WO2025153057A1 - Pharmaceutical composition comprising braf inhibitor and use of pharmaceutical composition in medicine - Google Patents

Abstract

The present invention relates to a pharmaceutical composition or a pharmaceutical preparation. The pharmaceutical composition or the pharmaceutical preparation comprises a therapeutically effective amount of an active ingredient M and a pharmaceutically acceptable excipient, wherein the active ingredient M is selected from a compound as shown in general formula I or a stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, and the pharmaceutical composition or the pharmaceutical preparation comprises 1-1000 mg of the active ingredient M. The present invention also relates to a use of the pharmaceutical composition or the pharmaceutical preparation in preparation of a related drug for treating cancers.

Description

A pharmaceutical composition containing a BRