mixture was stirred at 100 °C for 12 hours for reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 18 (22.34 mg, yield 1.7%). LCMS m / z = 472.5 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.84 (d, 1H), 7.62 (dd, 1H), 7.57 (d, 1H), 7.54 (dd, 1H), 7.45 (t, 1H), 6.95 (s, 1H), 4.78 (s, 4H), 4.18 (s, 4H), 3.63 (s, 3H). Example 19

Chemical Structure

[0152] Step 1: Add 19A (500 mg, 4.49 mmol), triethylamine (1.36 g, 13.47 mmol) and dichloromethane (10 mL) to a 50 mL reaction flask successively. After addition, stir at 0 °C for 20 minutes, then slowly dropwise add a solution of chlorosulfamic acid (520 mg, 4.49 mmol) in dichloromethane (7 mL), and stir at room temperature for 1 - 2 h for reaction. Dilute the reaction solution with dichloromethane (100 mL), wash successively with water (40 mL×1) and saturated brine (40 mL×1), dry the organic layer over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by column chromatography (DCM / MeOH = 12 / 1) to obtain 19B (600 mg, yield 70%).

[0153] Step 2: Add 1C (0.9 g, 2.87 mmol), 19B (0.6 g, 3.16 mmol), cesium carbonate (1.12 g, 3.44 mmol) and N,N - dimethylformamide (20 mL) to a 100 mL reaction flask successively. After addition, stir at 80 °C for 18 h for reaction. Add ethyl acetate (100 mL) to the reaction solution, and wash with water (40 mL×2), dry the organic layer over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by preparative liquid (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one - thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 19 (12 mg, yield 1%). LCMS m / z = 484.60[M + H] + ; 1 H NMR (400 MHz, DMSO - d6) δ 10.36 (s,1H),8.36 (s,1H),7.88 (t,1H),7.78 (d,1H),7.68 (dd,1H),7.56 (dd,1H),7.39 (d,1H),3.72 (s,4H),3.48 (s,3H),1.71 (m,4H),1.50 (m,4H).

[0154] 19 19F NMR (377 MHz, DMSO-d6) δ -127.31 (s). Examples 20 and 21 [Chemical formula]

[0155] Step 1: Take a 500 mL reaction flask, dissolve trimethylsulfoxonium iodide (100.45 g, 456.62 mmol) in tert-butanol (350 mL) at room temperature, then add lithium tert-butoxide (45.0 g, 401.83 mmol), react at 50 °C for 1 h, and cool to room temperature. Slowly add 20A (40.0 g, 182.65 mmol). After the addition is complete, react at 50 °C for 48 h. After complete reaction, add saturated ammonium chloride solution (20 mL) for quenching, add water (50 mL), extract with ethyl acetate (150 mL × 2). Combine the organic phases, wash with saturated brine (50 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 2:1) to obtain 10.0 g of the racemate. Separate the racemate by chiral preparative HPLC to obtain peak 1 (3.0 g, retention time 8.45 min, designated as 20B) and peak 2 (3.0 g, retention time 11.62 min, designated as 21B) respectively. Conditions for preparative chromatography separation: instrument SFC Prep 150 AP, chromatographic column: Daicel AD-H (19 mm × 250 mm), mobile phase system: A for CO2 and B for MeOH, gradient: B 10%, 5. Flow rate: 45 mL / min.

[0156] Step 2: Take a 100 mL reaction flask, dissolve compound 20B (3.0 g, 12.13 mmol) in methanol (30 mL) at room temperature, add Pd / C (0.3 g, Pd content 10%), and react for 3 hours under a hydrogen gas atmosphere. After complete reaction, filter, concentrate the filtrate, and obtain the crude title compound 20C (1.1 g, 80%), which was used directly in the next step reaction without purification. LCMS m / z = 114.2 [M+H] + 。

[0157] Step 3: Take a 50 mL reaction flask, dissolve compound 20C (1.1 g, 9.72 mmol) in 1,4-dioxane (15 mL) at room temperature, add sulfonamide (0.78 g, 8.11 mmol), and react at 100 °C for 12 hours. After complete reaction, add water (10 mL), extract with ethyl acetate (15 mL × 2), wash the combined organic phases with saturated brine (10 mL × 1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and then separate and purify the residue by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the title compound 20D (1.3 g, 70%). LCMS m / z = 193.1 [M+H] + 。

[0158] Step 4: In a 50 mL reaction flask, 1C (407.4 mg, 1.30 mmol), 20D (500 mg, 2.60 mmol), cesium carbonate (813.8 mg, 2.60 mmol) and N,N-dimethylformamide (10 mL) were sequentially added at room temperature. After the addition was complete, the mixture was stirred at 100 °C for 12 hours to react. After complete reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by preparative liquid, and the HPLC separation method was as follows: 1. Instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare the sample solution. 3. Conditions for preparative chromatography: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate), b. Gradient elution, the content of mobile phase A was 10% - 55%, c. Flow rate 12 mL / min, d. Elution time 20 min. The retention time was 7.0 min, and compound 20 (230 mg, 18%) was obtained. LCMS m / z = 486.1 [M + H] + 。 1 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.73 (d, 1H), 7.68 (s, 1H), 7.61 (d, 1H), 7.58 (dd, 1H), 7.52 (dd, 1H), 7.41 - 7.34 (m, 1H), 4.57 - 4.45 (m, 2H), 3.93 - 3.87 (m, 1H), 3.56 (s, 3H), 3.56 - 3.51 (m, 2H), 3.40 (d, 1H), 2.73 - 2.63 (m, 2H), 2.49 - 2.40 (m, 1H), 2.07 - 1.98 (m, 1H).

[0159] Using 21B (3 grams) as the raw material, compound 21 (200 mg) was obtained through the same synthetic method as compound 20. LCMS m / z = 486.1 [M + H] + 。 11H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.75 (s, 1H), 7.73 (d, 1H), 7.61 (d, 1H), 7.57 (dd, 1H), 7.51 (dd, 1H), 7.40 ‐ 7.34 (m, 1H), 4.56 ‐ 4.45 (m, 2H), 3.92 ‐ 3.86 (m, 1H), 3.56 (s, 3H), 3.55 ‐ 3.51 (m, 2H), 3.40 (d, 1H), 2.71 ‐ 2.63 (m, 2H), 2.47 ‐ 2.40 (m, 1H), 2.06 ‐ 1.98 (m, 1H). Example 22

Chemical Structure

[0160] Step 1: In a 100 mL reaction flask, dissolve 22A (0.8 g, 3.98 mmol) (for the synthesis of Compound 22A, refer to Patent WO2019 / 60611, 2019, A1) in acetonitrile (20 mL). Sequentially add potassium permanganate (1.20 g, 7.61 mmol) and basic alumina (1.0 g, 9.79 mmol). After addition, react at room temperature for 5 hours. After the reaction is complete, filter, concentrate the obtained filtrate, and separate and purify the residue by column chromatography (PE / EA = 1 / 1) to obtain 22B (0.65 g, yield 82%). LCMS m / z = 200.10 [M + H] + ;

[0161] Step 2: In a 100 mL reaction flask, dissolve 22B (0.6 g, 3.01 mmol) in N,N - dimethylformamide (10 mL). Next, add sodium thioethane (0.50 g, 5.94 mmol). After replacing the reaction solution with nitrogen gas three times, heat it to 130 °C and react for 10 hours. After the reaction is complete, filter, concentrate the obtained filtrate, and obtain 22C (0.45 g, yield 80%). LCMS m / z = 186.10 [M + H] + ;

[0162] Step 3: In a 100 mL reaction flask, dissolve 22C (0.45 g, 2.43 mmol) in N,N-dimethylformamide (10 mL). Slowly add cesium carbonate (1.20 g, 3.75 mmol) under an ice-water bath. After addition, stir at room temperature for 0.5 h. Then, slowly dropwise add a solution of 2,3,6-trifluorobenzonitrile (0.38 g, 2.43 mmol) in N,N-dimethylformamide (5 mL) under an ice-water bath. After addition, react at room temperature for 1 h. Dilute the reaction solution with ethyl acetate (50 mL), wash successively with water (50 mL×1) and saturated brine (50 mL×1). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Separate and purify the residue by column chromatography (PE / EA = 2 / 1) to obtain 22D (0.55 g, yield 70%). LCMS m / z = 323.30[M+H] + ;

[0163] Step 4: In a 100 mL reaction flask, successively add 22D (0.25 g, 0.78 mmol), 1B (0.21 g, 1.17 mmol), cesium carbonate (0.51 g, 1.56 mmol) and N,N-dimethylformamide (15 mL). After addition, stir and react at 100 °C for 12 h. Add ethyl acetate (30 mL) to the reaction solution and wash with water (30 mL×2). Dry the organic layer over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 10 min) to obtain compound 22 (150 mg, yield 40%). LCMS m / z = 479.10[M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.27 (s, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.87 (t, 1H), 7.62 (d, 1H), 7.59 (d, 1H), 7.58 - 7.53 (m, 2H), 3.83 (s, 4H), 2.08 (t, 4H), 1.75 - 1.66 (m, 2H). Example 23 [Chemical Structure]

[0164] Step 1: 23A (1.00 g, 9.11 mmol) and acetic acid (15 mL) were added to a one-necked flask, and then ethyl 3-ethoxy-2-methyl-2-acrylate (2.88 g, 18.22 mmol) was added. The mixture was heated and refluxed for 16 h. After monitoring the completion of the reaction by LCMS, acetic acid was removed by rotary evaporation. The remaining solid was triturated with ethyl acetate (20 mL), and the solid was filtered and dried to obtain product 23B (1.2 g, 74.7%). LC-MS (ESI): m / z = 177.1 [M + H] + .

[0165] Step 2: 23B (0.20 g, 1.14 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then cesium carbonate (0.74 g, 2.27 mmol) was added. While stirring at 0 °C, 2,3,6-trifluorobenzonitrile (0.23 g, 1.48 mmol) was added. After addition, the temperature was slowly raised to room temperature and reacted for 2 h. After monitoring the completion of the reaction by LCMS, the reaction solution was poured into water (15 mL), and a large amount of solid precipitated. The solid was filtered and dried to obtain product 23C (0.12 g, 33.6%). LC-MS (ESI): m / z = 314.1 [M + H] + .

[0166] Step 3: 23C (120.0 mg, 0.38 mmol), 1B (87.0 mg, 0.49 mmol), cesium carbonate (250.0 mg, 0.76 mmol) and N,N-dimethylformamide (5 mL) were sequentially added to a single-necked flask. After the addition was complete, the mixture was stirred at 80 °C for 18 h. After monitoring the completion of the reaction by LCMS, ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with water (40 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound 23 (50.0 mg, 28.0%). 1 H NMR ((400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.38 (d, 1H), 8.30 (d, 1H), 8.00 (dd, 1H), 7.86 (t, 1H), 7.78 (d, 1H), 7.53 (dd, 1H), 3.82 (s, 4H), 2.12 (s, 3H), 2.09 (t, 4H), 1.77 - 1.69 (m, 2H). LC-MS (ESI): m / z = 470.1 [M + H] + 。 Example 24

Chemical formula

[0167] Step 1: 24A (1.2 g, 10.95 mmol), triethylamine (3.32 g, 32.85 mmol) and acetonitrile (20 mL) were sequentially added to a 50 mL reaction flask. After the addition was complete, the mixture was stirred for 30 min, and 15B (4.97 g, 16.43 mmol) was slowly added dropwise. The mixture was stirred at 40 °C for 3 h. The reaction solution was concentrated under reduced pressure to obtain 24B (1 g, crude product).

[0168] Step 2: 24B (0.8 g, 3.17 mmol) and dichloromethane (6 mL) were sequentially added to a 50 mL reaction flask. Trifluoroacetic acid (2 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain 24C (0.8 g, crude product).

[0169] Step 3: To a 50 mL reaction flask, 24C (0.8 g, 5.26 mmol), cesium carbonate (2.57 g, 7.89 mmol), and N,N-dimethylformamide (15 mL) were sequentially added. After addition, the mixture was stirred at 50 °C for 2 hours for reaction, then 4E (2.08 g, 6.31 mmol) was added, and the mixture was stirred at 80 °C for 12 hours for reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (equipment: Waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 24 (91.8 mg, yield 3.79%). LCMS m / z = 462.1 [M + H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.80 (d, 1H), 7.65 - 7.61 (m, 2H), 7.58 (dd, 1H), 7.44 (t, 1H), 4.24 (t, 2H), 4.15 (s, 3H), 3.73 (t, 2H), 2.47 - 2.40 (m, 2H). Example 25

Chemical Structure

[0170] Step 1: To a 25 mL reaction flask, compound 1 (180 mg, 0.38 mmol), Lawesson's reagent (768 mg, 1.90 mmol), and dry tetrahydrofuran (9 mL) were sequentially added. After addition, the mixture was stirred at 80 °C for 4 hours for reaction, and the reaction solution was directly concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM / MeOH = 15 / 1) to obtain a crude product, which was further separated and purified by preparative liquid chromatography to obtain compound 25 (35 mg, yield 19%). LCMS m / z = 486.1 [M + H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.70 (s, 1H), 7.99 (d, 1H), 7.89 (dd, 2H), 7.77 (dd, 1H), 7.56 (dd, 1H), 3.87 (s, 3H), 3.83 (s, 4H), 2.09 (t, 4H), 1.78 ‐ 1.65 (m, 2H).

[0171] 19 19F NMR (377 MHz, DMSO-d6) δ -127.24 (s). Example 26 [Chemical formula]

[0172] Step 1: In a 250 mL reaction flask, dissolve 2-fluoroethylamine hydrochloride (9.0 g, 90.53 mmol) in water (80 mL). Under an ice-water bath, add an aqueous solution of sodium hydroxide (3.3 g, 82.54 mmol), stir for 30 minutes, then add 4B (4.0 g, 22.29 mmol), and stir at room temperature for 4 hours. After complete reaction, concentrate under reduced pressure. Dissolve the residue in a mixed solvent of dichloromethane (100 mL) and methanol (50 mL), filter, and then concentrate the filtrate under reduced pressure. Separate and purify the residue by column chromatography (PE / EA = 1 / 1) to obtain 26A (3.8 g, yield 86%). LCMS m / z = 199.10 [M + H] + ;

[0173] Step 2: In a 20 mL microwave tube, dissolve 26A (1.5 g, 8.58 mmol) in triethyl orthoformate (10 mL). Heat the reaction solution to 185 °C and react for 2 hours. After completion of the reaction, filter, and spin-dry the obtained filter cake to obtain 26B (1.6 g, yield 89%). LCMS m / z = 209.10 [M + H] + ;

[0174] Step 3: In a 100 mL reaction flask, 26B (1.5 g, 7.20 mmol) was dissolved in N,N-dimethylformamide (20 mL). Under an ice-water bath, cesium carbonate (3.52 g, 10.80 mmol) was slowly added. After stirring at room temperature for 30 minutes, a solution of 2,3,6-trifluorobenzonitrile (1.36 g, 8.64 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction was carried out at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed successively with water (100 mL×1) and saturated brine (100 mL×1). The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was separated and purified by column chromatography (PE / EA = 2 / 1) to obtain 26C (1.35 g, yield 54%). LCMS m / z=346.10[M+H] + ;

[0175] Step 4: In a 100 mL reaction flask, 26C (0.4 g, 1.16 mmol), 1B (0.31 g, 1.74 mmol), cesium carbonate (0.76 g, 2.32 mmol) and N,N-dimethylformamide (15 mL) were added sequentially. After the addition was complete, the reaction was carried out at 100 °C for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution, and it was washed with water (30 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 10 minutes) to obtain compound 26 (320 mg, yield 55%). LCMS m / z=502.10[M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.33 (s, 1H), 7.88 (t, 1H), 7.80 (d, 1H), 7.76 - 7.68 (m, 1H), 7.56 - 7.51 (m, 1H), 7.39 (d, 1H), 4.79 - 4.62 (m, 2H), 4.36 - 4.25 (m, 2H), 3.83 (s, 4H), 2.09 (t, 4H), 1.78 - 1.69 (m, 2H). Example 27

Chem.

[0176] Step 1: In a 100 mL single-neck flask, 27A (1.0 g, 8.96 mmol) was dissolved in dry acetonitrile (15 mL), 15B (2.71 g, 8.96 mmol) and triethylamine (1.81 g, 17.96 mmol) were added. After addition, the mixture was stirred at 30 °C for 1 h for reaction. After complete reaction, the reaction solution was concentrated, and the obtained solid was compound 27C. Without purification, the reaction of the next step was directly carried out.

[0177] Step 2: Compound 27C and dichloromethane (12 ml) were added to a single-neck flask, trifluoroacetic acid (6 ml) was added, and the reaction was carried out at room temperature for 2 h. After concentration, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 27D (800 mg, total yield of 2 steps 57.9%).

[0178] Step 3: In a 100 mL single-neck flask, dissolve 27D (0.45 g, 2.92 mmol) in dry N,N-dimethylformamide (6 mL), slowly add cesium carbonate (0.95 g, 2.92 mmol) and 4E (800 mg, 2.43 mmol). After addition, stir at 80 °C for 6 h for reaction. After complete reaction, filter the reaction solution, concentrate the filtrate to obtain an oily liquid, and separate and purify the residue by medium-pressure preparative chromatography (equipment: Biotage Isolera One, chromatography column: C18 spherical 20 - 35um 100A 80 g (Agela Technologies), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water, gradient: 5% - 90% acetonitrile, gradient elution, cycle time: 20 minutes, retention time: 7.5 minutes) to obtain compound 27 (85 mg, yield 7.5%). LCMS m / z = 464.1 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.96 ‐ 7.78 (m, 2H), 7.73 (dd, 1H), 7.56 (dd, 1H), 7.44 (d, 1H), 5.47 - 5.28 (m, 1H), 4.25 - 4.16 (m, 2H), 4.05 (s, 3H), 4.04 ‐ 3.95 (m, 2H).

[0179] 19 F NMR (377 MHz, DMSO-d6) δ -126.63 (s), -177.31 (s). Example 28

Chemical Structure

[0180] Step 1: In a 100 mL single-neck flask, 28A (1.0 g, 7.72 mmol) was dissolved in dry acetonitrile (15 mL), 15B (2.33 g, 7.72 mmol) and triethylamine (1.56 g, 15.44 mmol) were added. After addition, the mixture was stirred at 30 °C for 1 h for reaction. After complete reaction, the reaction solution was concentrated, and the solid obtained was the crude product of compound 28C. Without purification, the reaction of the next step was directly carried out.

[0181] Step 2: The crude product of compound 28C and dichloromethane (12 mL) were added to a single-neck flask, trifluoroacetic acid (6 mL) was added, and the mixture was reacted at room temperature for 2 h. After concentration, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 28D (670 mg, total yield of 2 steps 56.30%).

[0182] Step 3: In a 100 mL single-neck flask, 28D (0.47 g, 2.74 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), cesium carbonate (0.89 g, 2.74 mmol) and 4E (750 mg, 2.28 mmol) were slowly added. After addition, the mixture was stirred at 80 °C for 6 h for reaction. After complete reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid. The residue was separated and purified by medium-pressure preparative chromatography (equipment: Biotage Isolera One, chromatography column: C18 spherical 20 - 35um 100A 80g (Agela Technologies), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water, gradient: 5% - 90% acetonitrile, gradient elution, cycle time: 20 minutes, retention time: 8 minutes) to obtain compound 28 (180 mg, yield 16.4%). LCMS m / z = 482.1 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.91 (dd, 1H), 7.84 (d, 1H), 7.73 (dd, 1H), 7.58 (dd, 1H), 7.45 (d, 1H), 4.41 (t, 4H), 4.05 (s, 3H).

[0183] 19 19F NMR (377 MHz, DMSO-d6) δ -90.00 (s), -126.12 (s). Example 29

Chem.

[0184] Step 1: In a 100 mL single-neck flask, compound 29A (0.4 g, 2.64 mmol) was dissolved in acetonitrile (25 mL), then 15B (1.10 g, 3.64 mmol) was added. After addition, the reaction was carried out at 40 °C for 3 hours. After complete reaction, the reaction solution was concentrated to obtain compound 29B (1.5 g, crude product), and the reaction of the next step was carried out directly.

[0185] Step 2: In a 100 mL single-neck flask, compound 29B (1.5 g, 5.10 mmol) was dissolved in dichloromethane (30 mL), then trifluoroacetic acid (10 mL) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, it was concentrated, and the residue was purified by column chromatography (PE / EA = 1 / 1) to obtain compound 29C (420 mg, yield 43%). LCMS m / z = 502.10 [M + H] + ;

[0186] Step 3: In a 100 mL single-necked flask, compound 4E (0.5 g, 1.52 mmol) was dissolved in dry N,N-dimethylformamide (20 mL). After adding cesium carbonate (1.0 g, 3.07 mmol), the mixture was stirred at 50 °C for 0.5 h to react. Next, a solution of 29C (0.42 g, 2.16 mmol) in N,N-dimethylformamide (5 mL) was added dropwise. After the addition was complete, the reaction solution was stirred at 100 °C for 12 h. After the reaction was completed, it was filtered, the filtrate was concentrated, and the obtained residue was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 10 minutes) to obtain compound 29 (80 mg, yield 10%). LCMS m / z = 504.10[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.63 (s, 1H), 7.89 (t, 1H), 7.83 (d, 1H), 7.75 - 7.68 (m, 1H), 7.57 - 7.53 (m, 1H), 7.42 (d, 1H), 5.04 - 4.84 (m, 1H), 4.18 (d, 1H), 4.04 (s, 3H), 3.94 (d, 1H), 3.86 - 3.79 (m, 2H), 2.19 - 2.10 (m, 1H), 2.02 - 1.78 (m, 2H), 1.70 - 1.62 (m, 1H). Example 30

Chemical Structure

[0187] Step 1: In a 250 mL single-necked flask, 4B (4 g, 22.29 mmol) was dissolved in an aqueous solution (40 mL) of sodium hydroxide (2.85 g, 71.33 mmol), 1-methylcyclopropanamine hydrochloride (8.39 g, 78.02 mmol) was added, and the mixture was stirred at room temperature overnight. After complete reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in a mixed solvent of dichloromethane (200 mL) and methanol (10 mL), dried over anhydrous sodium sulfate, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain 30A (4.0 g, yield 87%).

[0188] Step 2: In a 50 mL single-necked flask, 30A (4.0 g, 19.39 mmol) was dissolved in trimethyl orthoformate (32 mL). After addition, the mixture was stirred at 105 °C for 4 h. After complete reaction, the reaction solution was concentrated under reduced pressure, the residue was triturated and purified with petroleum ether, the solid was filtered and dried to obtain 30B (2.4 g, yield 57%). LCMS m / z = 217.1 [M+H] + ;

[0189] Step 3: In a 100 mL single-necked flask, 30B (2.0 g, 9.25 mmol) was dissolved in dry N,N-dimethylformamide (40 mL). Under an ice bath, cesium carbonate (3.62 g, 11.1 mmol) was slowly added. After addition, the mixture was stirred at room temperature for 0.5 h. Under an ice bath, a solution of 2,3,6-trifluorobenzonitrile (1.45 g, 9.25 mmol) in N,N-dimethylformamide (10 mL) was slowly added dropwise. After addition, the mixture was stirred at room temperature for 1 h. After complete reaction, the reaction solution was poured into ice water (250 mL), stirred for 30 min, filtered, and the obtained solid was dried and then triturated and purified with a mixed solvent of petroleum ether (100 mL) and ethyl acetate (10 mL), and the solid was filtered and dried to obtain 30C (2.5 g, yield 76%). LCMS m / z = 354.1 [M+H] + ;

[0190] Step 4: In a 100 mL single-necked flask, dissolve compound 1B (240 mg, 1.36 mmol) in dry N,N-dimethylformamide (8 mL). Under an ice bath, slowly add cesium carbonate (552 mg, 1.69 mmol), and after addition, stir at 50 °C for 0.5 h for reaction. Under an ice bath, slowly dropwise add a solution of compound 30C (400 mg, 1.13 mmol) in N,N-dimethylformamide (2 mL). After addition, stir at 100 °C for 6 h for reaction. After complete reaction, pour the reaction solution into ice water (50 mL), stir for 30 min, filter, and dry the obtained solid. Then separate and purify by preparative liquid (equipment: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 min) to obtain compound 30 (240 mg, yield 42%). LCMS m / z = 510.2 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.36 (s, 1H), 7.93 - 7.84 (m, 1H), 7.77 (d, 1H), 7.68 (dd, 1H), 7.54 (dd, 1H), 7.35 (d, 1H), 3.84 (s, 4H), 2.10 (t, 4H), 1.75 (dd, 2H), 1.45 (s, 3H), 1.06 (t, 2H), 0.94 (t, 2H).

[0191] 19 F NMR (377 MHz, DMSO-d6) δ -127.33 (s). Example 31

Chemical Structure

[0192] Step 1: In a 250 mL reaction flask, 31A (10 g, 39.61 mmol), aqueous ammonia (20 mL), and 1,4-dioxane (100 mL) were sequentially added, and the mixture was stirred at 100 °C for 24 h to react. The reaction solution was extracted (with ethyl acetate), washed, and concentrated to obtain a crude product. It was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain 31B (8.5 g, yield 86.02%).

[0193] Step 2: In a 50 mL reaction flask, 31B (2 g, 8.02 mmol), 6-hydroxy-3-methylquinazolin-4(3H)-one (CAS: 19181-69-2, 2.31 g, 12.03 mmol), 18-crown-6 (2.12 g, 8.02 mmol), potassium carbonate (3.33 g, 24.06 mmol), and N-methylpyrrolidone (20 mL) were sequentially added. After the addition was complete, the mixture was stirred at 110 °C for 12 h to react. The reaction solution was extracted (with ethyl acetate), washed, and concentrated to obtain a crude product. It was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain 31C (500 mg, yield 17.28%).

[0194] Step 3: In a 50 mL reaction flask, 31C (0.25 g, 0.73 mmol), copper(II) bromide (0.49 g, 2.19 mmol), tert-butyl nitrite (0.23 g, 2.19 mmol), and acetonitrile (3 mL) were sequentially added. After the addition was complete, the mixture was stirred at room temperature for 1 h to react. The reaction solution was extracted (with ethyl acetate), washed, and concentrated to obtain a crude product. It was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain 31D (250 mg, yield 83.81%).

[0195] Step 4: To a 50 mL reaction flask, 31D (250 mg, 0.61 mmol), 1B (0.22 g, 1.22 mmol), potassium carbonate (100 mg, 0.73 mmol), Xantphos (71 mg, 0.12 mmol), Pd2(dba)3 (56 mg, 0.06 mmol) and 1,4-dioxane (5 mL) were sequentially added, and the mixture was stirred at 120 °C for 5 h for reaction. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid chromatography to obtain compound 31 (88.1 mg, yield 28.6%). LCMS m / z = 504.8 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.79 (d, 1H), 7.64 - 7.56 (m, 3H), 3.99 (s, 4H), 3.60 (s, 3H), 2.20 (t, 4H), 1.89 - 1.81 (m, 2H). Example 32

Chemical formula

[0196] Step 1: To a 50 mL reaction flask, 31B (2 g, 8.02 mmol), 4D (2.31 g, 12.03 mmol), 18-crown-6 (2.12 g, 8.02 mmol), potassium carbonate (3.33 g, 24.06 mmol) and N-methylpyrrolidone (20 mL) were sequentially added. After the addition was completed, the mixture was stirred at 110 °C for 12 h for reaction. The reaction solution was extracted (ethyl acetate), washed and concentrated to obtain a crude product. It was separated by column chromatography (petroleum ether:ethyl acetate = 1:0~0:1) to obtain 32A (500 mg, yield 17.28%).

[0197] Step 2: 32A (0.13 g, 0.36 mmol), copper bromide (0.24 g, 1.08 mmol), tert-butyl nitrite (0.11 g, 1.08 mmol) and acetonitrile (3 mL) were sequentially added to a 50 mL reaction flask. After the addition was completed, the mixture was stirred at room temperature for 2 hours for reaction. The reaction solution was extracted (with ethyl acetate), washed, and concentrated to obtain a crude product. It was separated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain 32B (90 mg, yield 58.88%).

[0198] Step 3: 32B (90 mg, 0.21 mmol), 1B (74 g, 0.42 mmol), potassium carbonate (35 mg, 0.25 mmol), Xantphos (24 mg, 0.04 mmol), Pd2(dba)3 (19 mg, 0.02 mmol) and 1,4-dioxane (3 mL) were sequentially added to a 50 mL reaction flask. The mixture was stirred at 120 °C for 5 hours for reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 32 (18.28 mg, yield 16.74%). LCMS m / z = 520.9 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.84 (d, 1H), 7.66 - 7.59 (m, 3H), 4.17 (s, 3H), 3.99 (s, 4H), 2.20 (t, 4H), 1.89 - 1.81 (m, 2H). Example 33

Chemical Structure

[0199] Step 1: 33A (2.92 g, 39.98 mmol) and water (40 mL) were added to a 250 mL single-neck flask. 4B (2.10 g, 11.76 mmol) was added at 0 - 5 °C, and the reaction was carried out at room temperature for 4 hrs. After complete reaction, the reaction was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 33B (2.2 g, yield 89%). LCMS m / z = 209.1 [M+H] + ;

[0200] Step 2: In a 100 mL single-neck flask, 33B (2.0 g, 9.61 mmol) was added to trimethyl orthoformate (20 mL), and the reaction was carried out at 105 °C overnight. After complete reaction, it was cooled to room temperature. After concentrating the reaction, it was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain 33C (870 mg, yield 41%). LCMS m / z = 219.1 [M+H] + ;

[0201] Step 3: In a 25 mL single-neck flask, 33C (0.87 g, 3.99 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Under an ice bath, cesium carbonate (1.56 g, 4.79 mmol) was slowly added. After addition, it was stirred at room temperature for 0.5 h for reaction. Under an ice bath, 2,3,6-trifluorobenzonitrile (0.66 g, 4.19 mmol) was slowly added dropwise. After addition, it was stirred at room temperature overnight for reaction. After complete reaction, ethyl acetate (15 mL) was added to the reaction system to dilute the reaction, then water (20 mL) was added to quench the reaction. It was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with water (20 mL × 2). After concentrating the organic phase, it was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 33D (0.71 g, yield 50%). LCMS m / z = 356.2 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.00 ‐ 7.94 (m, 1H), 7.82 - 7.80 (d, 1H), 7.76 - 7.73 (dd, 1H), 7.61 - 7.55 (m, 2H), 5.55 - 4.47 (p, 1H), 4.97 - 4.93 (t, 2H), 4.89 - 4.85 (t, 2H).

[0202] Step 4: In a 25 mL single-neck flask, 1B (0.22 g, 1.24 mmol) and cesium carbonate (0.44 g, 1.36 mmol) were added to dry N,N-dimethylformamide (10 mL). After reacting at 50 °C for 30 min, a solution of 33D (0.40 g, 1.13 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50 °C. After the addition was complete, the mixture was stirred at 80 °C for 4 h. After complete reaction, the reaction mixture was filtered, and the filtrate was separated and purified by preparative liquid purification (equipment: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 min) to obtain 220 mg of a solid. The solid was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 33 (160 mg, yield 27%). LCMS m / z = 512.6 [M + H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.38 (s, 1H), 7.89 ‐ 7.80 (m, 2H), 7.72 - 7.69 (dd, 1H), 7.55 - 7.52 (dd, 1H), 7.37 - 7.36 (d, 1H), 5.53 - 5.45 (p, 1H), 4.96 - 4.92 (t, 2H), 4.88 - 4.84 (t, 2H), 3.83 (s, 4H), 2.12 - 2.08 (t, 4H), 1.78 ‐ 1.70 (m, 2H).

[0203] 1919F NMR (377 MHz, DMSO-d6) δ -127.30 (s). Example 34 [Chemical formula]

[0204] Step 1: 34A (2.00 g, 17.57 mmol) and water (20 mL) were added to a 250 mL single-necked flask. A solution of sodium hydroxide (0.62 g, 15.62 mmol) in water (20 mL) was slowly added dropwise at 0 - 5 °C, and the reaction was carried out at 0 - 5 °C for 10 min. Then 4B (0.87 g, 4.88 mmol) was added at 0 - 5 °C, and the reaction was carried out at room temperature for 4 hrs. After complete reaction, the reaction was concentrated and then purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 34B (0.83 g, yield 80%). LCMS m / z = 213.1 [M+H] + ;

[0205] Step 2: In a 100 mL single-necked flask, 34B (0.72 g, 3.39 mmol) was added to trimethyl orthoformate (10 mL), and the reaction was carried out at 105 °C overnight. After complete reaction, it was cooled to room temperature, the reaction was concentrated, and then purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain 34C (280 mg, yield 37%). LCMS m / z = 223.2 [M+H] + ;

[0206] Step 3: In a 25 mL single-necked flask, 34C (0.28 g, 1.26 mmol) was dissolved in dry N,N-dimethylformamide (4 mL). Under an ice bath, cesium carbonate (0.49 g, 1.51 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 0.5 h for reaction. Under the ice bath, 2,3,6-trifluorobenzonitrile (0.22 g, 1.39 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight for reaction. After complete reaction, ethyl acetate (10 mL) was added to the reaction system to dilute the reaction, then water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was washed with water (10 mL × 2). After concentrating the organic phase, it was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 34D (0.25 g, yield 55%). LCMS m / z = 360.1[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s,1H), 8.01 ‐ 7.95 (m,1H), 7.81 - 7.73 (m,2H), 7.62 ‐ 7.56 (m,2H), 5.17 ‐ 5.04 (m,1H), 4.91-4.86 (dd,0.5H), 4.79 ‐ 4.75 (m,1H), 4.67-4.63 (dd,0.5H), 1.48-1.45 (dd,3H).

[0207] Step 4: In a 25 mL single-neck flask, 1B (0.13 g, 0.73 mmol) and cesium carbonate (0.27 g, 0.84 mmol) were added to dry N,N-dimethylformamide (6 mL). After reacting at 50 °C for 30 min, a solution of 34D (0.25 g, 0.70 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50 °C. After the addition was complete, the mixture was stirred at 80 °C for 4 h. After complete reaction, the reaction was filtered, and the filtrate was separated and purified by preparative liquid purification (equipment: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 min) to obtain compound 34 (110 mg, yield 30%). LCMS m / z = 516.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.42 (s, 1H), 7.90 - 7.85 (dd, 1H), 7.82 - 7.79 (d, 1H), 7.73 - 7.70 (dd, 1H), 7.56 - 7.52 (dd, 1H), 7.38 - 7.37 (d, 1H), 5.13 - 5.04 (m, 1H), 4.90 - 4.85 (dd, 0.5H), 4.78 ‐ 4.73 (m, 1H), 4.65 - 4.62 (dd, 0.5H), 3.84 (s, 4H), 2.11 - 2.07 (t, 4H), 1.77 ‐ 1.70 (m, 2H), 1.45 ‐ 1.44 (m, 3H).

[0208] 19 F NMR (377 MHz, DMSO-d6) δ -72.80 (s), -127.34 (s). Example 35

Chemical Structure

[0209] Step 1: 35A (2.50 g, 22.01 mmol) and water (25 mL) were added to a 250 mL single-neck flask. A solution of sodium hydroxide (0.79 g, 19.78 mmol) in water (25 mL) was slowly added dropwise at 0 - 5 °C, and the reaction was carried out at 0 - 5 °C for 10 min. Then 4B (1.10 g, 6.18 mmol) was added at 0 - 5 °C, and the reaction was carried out at room temperature for 4 hrs. After complete reaction, the reaction was concentrated and then purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 35B (0.65 g, yield 49%). LCMS m / z = 213.1[M+H] + ;

[0210] Step 2: In a 100 mL single-neck flask, 35B (0.72 g, 3.39 mmol) was added to triethyl orthoformate (10 mL), and the reaction was carried out at 180 °C for 2.5 hrs under microwave irradiation. After complete reaction, it was cooled to room temperature, the reaction was concentrated to obtain crude 35C, and the reaction of the next step was carried out directly. LCMS m / z = 223.2[M+H] + ;

[0211] Step 3: In a 25 mL single-neck flask, the crude 35C was dissolved in dry N,N-dimethylformamide (10 mL). Under an ice bath, cesium carbonate (1.1 g, 3.41 mmol) was slowly added dropwise. After addition, it was stirred at room temperature for 0.5 h for reaction. Under an ice bath, 2,3,6-trifluorobenzonitrile (0.49 g, 3.12 mmol) was slowly added dropwise. After addition, it was stirred at room temperature overnight for reaction. After complete reaction, ethyl acetate (20 mL) was added to the reaction system to dilute the reaction, then water (20 mL) was added to quench the reaction. It was extracted with ethyl acetate (20 mL × 2), the organic phase was washed with water (20 mL × 2), the organic phase was concentrated and then purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 35D (0.16 g, yield 15%). LCMS m / z = 360.1[M+H] + ;

[0212] Step 4: In a 25 mL single-neck flask, 1B (83.27 mg, 0.47 mmol) and cesium carbonate (0.17 g, 0.54 mmol) were added to dry N,N-dimethylformamide (4 mL). After reacting at 50 °C for 30 min, a solution of 35D (0.16 g, 0.45 mmol) in N,N-dimethylformamide (1 mL) was added dropwise at 50 °C. After the addition was complete, the mixture was stirred at 80 °C for 3 h. After complete reaction, the reaction mixture was filtered, and the filtrate was separated and purified by preparative liquid purification (equipment: Waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 min) to obtain compound 35 (105 mg, yield 45%). LCMS m / z = 516.6 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.42 (s, 1H), 7.90 - 7.79 (m, 2H), 7.73 - 7.70 (dd, 1H), 7.56 - 7.52 (dd, 1H), 7.38 - 7.37 (d, 1H), 5.13 - 5.04 (m, 1H), 4.89 - 4.85 (dd, 0.5H), 4.78 - 4.73 (m, 1H), 4.65 - 4.62 (dd, 0.5H), 3.83 (s, 4H), 2.11 - 2.07 (t, 4H), 1.77 - 1.70 (m, 2H), 1.46 - 1.44 (d, 3H).

[0213] 19 F NMR (377 MHz, DMSO-d6) δ -74.66 (s), -129.42 (s). Example 36 and Example 37

Chemical Structure

[0214] Compound 17 (300 mg) was resolved by chiral SFC to obtain P1 (retention time: 0.588 min, designated as compound 36) and P2 (retention time: 0.694 min, designated as compound 37). Resolution method: Instrument name: Waters 150 Prep-SFC F, Chromatography column: Chiralcel AD-Column, Mobile phase: A for CO2 and B for 0.1% NH3·H2O in MEOH and ACN, Gradient: Isocratic elution, Mobile phase B content 35%, Flow rate: 120 mL / min. Sample preparation: The compound was dissolved in acetonitrile with a concentration of 10 mg / mL, Injection: 2.0 mL of sample was taken each time, Treatment: After separation, it was concentrated by a rotary evaporator at 35 °C, and then the solvent was dried by a freeze dryer at -80 °C to obtain compound 36 (86 mg, 29%) and compound 37 (74 mg, 25%).

[0215] Compound 36: LCMS m / z = 456.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.35 (s, 1H), 7.84 (t, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.62 (dd, 1H), 7.37 (d, 1H), 3.47 (s, 3H), 3.40 ‐ 3.34 (m, 1H), 3.17 (dd, 1H), 2.93 (dd, 1H), 2.10 ‐ 2.01 (m, 1H), 1.96 (dd, 1H), 1.60 (dt, 1H), 0.81 ‐ 0.75 (m, 1H), 0.50 (dd, 1H).

[0216] 19 F NMR (377 MHz, DMSO-d6) δ -128.22 (s).

[0217] Compound 37: LCMS m / z = 456.1 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.36 (s, 1H), 7.85 (t, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.62 (dd, 1H), 7.38 (d, 1H), 3.47 (s, 3H), 3.37 (s, 1H), 3.17 (s, 1H), 2.93 (dd, 1H), 2.09 ‐ 2.00 (m, 1H), 1.98 (d, 1H), 1.60 (s, 1H), 0.78 (s, 1H), 0.50 (d, 1H).

[0218] 19 19F NMR (377 MHz, DMSO-d6) δ -128.22 (s). Example 38

Chemical Structure

[0219] Step 1: 38A (16.66 g, 119.37 mmol) and water (120 mL) were added to a 1000 mL single-necked flask. A solution of sodium hydroxide (4.29 g, 107.30 mmol) in water (120 mL) was slowly added dropwise at 0 - 5 °C, and the mixture was reacted at 0 - 5 °C for 10 min. Then, 6-hydroxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (6.00 g, 33.53 mmol) was added at 0 - 5 °C, and the reaction was carried out at room temperature for 4 hrs. After complete reaction, the reaction was concentrated and then purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 38B (3.0 g, yield 37.56%). LCMS m / z = 239.1 [M + H] + ;

[0220] Step 2: In a 100 mL single-necked flask, 38B (2.7 g, 11.33 mmol) was added to dry N,N-dimethylformamide (30 mL). Triethyl orthoformate (30 mL) was added at room temperature, and the reaction was carried out at 150 °C for 4 hrs. After complete reaction, the reaction was cooled to room temperature, concentrated, and the crude product 38C was obtained, and the reaction of the next step was carried out directly. LCMS m / z = 249.1 [M+H] + ;

[0221] Step 3: In a 25 mL single-necked flask, 38C was dissolved in dry N,N-dimethylformamide (30 mL) at 38 °C. Under an ice bath, cesium carbonate (4.11 g, 13.54 mmol) was slowly added dropwise. After addition was complete, the mixture was stirred at room temperature for 0.5 h for reaction. Under an ice bath, 2,3,6-trifluorobenzonitrile (1.95 g, 12.41 mmol) was slowly added dropwise. After addition was complete, the mixture was stirred at room temperature overnight for reaction. After complete reaction, ethyl acetate (100 mL) was added to the reaction system to dilute the reaction, then water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with water (100 mL × 2). After concentration of the organic phase, it was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 38D (2.4 g, yield 55%). LCMS m / z = 386.2 [M+H] + ;

[0222] Step 4: In a 25 mL single-necked flask, 1B (1.32 g, 7.48 mmol) and cesium carbonate (3.04 g, 9.37 mmol) were added to dry N,N-dimethylformamide (20 mL). After reacting at 50 °C for 30 min, a solution of 38D (2.40 g, 6.23 mmol) in N,N-dimethylformamide (10 mL) was added dropwise at 50 °C. After addition was complete, the mixture was stirred at 80 °C overnight for reaction. After complete reaction, the reaction was filtered. After concentration of the filtrate organic phase, it was purified by column chromatography (dichloromethane / petroleum ether = 10 / 1) to obtain compound 38E (2.1 g, yield 62%). LCMS m / z = 542.4 [M+H] + ;

[0223] Step 5: In a 25 mL single-neck flask, add 38E (2.00 g, 3.69 mmol) to methanol (5 mL), and dropwise add an aqueous ammonia-methanol solution (7.0 M, 40 mL) at 0 - 5 °C. After addition, stir at room temperature overnight for reaction. After complete reaction, concentrate the reaction solution to obtain compound 38F (crude product), and carry out the reaction of the next step. LCMS m / z = 513.1 [M + H] + ;

[0224] Step 6: In a 25 mL single-neck flask, add 38F (0.21 g, 0.41 mmol) to dry dichloromethane (6 mL), and add the Burgess reagent (195.41 g, 0.82 mmol) at 0 - 5 °C. After addition, stir at room temperature overnight for reaction. Filter the reaction, and separate and purify the filtrate by preparative liquid purification (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 38 (35 mg, yield 17%). LCMS m / z = 495.1 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.40 (s, 1H), 7.90 - 7.82 (m, 2H), 7.75 - 7.73 (dd, 1H), 7.56 - 7.52 (dd, 1H), 7.44 - 7.43 (d, J = 2.9 Hz, 1H), 5.08 (s, 2H), 3.84 (s, 4H), 2.11 - 2.08 (t, 4H), 1.78 - 1.70 (m, 2H).

[0225] 19 F NMR (377 MHz, DMSO-d6) δ -127.33 (s). Example 39

Chemical formula

[0226] Step 1: In a 100 mL single-necked flask, 26B (627 mg, 3.01 mmol), 39A (701 mg, 3.01 mmol), and cesium carbonate (1.47 g, 4.51 mmol) were dissolved in dry N,N-dimethylformamide (25 mL). After addition, the mixture was stirred at room temperature for 2 h for reaction. After complete reaction, the reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed twice with water (60 mL), twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Then, it was purified by column chromatography (PE:EA = 1:1) to obtain compound 39C (800 mg, yield: 74%).

[0227] Step 2: Compound 39C (800 mg, 2.22 mmol), copper(II) bromide (992 mg, 4.44 mmol), and acetonitrile (40 ml) were added to a single-necked flask. Under an ice bath, tert-butyl nitrite (458 mg, 4.44 mmol) was slowly added dropwise. After addition, the mixture was reacted at room temperature for 1 h. After complete reaction, diatomaceous earth was spread, filtered, and the filtrate was concentrated. Then, the residue was separated by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 0:1) to obtain compound 39D (814 mg, yield: 86%).

[0228] Step 3: In a 100 mL single-necked flask, 39D (550 mg, 1.30 mmol), 39E (275 mg, 1.56 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (110 mg, 0.26 mmol), allyl palladium chloride (71 mg, 0.20 mmol), and potassium carbonate (629 mg, 4.55 mmol) were dissolved in dry methyl tetrahydrofuran (40 mL). After addition, the mixture was purged with nitrogen gas and stirred at 70 °C for 5 h for reaction. After complete reaction, the reaction solution was filtered, the filtrate was concentrated, and the obtained oily liquid was purified by column chromatography (DCM:EA = 1:2) to obtain a crude compound. The crude product was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 30% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 39 (210 mg, yield: 31%). LCMS m / z = 520.50[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.80 (d, 1H), 7.75 (dd, 1H), 7.59 (d, 1H), 7.53 (dd, 1H), 4.72 (dt, 2H), 4.32 (dt, 2H), 3.85 (s, 4H), 2.10 (t, 4H), 1.79 ‐ 1.68 (m, 2H).

[0229] 19 F NMR (376 MHz, DMSO-d6) δ -121.46 (s), -150.87 (s), -222.31 (s). Example 40 and Example 41:

Chemical formula

[0230] Step 1: In a 25 mL single-neck flask, 29C (0.400 g, 2.06 mmol) and cesium carbonate (1.01 g, 3.09 mmol) were added to dry N,N-dimethylformamide (10 mL). After reacting at 50 °C for 30 min, a solution of 10E (0.748 g, 2.06 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50 °C. After the addition was complete, the mixture was stirred at 100 °C overnight. After complete reaction, the reaction solution was filtered. The filter cake was washed with N,N-dimethylformamide (4 mL), and the filtrate was concentrated and then dissolved in water (15 mL) and ethyl acetate (10 mL). The liquids were separated, and the aqueous phase was extracted once with ethyl acetate (10 mL). Then, the pH was adjusted to about 7 with saturated ammonium chloride solution, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 40A crude product, which was directly used in the reaction of the next step. LCMS m / z = 538.5 [M+H] + ;

[0231] Step 2: The crude product 40A was resolved by chiral SFC to obtain P1 (retention time: 14.73 min, designated as compound 40) and P2 (retention time: 24.02 min, designated as compound 41). Resolution method: Instrument name: Waters 150 SFC, chromatography column: AD, mobile phase: A for CO2 and B for IPA+MeOH (0.05% NH3·H2O), flow rate: 42 mL / min, column pressure: 100 bar, column temperature: 25 °C, absorption wavelength: 220 nm, cycle time: 40 min). Sample preparation: The compound was dissolved in methanol at a concentration of 40 mg / mL. Injection: 5 mL was sampled each time. Treatment: After separation, it was concentrated by a rotary evaporator at 35 °C, and then the solvent was dried by a freeze dryer at -80 °C to obtain P1 and P2.

[0232] Compound 40: (P1: 120 mg, 11%) 11H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.33 (s, 1H), 7.83 - 7.80 (m, 2H), 7.72 - 7.69 (dd, 1H), 7.54 - 7.50 (dd, 1H), 7.43 - 7.42 (d, 1H), 6.51 - 6.22 (m, 1H), 5.02 - 4.99 (dt, 1H), 4.51 - 4.43 (td, 2H), 4.16 - 4.14 (d, 1H), 3.92 - 3.77 (m, 3H), 2.18 - 2.07 (m, 1H), 2.00 - 1.79 (m, 2H), 1.69 - 1.62 (m, 1H).

[0233] 19 19F NMR (376 MHz, DMSO-d6) δ -120.44 (s), -171.59 (s), -216.41 (s).

[0234] Compound 41: (P2: 140 mg, 13%) 1 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.34 (s, 1H), 7.88 - 7.80 (m, 2H), 7.73 - 7.70 (dd, 1H), 7.54 - 7.51 (dd, 1H), 7.43 - 7.42 (d, 1H), 6.51 - 6.22 (m, 1H), 5.03 - 4.99 (dt, 1H), 4.51 - 4.43 (td, 2H), 4.17 - 4.15 (d, 1H), 3.93 - 3.78 (m, 3H), 2.18 - 2.10 (m, 1H), 2.00 - 1.79 (m, 2H), 1.69 - 1.62 (m, 1H).

[0235] 19 19F NMR (376 MHz, DMSO-d6) δ -120.44 (s), -127.17 (s), -171.59 (s). Example 42

Chem.

[0236] Step 1: 42A (420 mg, 1.70 mmol) and acetonitrile (5 mL) were added to a 25 mL single-necked flask. Triethylamine (0.430 g, 4.25 mmol) and (tert-butoxycarbonyl)((4-(dimethylimino)pyridin-1(4H)yl)sulfonyl)amide (0.615 g, 2.04 mmol) were slowly added dropwise at 0 - 5 °C, and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction was concentrated to obtain crude product 42B, and the reaction of the next step was carried out directly. LCMS m / z = 257.1[M+H] + ;

[0237] Step 2: In a 25 mL single-necked flask, the crude product 42B was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 mL) was slowly added dropwise at 0 - 5 °C. After the addition was complete, the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction was concentrated, and after concentrating the organic phase, it was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain 42C (0.250 g, yield 70%). LCMS m / z = 213.2[M+H] + ;

[0238] Step 3: In a 25 mL single-necked flask, 42C (0.250 g, 1.18 mmol) and cesium carbonate (0.577 g, 1.77 mmol) were added to dry N,N-dimethylformamide (5 mL). After reacting at 50 °C for 30 min, a solution of 10E (0.429 g, 1.18 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50 °C. After the addition was complete, the mixture was stirred and reacted overnight at 80 °C. After the reaction was complete, the reaction solution was filtered, and the filtrate was separated and purified by preparative liquid purification (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 42 (110 mg, yield 17%). LCMS m / z = 556.0 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.34 (s, 1H), 7.92 ‐ 7.87 (m, 1H), 7.83 - 7.80 (d, 1H), 7.73 - 7.70 (dd, 1H), 7.55 - 7.52 (dd, 1H), 7.44 (d, 1H), 6.51 - 6.22 (m, 1H), 4.52 - 4.43 (m, 2H), 4.08 - 4.06 (d, 2H), 3.91 - 3.88 (d, 2H), 2.47 ‐ 2.42 (m, 2H), 2.04 - 2.00 (m, 2H).

[0239] 19 F NMR (376 MHz, DMSO-d6) δ -98.98 (s), -120.45 (s), -126.75 (s). Example 43

Chemical Structure

[0240] Step 1: In a 100 mL single-necked flask, 10C (700 mg, 3.09 mmol), 39A (720 mg, 3.09 mmol), and cesium carbonate (1.53 g, 4.63 mmol) were dissolved in dry N,N-dimethylformamide (25 mL). After addition, the mixture was stirred at room temperature for 2 h for reaction. After complete reaction, the reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed twice with water (60 mL) and twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and then purified by column chromatography (PE:EA = 1:1) to obtain compound 43C (830 mg, yield: 71%).

[0241] Step 2: Compound 43C (830 mg, 2.22 mmol), copper bromide (992 mg, 4.44 mmol), and acetonitrile (40 ml) were added to a one-neck flask. tert-Butyl nitrite (458 mg, 4.44 mmol) was slowly added dropwise under an ice bath. After the addition was complete, the reaction was carried out at room temperature for 1 hour. After complete reaction, diatomaceous earth was spread and filtered. After concentrating the filtrate, the residue was separated by column chromatography (petroleum ether: ethyl acetate (v / v) = 1:0 to 0:1) to obtain Compound 43D (800 mg, yield: 82%).

[0242] Step 3: In a 100 mL one-neck flask, 43D (800 mg, 1.81 mmol), 1B (400 mg, 2.26 mmol), 2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl (154 mg, 0.36 mmol), allyl palladium chloride (99 mg, 0.27 mmol), and potassium carbonate (625 mg, 4.25 mmol) were dissolved in dry methyl tetrahydrofuran (40 mL). After the addition was complete, it was replaced with nitrogen gas and stirred at 70 °C for 5 h for reaction. After complete reaction, the reaction solution was filtered, the filtrate was concentrated, and the obtained oily liquid was purified by column chromatography (DCM:EA = 1:2) to obtain a crude compound. The crude product was separated and purified by preparative liquid (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 30% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain Compound 43 (56 mg, yield: 6%). LCMS m / z = 538.1 [M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.81 (d, 1H), 7.77 (dd, 1H), 7.59 (d, 1H), 7.52 (dd, 1H), 6.52 - 6.23 (m, 1H), 4.49 (td, 2H), 3.83 (s, 4H), 2.08 - 2.11 (m, 4H), 1.77 - 1.70 (m, 2H). Example 44

Chemical Structure

[0243] Step 1: 44A (4.5 g, 23.13 mmol) and isopropyl alcohol (50 mL) were added to a 250 mL single-neck flask, and then triethylamine (4.68 g, 46.26 mmol) and isopropanolamine (2.08 g, 27.76 mmol) were added. The reaction was carried out at 80 °C for 1 hr. After the reaction was complete, the reaction mixture was concentrated, then triturated with ethyl acetate (50 mL), filtered, and the filter cake was washed with petroleum ether (50 mL) to obtain 44B (5.30 g, yield 98%). LCMS m / z = 234.3 [M+H] + ;

[0244] Step 2: Phosphoryl chloride (60 mL) was added to a 250 mL single-neck flask, and 44B (5.3 g, 22.72 mmol) was slowly added portionwise at 0 - 5 °C. After addition was complete, the reaction was carried out at 110 °C for 5 hrs. After the reaction was complete, the reaction solution was concentrated, and water (100 mL) was slowly added at 0 - 5 °C to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 2), and the organic phase was concentrated and then purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 44C (3.6 g, yield 73%). LCMS m / z = 216.2 [M+H] + ;

[0245] Step 3: 4C (2.80 g, 13.01 mmol) and acetonitrile (30 mL) were added to a 100 mL single-neck flask. Next, alumina (2.65 g, 25.99 mmol) and potassium permanganate (3.08 g, 19.49 mmol) were added. After addition, the mixture was stirred at room temperature overnight for reaction. After complete reaction, the reaction solution was filtered, and the filtrate was concentrated. Then, it was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain 44D (0.88 g, yield 31%). LCMS m / z = 214.1[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.86 - 7.84 (d, 1H), 7.74 - 7.73 (d, 1H), 7.35 (s, 1H), 7.32 - 7.29 (dd, 1H), 3.94 (s, 3H), 2.58 (s, 3H).

[0246] Step 4: 4D (0.88 g, 4.13 mmol) and N,N-dimethylformamide (10 mL) were added to a 50 mL single-neck flask. Next, sodium thioethane (1.04 g, 12.35 mmol) was added. After addition, it was protected with nitrogen gas and stirred at 130 °C overnight for reaction. After complete reaction, the reaction solution was concentrated, dilute hydrochloric acid was added to adjust the pH value to acidic, and after concentration, a residue was obtained. The residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain 44E (0.68 g, yield 82%). LCMS m / z = 200.1[M+H] + ;

[0247] Step 5: In a 25 mL single-neck flask, 44E (0.30 g, 1.51 mmol) was dissolved in dry N,N-dimethylformamide (8 mL). Under an ice bath, cesium carbonate (0.74 g, 2.26 mmol) was slowly added. After the addition, the mixture was stirred at room temperature for 0.5 h for reaction. Under the ice bath, 2,3,6-trifluorobenzonitrile (0.28 g, 1.81 mmol) was slowly added dropwise. After the addition, the mixture was stirred at room temperature overnight for reaction. After complete reaction, the reaction solution was filtered, and the filtrate was concentrated. Then, it was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 44F (0.45 g, yield 88%). LCMS m / z=337.0[M+H] + ;

[0248] Step 6: In a 25 mL single-neck flask, 1B (0.21 g, 1.16 mmol) and cesium carbonate (0.47 g, 1.46 mmol) were added to dry N,N-dimethylformamide (5 mL). After reacting at 50 °C for 30 min, a solution of 44F (0.36 g, 0.97 mmol) in N,N-dimethylformamide (1 mL) was added dropwise at 50 °C. After the addition, the mixture was stirred at 80 °C for 4 h for reaction. After complete reaction, the reaction solution was filtered, the filter cake was washed with N,N-dimethylformamide (2 mL), and the filtrate was concentrated. Then, ethyl acetate (15 mL) and water (15 mL) were added to dissolve it. The liquid was separated, and the pH value of the aqueous phase was adjusted to neutral with saturated ammonium chloride. It was extracted with dichloromethane (20 mL × 3). After combining the organic phases, they were dried over anhydrous sodium sulfate and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 44 (61 mg, yield 12%). LCMS m / z=493.5[M+H] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.19 (s, 1H), 8.00 - 7.98 (d, 1H), 7.93 - 7.88 (t, 1H), 7.81 (s, 1H), 7.59 - 7.55 (m, 2H), 7.52 - 7.51 (d, 1H), 3.84 (s, 4H), 2.36 (s, 3H), 2.10 - 2.06 (t, 4H), 1.73 ‐ 1.65 (m, 2H).

[0249] 19 19F NMR (376 MHz, DMSO-d6) δ -127.37 (s). Example 45

Chem.

[0250] Step 1: 45A (10 g, 61.33 mmol) and N,N-dimethylformamide (100 mL) were added to a 250 mL single-neck flask. At 0 - 5 °C, N,N-diisopropylethylamine (15.85 g, 122.64 mmol) and 1-fluoro-2-iodoethane (12.80 g, 73.63 mmol) were slowly added dropwise, and the reaction was carried out at 80 °C overnight. After the reaction was complete, the reaction solution was added dropwise to water (500 mL), and a large amount of solid precipitated. After stirring for 30 min, the mixture was filtered, and the filter cake was washed with water (100 mL) and petroleum ether (50 mL). Then the filter cake was concentrated to obtain 45B (10.0 g, yield 78%). LCMS m / z = 210.2 [M + H] + ;

[0251] Step 2: In a 500 mL single-neck flask, 45B (10 g, 47.81 mmol) was dissolved in dichloromethane (260 mL) and methanol (26 mL). Hydrazine hydrate (5.98 g, 95.62 mmol) was slowly added dropwise at room temperature. After the addition was complete, the reaction was carried out at room temperature for 2.5 hrs. After complete reaction, the reaction solution was filtered, and the filtrate was washed with 5N aqueous ammonia (200 mL), extracted with dichloromethane (200 mL × 2), the organic phase was dried over anhydrous sodium sulfate and then concentrated. The residue was dissolved in ethanol (50 mL), then concentrated hydrochloric acid (8 mL) was added, and after stirring for 30 min, it was concentrated again. The obtained residue was triturated with ethyl acetate (30 mL) and filtered to obtain 45C (1.90 g, yield 34%). 1 H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 3H), 4.74 ‐ 4.72 (m, 1H), 4.62 ‐ 4.60 (m, 1H), 4.36 ‐ 4.34 (m, 1H), 4.29 ‐ 4.27 (m, 1H).

[0252] Step 3: 45C (0.49 g, 3.23 mmol) and water (10 mL) were added to a 250 mL single-neck flask. A solution of sodium hydroxide (0.12 g, 3.04 mmol) in water (10 mL) was slowly added dropwise at 0 - 5 °C, and the reaction was carried out at 0 - 5 °C for 10 min. Then, 6-hydroxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (0.17 g, 0.95 mmol) was added at 0 - 5 °C, and the reaction was carried out overnight at room temperature. After complete reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain 45D (0.20 g, yield 98%). LCMS m / z = 215.1 [M + H] + ;

[0253] Step 4: In a 100 mL single-neck flask, 45D (0.2 g, 0.93 mmol) was added to triethyl orthoformate (3 mL) and N,N-dimethylformamide (3 mL), and reacted at 150 °C for 4 hrs. After complete reaction, it was cooled to room temperature, and after concentrating the reaction solution, crude product 45E was obtained and directly used for the reaction in the next step. LCMS m / z=225.1[M+H] + ;

[0254] Step 5: In a 25 mL single-neck flask, 45E (0.31 g, 1.38 mmol) was dissolved in dry N,N-dimethylformamide (5 mL). Under an ice bath, cesium carbonate (0.54 g, 1.66 mmol) was added, and 2,3,6-trifluorobenzonitrile (0.24 g, 1.52 mmol) was slowly added dropwise. After addition was complete, it was stirred at room temperature overnight for reaction. After complete reaction, the reaction was filtered, and after concentrating the filtrate, it was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain 45F (0.36 g, yield 72%). LCMS m / z=362.4[M+H] + ;

[0255] Step 6: In a 25 mL single-neck flask, 1B (0.21 g, 1.20 mmol) and cesium carbonate (0.49 g, 1.5 mmol) were added to dry N,N-dimethylformamide (8 mL), and reacted at 50 °C for 30 min. Then, a solution of 45F (0.36 g, 1.00 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50 °C. After addition was complete, it was stirred at 80 °C overnight for reaction. After complete reaction, the reaction solution was filtered, and the filtrate was separated and purified by preparative liquid purification (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm×150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 45 (83.0 mg, yield 16%). LCMS m / z=518.2[M+H]+ ; 1 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.58 (s, 1H), 7.91 - 7.83 (m, 2H), 7.74 - 7.71 (dd, 1H), 7.56 - 7.53 (dd, 1H), 7.42 - 7.41 (d, 1H), 4.83 - 4.69 (m, 2H), 4.59 - 4.49 (m, 2H), 3.84 (s, 4H), 2.12 - 2.08 (t, 4H), 1.78 - 1.70 (m, 2H).

[0256] 19 19F NMR (376 MHz, DMSO-d6) δ -127.24 (s), -220.60 (s). Example 46

Chemical Structure

[0257] Step 1: In a 25 mL single-neck flask, 22C (1.35 g, 7.29 mmol) was dissolved in dry N,N-dimethylformamide (30 mL). Under an ice bath, cesium carbonate (4.75 g, 14.58 mmol) was slowly added dropwise. After addition, the mixture was stirred at room temperature for 0.5 h for reaction. Under the ice bath, 39A (1.51 g, 8.75 mmol) was slowly added dropwise. After addition, the mixture was stirred at 30 °C overnight for reaction. After complete reaction, the reaction solution was filtered, and the filtrate was concentrated and then purified by column chromatography (petroleum ether / ethyl acetate = 3 / 7) to obtain 46A (2.3 g, yield 93%). LCMS m / z = 338.3 [M + H] + ;

[0258] Step 2: In a 25 mL single-necked flask, 46A (2.30 g, 6.82 mmol) was dissolved in dry acetonitrile (50 mL). At 0 - 5 °C, tert-butyl nitrite (0.71 g, 6.89 mmol) and copper(II) bromide (1.54 g, 6.90 mmol) were sequentially added slowly. After the addition was complete, the mixture was stirred at room temperature overnight for reaction. After complete reaction, the reaction solution was concentrated. After concentration, saturated sodium bicarbonate (100 mL) was added to quench the reaction, and it was dissolved in ethyl acetate (100 mL), then filtered. The filtrate was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, then concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain 46B (1.00 g, yield 36%). LCMS m / z = 401.0[M + H] + ;

[0259] Step 3: 46B (0.80 g, 1.99 mmol), 1B (0.46 g, 2.59 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.10 g, 0.20 mmol), potassium carbonate (0.41 g, 2.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.11 g, 0.19 mmol) were added to dry 1,4-dioxane (16 mL). After purging with nitrogen gas for 2 min, the reaction was carried out at 120 °C under microwave irradiation for 1 h. After the reaction was complete, the filtrate was concentrated, ethyl acetate (20 mL) and water (20 mL) were added and dissolved, the liquids were separated, the pH value of the aqueous phase was adjusted to neutral with saturated ammonium chloride, and extracted with ethyl acetate (20 mL × 3). After combining the organic phases, they were dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 2). After purification, it was resolved by chiral SFC to obtain compound 46 (retention time: 2.08 min). Resolution method: Instrument name: Waters 150 Prep-SFC F, chromatography column: Chiralcel AD column, mobile phase: A for CO2 and B for MeOH (0.1% NH3·H2O), gradient: B 40%, flow rate: 100 mL / min, column pressure: 100 bar, column temperature: 25 °C, absorption wavelength: 220 nm cycle time: 3.8 min). Sample preparation: The compound was dissolved in acetonitrile at a concentration of 10 mg / mL, injection: 3.5 mL was sampled each time, treatment: after separation, it was concentrated by a rotary evaporator at 35 °C, and then the solvent was dried by a freeze dryer at -80 °C to obtain compound 46 (0.18 mg, yield 18%). LCMS m / z = 497.8 [M + H] + ; 11H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.10 - 8.09 (d, 1H), 8.02 - 7.99 (d, 1H), 7.78 - 7.77 (d, 1H), 7.62 ‐ 7.58 (m, 2H), 7.50 - 7.46 (m, 1H), 3.79 (s, 4H), 2.10 - 2.06 (t, 4H), 1.75 ‐ 1.67 (m, 2H). Example 47

Chem.

[0260] Step 1: In a 250 mL single-neck flask, compound 5B (0.55 g, 3.39 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). After adding cesium carbonate (1.42 g, 4.36 mmol), the mixture was reacted at 50 °C for 0.5 h. Next, a solution of 26C (1 g, 2.90 mmol) in N,N-dimethylformamide (10 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at 85 °C for 12 h. After the reaction was completed, ethyl acetate (100 mL) was added, and the mixture was washed with water (70 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 25% - 65% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 47 (700 mg, yield 49%). LCMS m / z = 488.30 [M + H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.33 (s, 1H), 7.88 (t, 1H), 7.80 (d, 1H), 7.76 - 7.68 (m, 1H), 7.61 - 7.56 (m, 1H), 7.41 (d, 1H), 4.79 - 4.62 (m, 2H), 4.36 - 4.25 (m, 2H), 3.97 (s, 4H), 0.61 (s, 4H). Example 48 [Chemical formula]

[0261] Step 1: In a 250 mL single-neck flask, dissolve compound 5B (8.2 g, 50.55 mmol) in dry N,N-dimethylformamide (50 mL). After adding cesium carbonate (16.6 g, 7.41 mmol), stir at 50 °C for 0.5 h. Next, slowly add a solution of 9E (2.5 g, 6.88 mmol) in N,N-dimethylformamide (15 mL). After addition, stir the reaction mixture at 85 °C for 12 h. After completion of the reaction, filter and concentrate the filtrate. The resulting residue is separated and purified by preparative liquid chromatography (equipment: Waters 2767 preparative liquid chromatograph, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 70% acetonitrile, gradient elution, cycle time: 10 minutes) to obtain compound 48 (250 mg, yield 7%). LCMS m / z = 506.90 [M + H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.93 (t, 1H), 7.86 - 7.76 (m, 3H), 7.74 - 7.69 (m, 1H), 7.48 (d, 1H), 6.54 - 6.18 (m, 1H), 4.53 - 4.43 (m, 1H), 3.55 (s, 2H), 3.25 (s, 2H), 0.64 (s, 4H). Example 49 [Chemical formula]

[0262] Step 1: Dissolve raw material 5B (0.45 g, 2.77 mmol) in DMF (10 mL), then add cesium carbonate (0.91 g, 2.79 mmol). Heat the reaction solution to 50 °C and stir for 30 min. Next, add raw material 22D (0.6 g, 1.86 mmol). Heat the reaction solution to 85 °C and stir overnight. After the reaction is completed, filter by laying diatomaceous earth. After concentrating the filtrate, the obtained residue is triturated and purified with EA to obtain 0.50 g of a white solid. Then, pass it through a silica gel column (dichloromethane:methanol = 20:1) to obtain compound 49 (0.38 g, 43.99%). LCMS m / z = 465.3[M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.74 (t, 1H), 7.63 (d, 1H), 7.60 ‐ 7.52 (m, 3H), 3.89 (s, 4H), 0.57 (s, 4H). Example 50

Chemical Structure

[0263] Step 1: In a 100 mL single-necked flask, 39D (500 mg, 1.18 mmol), 5B (230 mg, 1.42 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (100 mg, 0.24 mmol), allyl palladium chloride (65 mg, 0.18 mmol), and potassium carbonate (571 mg, 4.13 mmol) were dissolved in dry methyl tetrahydrofuran (40 mL). After addition, it was replaced with nitrogen gas and stirred at 70 °C for 5 h for reaction. After complete reaction, the reaction solution was filtered, the filtrate was concentrated, and the obtained oily liquid was purified by column chromatography (DCM:EA = 1:2) to obtain a crude compound. The crude product was separated and purified by preparative liquid (equipment: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 30% - 80% acetonitrile, gradient elution, cycle time: 20 minutes) to obtain compound 50 (72 mg, yield: 12%). LCMS m / z = 506.1[M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.79 (d, 1H), 7.74 (dd, 1H), 7.57 (d, 1H), 7.51 (dd, 1H), 4.71 (dt, 2H), 4.32 (dt, 2H), 3.93 (s, 4H), 0.59 (s, 4H). Example 51

Chemical Structure

[0264] Step 1: In a 100 mL single-necked flask, 39D (500 mg, 1.18 mmol), (3R)-3-fluoropyrrolidine-1-sulfonamide (238 mg, 1.42 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (100 mg, 0.24 mmol), allylpalladium chloride (65 mg, 0.18 mmol), and potassium carbonate (571 mg, 4.13 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After addition, the mixture was purged with nitrogen gas and stirred at 70 °C for 5 h to react. After complete reaction, the reaction solution was filtered, and the filtrate was concentrated. The obtained oily liquid was purified by column chromatography (DCM:EA = 1:2) to obtain a crude compound. The crude product was separated and purified by preparative liquid (instrument: waters 2767 preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 150 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing one-thousandth trifluoroacetic acid), gradient: 20% - 80% acetonitrile, gradient elution, cycle time: 15 minutes) to obtain compound 51 (210 mg, yield: 31%). LCMS m / z = 512.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.80 (d, 1H), 7.74 (dd, 1H), 7.58 (d, 1H), 7.52 (dd, 1H), 5.40 (s, 1H), 5.26 (s, 1H), 4.72 (dt, 2H), 4.32 (dt, 2H), 3.57 ‐ 3.31 (m, 4H), 2.23 ‐ 1.99 (m, 2H). Example 52

Chemical Structure

[0265] Step 1: 43D (800 mg, 1.81 mmol), 5B (352 mg, 2.17 mmol), 2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl (80 mg, 0.18 mmol), potassium carbonate (876 mg, 6.33 mmol) were dissolved in dry 1,4-dioxane (40 mL), allylpalladium chloride (33 mg, 0.09 mmol) was added. After addition, it was replaced with nitrogen gas and stirred at 85 °C for 10 h for reaction. After monitoring by TLC (dichloromethane:methanol = 20:1 (v / v)) to confirm complete reaction, the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 50:1 (v / v)) to obtain the target compound 52 (340 mg, yield: 36%). LCMS m / z = 524.2 [M+1] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.81 (d, 1H), 7.77 (dd, 1H), 7.62 (d, 1H), 7.57 (dd, 1H), 6.37 (tt, 1H), 4.49 (td, 2H), 3.99 (s, 4H), 0.61 (s, 4H). Example 53

Chemical Structure

[0266] Step 1: 43D (800 mg, 1.81 mmol), (3R)-3-fluoropyrrolidine-1-sulfonamide (365 mg, 2.17 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (80 mg, 0.18 mmol), potassium carbonate (876 mg, 6.33 mmol) were dissolved in dry 1,4-dioxane (40 mL), allylpalladium chloride (33 mg, 0.09 mmol) was added, and after the addition was complete, the mixture was replaced with nitrogen gas and stirred at 85 °C for 10 h for reaction. After monitoring by TLC (dichloromethane:methanol = 20:1 (v / v)) to confirm complete reaction, the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 65:1 (v / v)) to obtain the target compound 53 (650 mg, yield: 68%). LCMS m / z = 530.1 [M + 1] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.81 (d, 1H), 7.75 (dd, 1H), 7.60 (d, 1H), 7.52 (dd, 1H), 6.37 (tt, 1H), 5.33 (d, 1H), 4.49 (td, 2H), 3.58 ‐ 3.34 (m, 4H), 2.21 ‐ 2.01 (m, 2H).

[0267] Biological Test Example 1: BRAF V600E Enzyme Activity Test BRAF V600E (ABCAM, ab204154), ΜEK1 K97R (USBio, M2865-06J) proteins were diluted at an appropriate multiple using 1× Assay buffer (PH = 7.4 Tris-HCl buffer supplemented with 10 mM MgCl2), and the final concentration of BRAF V600E was set to 10 ng / μL, and the final concentration of the substrate ΜEK1 K97R was set to 1 μM. 1 μL of BRAF V600E, 1 μL of the compound dilution solution (starting from a final concentration of 2 μM, 5-fold dilution, 8 concentrations) was aspirated respectively, 6 μL of Assay buffer was transferred into a 384-well reaction plate with a volume of 20 μL, and pre-incubated at 37 °C for 30 min in a constant temperature incubator. Subsequently, 1 μL of ATP with a concentration of 200 μM and 1 μM of MEK1 K97R were added to the corresponding reaction wells of the compound incubation, shaken uniformly, pre-incubated at 37 °C for 60 min in a constant temperature incubator, and an enzymatic reaction was carried out. After the reaction was completed, 5 μL of the above reaction product was aspirated and put into another 384-well plate, and 5 μL of the prepared ADP-Glo TM Reagent (Promega, V9101) was added, pipetted and mixed uniformly, and left at room temperature for 40 min. 10 μL of Kinase Detection Reagent was added to the 384-well plate, incubated at room temperature for 40 min, and finally, using a microplate reader (BMG LRBTECH), the Luminescence module was selected to detect the LUM fluorescence value of each well (the gain value Gain is constant at 3600), and the formula [Number] was used to calculate the inhibition rate of the compound against BRAF V600E . Fitting analysis was performed using the Graphpad software log(inhibitor) vs. response -- Variable slope (four parameters) equation, and the IC 50 value of the sample was calculated.

[0268] The compounds of the present invention, for example, the example compounds, have very good enzymatic activity, and IC 50 ≤ 100 nM. The inhibitory activity of some compounds against BRAF V600E is as shown in Table 1.

[0269] [Table 3]

[0270] A represents IC 50 ≤ 10 nM, and B represents 10 nM < IC 50 ≤ 50 nM, and C represents 50 nM < IC 50 ≤ 100 nM.

[0271] Conclusion: The compounds of the present invention, for example, the example compounds, showed high inhibitory activity against BRAF V600E showed high inhibitory activity.

[0272] Biological Test Example 2: Inhibition of A375 Cell Proliferation A375 cells (ATCC, CRL-1619) were cultured in DMEM complete medium (+10% FBS) in a CO2 incubator at 37 °C for 48 h. The cells were digested with pancreatin, counted, and the density was adjusted to 1.67×10 4 cells / mL. 90 μL (1500 cells) of cells per well were inoculated into a 96-well plate with a transparent bottom, transferred to a CO2 incubator, and cultured overnight at 37 °C. After the cells were incubated overnight, diluted compounds (starting from a final concentration of 10 μM, 3-fold dilution, 11 concentrations) were added at 10 μL per well using a pipette. The positive control was serum-free medium containing DMSO. After mixing uniformly, it was placed in a CO2 incubator and incubated at 37 °C for 72 h. After the incubation was completed, CellCounting-Lite (R) 2.0 kit detection solution (Vazyme, DD1101-03) was taken out, returned to room temperature, 100 μL of CellCounting-Lite2.0 detection solution was added to each well, sealed with a sealing film, the plate was placed on a shaker and shaken for 15 min (it is necessary to operate in the dark throughout the whole process), and the fluorescence signal value LUM of each well was detected using the Luminescence module of a microplate reader (BMG LRBTECH). Formula:

Number

[0273] The compounds of the present invention, for example, the compounds of the examples, have very good cell activity, and the IC 50 ≤ 100 nM. The inhibitory activities of some compounds against A357 cells are as shown in Table 2.

[0274]

Table 4

[0275] A represents IC 50 ≤ 10 nM, B represents 10 nM < IC 50 ≤ 50 nM, and C represents 50 nM < IC 50 ≤ 100 nM.

[0276] Conclusion: The compounds of the present invention, for example, the example compounds, showed high activity at the cell level.

[0277] Biological test example 3: Pharmacokinetics test of mice 1.1 Test animals: Male ICR mice, 20 - 25 g, 12 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0278] 1.2 Test design: On the test day, 12 ICR mice were randomly grouped by body weight. They were fasted for 12 - 14 h without water restriction one day before administration and fed 4 h after administration.

[0279]

Table 5

[0280] Before and after administration, 0.06 mL of blood was collected from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm for 10 min at 4 °C, and plasma was collected. The blood sampling time points for both the intravenous group and the intragastric administration group were 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. Before analysis and detection, all samples were stored at -80 °C, and quantitative analysis of the samples was performed by LC-MS / MS.

[0281]

Table 6

[0282] Conclusion: The compound of the present invention, for example, the example compound, has a good pharmacokinetic profile in mice in vivo and has better brain penetration characteristics than the control compound.

[0283] Biological Test Example 4: Pharmacokinetic Test of Beagle Dogs Test animals: Male Beagle dogs, about 8 - 11 kg, 6 animals / compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0284] Test method: On the test day, 6 Beagle dogs were randomly grouped by body weight. They were fasted for 12 - 14 h without water restriction one day before administration and fed 4 h after administration. Administration was carried out according to Table 1.

[0285]

Table 7

[0286] Before and after administration, 1 mL of blood was collected from the jugular vein or peripheral vein and placed in an EDTAK2 centrifuge tube. It was centrifuged at 5000 rpm for 10 min at 4 °C, and plasma was collected. The blood sampling time points for both the intravenous group and the intragastric administration group were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h. Before analysis and detection, all samples were stored at -80 °C, and quantitative analysis of the samples was performed by LC-MS / MS.

[0287]

Table 8

[0288] Conclusion: The compounds of the present invention, for example, the example compounds, have good pharmacokinetic profiles in beagle dogs in vivo.

[0289] Biological Test Example 5: Pharmacokinetic Test in Rats 5.1 Test Animals: Male SD rats, about 220 g, 6 - 8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0290] 5.2 Test Design: On the test day, 6 SD rats were randomly grouped according to body weight. They were fasted for 12 - 14 h without water restriction one day before administration and fed 4 h after administration.

[0291]

Table 9

[0292] Vehicle for Administration: 0.5% MC Before and after administration, 0.1 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and plasma was collected. The blood sampling time points for the intravenous group were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h, and those for the intragastric administration group were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and detection, all samples were stored at -80°C.

[0293]

Table 10

[0294] Conclusion: The compounds of the present invention, for example, the example compounds, have good bioavailability and pharmacokinetic profiles in rats in vivo.

Claims

1. A compound represented by Formula I, a stereoisomer thereof, a deuteride, or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 Cy is selected from P1, P2, P3, P4, P5, P6, P7, or P8, 【Chemical 2】 Ring A is a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, S, O, and the heteroaryl group is optionally substituted with 1 to 2 groups selected from halogen, C １－４ alkoxy group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ , CN, C １－４ alkyl group, haloC １－４ alkoxy group and haloC １－４ alkyl group Ring B is a 5-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the heterocycle is optionally ═O, halogen, C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, OH and halo C １－４ alkyl group, and is substituted with 1 to 3 groups selected from alkoxy groups, # indicates selecting the site of attachment to Y, n = 0, 1, Each X １ is independently N or C, X ２ is N or CR ３ and X ３ is N or CR ３１ and X ４ is N or CR ３２ and X ５ is N or CR ３３ and X ６ is C(O), S(O) or S(O) ２ and X ７ is CR ７ or N, and R １ 、 R ２ and R ４ are, independently, H, halogen, OH, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ , CN, C １－４ alkyl group, C １－４ alkoxy group, haloC １－４ alkoxy group, haloC １－４ alkyl group, C ２－４ alkenyl group or C ２－４ alkynyl group, and R ３ 、R ３１ 、R ３２ 、R ３３ are, independently, H, halogen, C １－４ alkyl group, halo C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ , CN or C ３－６ cycloalkyl group, or R ３１ and R ３２ , or R ３２ and R ３３ and the atoms linked thereto together form a 5- to 6-membered heterocycle containing a carbocycle or 1 to 3 heteroatoms selected from N, S, O, and the carbocycle or heterocycle is optionally substituted with 1 to 3 groups selected from halogen, C ３－６ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, OH, NH １－４ and CN ２ and is substituted with 1 to 3 groups selected from R ５ is a C １－４ alkyl group, halo C １－４ alkyl group, C ３－６ cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, C １－４ alkoxy group, halo C １－４ alkoxy group or C ３－６ cycloalkyloxy group, and optionally substituted with 1 to 3 groups selected from halogen, -NH C １－４ alkyl group, -N(C １－４ alkyl) ２ , C １－４ alkoxy group, halo C １－４ alkoxy group, halo C １－４ alkyl group, CN, C １－４ alkyl group or =O R ６ is H, halogen, C １－４ alkyl group or halo C １－４ alkyl group, and or R ５ and R ６ and the atoms linked thereto together form a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and the heterocycle is optionally substituted with 1 to 3 groups selected from halogen, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ , CN and C １－４ alkyl group R ７ 、 R ８ 、 R ９ independently represents H, halogen, -NH C １－４ alkyl group, -N(C １－４ alkyl) ２ , CN, C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, halo C １－４ alkyl group, C １－４ alkoxy group or halo C １－４ alkoxy group, and Y is C １－２ an alkylene group, O or NR ｙ wherein R ｙ is H or C １－４ and is an alkyl group, M is C １－２ an alkylene group, O or NR ｍ wherein W is a bond, O or NR ｗ and R ｍ and R ｗ each independently is H or C １－４ alkyl group, R is C １－４ an alkyl group, C ３－８ a cycloalkyl group, a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O or -O-C ３－６ a cycloalkyl group, wherein the alkyl group, cycloalkyl group and heterocycle are optionally substituted with 1 to 3 groups selected from halogen, C １－４ an alkyl group, C １－４ an alkoxy group, halo C １－４ an alkoxy group, OH, NH ２ , -NHC １－４ an alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ an alkyl group When Cy is P2, R is a 4- to 10-membered saturated heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and optionally, halogen, C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ alkyl group, and a compound represented by Formula I, its stereoisomers, deuterides or pharmaceutically acceptable salts thereof, which are substituted with 1 to 3 groups selected from

2. Ring A is a 5-membered heteroaryl group, and the heteroaryl group is optionally substituted with one or two groups selected from halogen, C １－４ alkoxy group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ , CN, C １－４ alkyl group, haloC １－４ alkoxy group and haloC １－４ alkyl group. When Cy is P3, the compound is (1) R ５ is a substituted or unsubstituted C ３－６ cycloalkyl group, a substituted or unsubstituted 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, a substituted or unsubstituted C ３－６ cycloalkyloxy group, a substituted or unsubstituted C １－４ alkoxy group or a substituted or unsubstituted halo C １－４ alkoxy group, provided that R is a C ３－８ cycloalkyl group, a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O or -O-C ３－６ cycloalkyl group, and optionally is substituted with 1 to 3 groups selected from halogen, C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ alkyl group. (2) R ５ and R ６ and the atoms linked thereto together form a 5- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and said heterocycle is optionally substituted with 1 to 3 groups selected from halogen, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ , CN and C １－４ alkyl group, provided that it is substituted with 1 to 3 groups selected therefrom (3) X ２ is N or CR ３ and R ３ is C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ or CN, and the condition that W is O (4) R ３１ and R ３２ or R ３２ and R ３３ and the atoms linked thereto together form a 5- or 6-membered heterocycle containing a carbocyclic ring or 1 to 3 heteroatoms selected from N, S, O, provided that the carbocyclic ring or heterocycle is optionally substituted with 1 to 3 groups selected from halogen, C ３－６ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, OH, NH １－４ and CN ２ and CN (5) X ２ is N or CR ３ and R ３ is C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ or CN, W is NR ｗ and R is C ３－８ cycloalkyl group or a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, and optionally substituted with 1 to 3 groups selected from halogen, C １－４ alkyl group, C １－４ alkoxy group, C １－４ haloalkoxy group, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ alkyl group under the condition of being substituted with 1 to 3 groups selected from (6) X ２ is N or CR ３ and X ６ is SO or SO ２ and W is a bond, and R ３ is C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ or CN, and R is C ３－４ cycloalkyl group or a 4-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, and O, a 6- to 8-membered monocyclic heterocycloalkyl group, a 5- to 6-membered monocyclic heteroaryl group, a 5- to 10-membered fused-ring heterocycloalkyl group, a 5- to 10-membered fused-ring heterocycloalkyl group or a 6- to 10-membered spiro-ring heterocycloalkyl group, and optionally, is substituted with 1 to 3 groups selected from halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ alkyl group, under the condition that it is substituted with 1 to 3 groups selected therefrom (7) X ６ is CO, and X ２ is N or CR ３ and W is a bond, and R ３ is C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ or the condition that it is CN, (8) X ２ , X ３ , X ４ , X ５ Among them, at least one is N, and when X ２ is CR ３ , R ３ is H, C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ or CN under the condition that (9) X ２ is N or CR ３ where R ３ is H, C １－４ alkyl group, halo C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ or CN, and R ８ is halogen, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ CN, C １－４ alkoxy group or halo C １－４ alkoxy group, and satisfies at least one of the conditions, the compound according to claim 1, its stereoisomer, deuteride or pharmaceutically acceptable salt.

3. R ３ 、 R ３１ 、 R ３２ 、 R ３３ is independently H, halogen, C １－４ alkyl group, halo C １－４ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２、 CN or C ３－６ cycloalkyl group, or R ３１ and R ３２ 、 or R ３２ and R ３３ and the atoms linked thereto together form a C ３－６ cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the cycloalkyl group and the heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, OH, NH ２ and CN R ５ is a C １－４ alkyl group, halo C １－４ alkyl group, C ３－６ cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, C １－４ alkoxy group, halo C １－４ alkoxy group or C ３－６ cycloalkyloxy group, and optionally substituted with 1 to 3 groups selected from halogen, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ , C １－４ alkoxy group, halo C １－４ alkoxy group, halo C １－４ alkyl group, CN, C １－４ alkyl group and =O, R ６ is H, halogen, C １－４ alkyl group or halo C １－４ alkyl group, and or R ５ and R ６ and the atoms linked thereto together form a 5- to 6-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the heterocycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ , CN and C １－４ alkyl group R is C １－４ an alkyl group, C ３－８ a cycloalkyl group, a 4- to 10-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, or -O-C ３－６ a cycloalkyl group, wherein the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted with 1 to 3 groups selected from halogen, C １－４ an alkyl group, C １－４ an alkoxy group, halo C １－４ an alkoxy group, OH, NH ２ , -NHC １－４ an alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ an alkyl group, and the compound according to claim 2, its stereoisomers, deuterides, or pharmaceutically acceptable salts thereof.

4. The compound has the structure of Formula I-1 below, [Chemical Formula 3] Here, R is C １－４ an alkyl group, C ３－８ a cycloalkyl group or a 4- to 7-membered monocyclic heterocycloalkyl group, a 5- to 10-membered fused-ring heterocycloalkyl group, a 5- to 10-membered fused-ring heterocycloalkyl group or a 6- to 10-membered spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, optionally substituted with 1 to 3 groups selected from halogen, C １－４ an alkyl group, C １－４ an alkoxy group, halo C １－４ an alkoxy group, OH, NH ２ , -NHC １－４ an alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ an alkyl group, the compound according to claim 3, its stereoisomers, deuterides or pharmaceutically acceptable salts.

5. The compound has the structure of Formula I-2 below, 【Chemical 4】 Here, ring B is a 5-membered heteroaryl group or a 5-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and optionally, =O, halogen, C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, OH and halo C １－４ alkyl group, and is substituted with 1 to 3 groups selected from alkoxy groups, R is a 4- to 7-membered saturated monocyclic heterocycloalkyl group, a 5- to 10-membered saturated fused-ring heterocycloalkyl group, a 5- to 10-membered saturated fused-ring heterocycloalkyl group or a 6- to 10-membered saturated spiro-ring heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and optionally, halogen, C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ alkyl group, and is substituted with 1 to 3 groups selected therefrom, the compound according to claim 3, its stereoisomers, deuterides or pharmaceutically acceptable salts.

6. The compound has the structure of Formula I-3 below [Chemical Formula 5] The compound according to Claim 3, a stereoisomer thereof, a deuteride, or a pharmaceutically acceptable salt thereof.

7. R ６ 、R ９ is H, Y is O, M is NH, X ２ is N or CR ３ and X ６ is SO or SO ２ and W is a bond R ３ is C １－４ alkyl group, halo C １－４ alkyl group, C １－４ alkoxy group, halo C １－４ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ or CN, and R is a 4-membered monocyclic heterocycloalkyl group, 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group, 6- to 10-membered spiro-ring heterocycloalkyl group or -O-C ３－６ cycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, and the 4-membered monocyclic heterocycloalkyl group is substituted with 1 to 3 groups selected from halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ alkyl group, and the 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group or 6- to 10-membered spiro-ring heterocycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, C １－４ alkyl group, C １－４ alkoxy group, OH, NH ２ , -NHC １－４ alkyl group, -N(C １－４ alkyl) ２ and halo C １－４ alkyl group, and the compound according to claim 6, its stereoisomers, deuterides or pharmaceutically acceptable salts thereof.

8. X ２ is CR ３ and X ３ is CR ３１ and X ４ is CR ３２ and X ５ is CH and X ６ is SO ２ and X ７ is CH R ３ is a C １－２ alkyl group, halo C １－２ alkyl group, C １－２ alkoxy group, halo C １－２ alkoxy group, C ２－４ alkenyl group, C ２－４ alkynyl group, -NHC １－２ alkyl group, -N(C １－２ alkyl) ２ or CN, and R ３１ 、R ３２ is, independently of each other, H, F, Cl, C １－２ alkyl group, halo C １－２ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, C １－２ alkoxy group, halo C １－２ alkoxy group, -NHC １－２ alkyl group, -N(C １－２ alkyl) ２、 CN or C ３－６ cycloalkyl group, and R ５ is a C １－２ alkyl group, CN or C １－２ alkyl group substituted with =O, halo C １－２ alkyl group, C ３－４ cycloalkyl group, 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, C １－２ alkoxy group, halo C １－２ alkoxy group or C ３－４ cycloalkyloxy group, and R ８ is selected from H, F, Cl, CN, C １－２ alkyl group, C ２－４ alkenyl group, C ２－４ alkynyl group, halo C １－２ alkyl group, C １－２ alkoxy group or halo C １－２ alkoxy group, and R is a 4- to 5-membered monocyclic heterocycloalkyl group, a 6- to 8-membered monocyclic heterocycloalkyl group, a 5- to 6-membered monocyclic heteroaryl group, a 5- to 10-membered fused-ring heterocycloalkyl group, a 5- to 10-membered fused-ring heterocycloalkyl group, a 6- to 10-membered spiro-ring heterocycloalkyl group or -O-C ３－６ cycloalkyl group, and the 4-membered monocyclic heterocycloalkyl group is substituted with 1 to 3 groups selected from F, Cl, C １－２ alkyl group, C １－２ alkoxy group, OH, NH ２ , -NHC １－２ alkyl group, -N(C １－２ alkyl) ２ and halo C １－２ alkyl group, and the 6- to 8-membered monocyclic heterocycloalkyl group, 5- to 6-membered monocyclic heteroaryl group, 5- to 10-membered fused-ring heterocycloalkyl group, 5- to 10-membered fused-ring heterocycloalkyl group, 6- to 10-membered spiro-ring heterocycloalkyl group or C ３－６ cycloalkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, C １－２ alkyl group, C １－２ alkoxy group, OH, NH ２ , -NHC １－２ alkyl group, -N(C １－２ alkyl) ２ and halo C １－２ alkyl group, and the compound according to claim 7, its stereoisomer, deuteride or pharmaceutically acceptable salt.

9. R ３ is CN, R ３１ 、 R ３２ are each independently H, F, Cl or C ３－６ cycloalkyl group, R ５ is a C １－２ alkyl group, halo C １－２ alkyl group, C １－２ alkoxy group, or a C substituted with CN or =O １－２ alkyl group selected from, R ８ is H, R is a 6- to 10-membered spirocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O, a 4- to 5-membered monocyclic heterocycloalkyl group containing 1 to 3 heteroatoms selected from N, S, O or -O-C ３－６ is a cycloalkyl group, and the 6- to 10-membered spirocyclic heterocycloalkyl group, 4- to 5-membered monocyclic heterocycloalkyl group, C ３－６ The cycloalkyl group is optionally substituted with 1 to 3 groups selected from F, Cl, C １－２ alkyl group or C １－２ alkoxy group, and the compound according to claim 8, its stereoisomer, deuteride or pharmaceutically acceptable salt.

10. The compound according to Claim 1, a stereoisomer thereof, a deuteride, or a pharmaceutically acceptable salt thereof, which is selected from one of the structures in Table 1 or Table 2.

11. A pharmaceutical composition or pharmaceutical preparation containing the compound according to any one of Claims 1 to 10, a stereoisomer thereof, a deuteride, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

12. The pharmaceutical composition or pharmaceutical preparation according to Claim 11, containing 1 to 1500 mg of the compound according to any one of Claims 1 to 10, a stereoisomer thereof, a deuteride, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

13. Use of the compound according to any one of Claims 1 to 10, a stereoisomer thereof, a deuteride, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating / preventing BRAF-mediated diseases.

14. A method for treating a mammalian disease, the method comprising administering to a subject a therapeutically effective amount of the compound according to any one of Claims 1 to 10, a stereoisomer thereof, a deuteride, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably a tumor, more preferably a brain tumor.

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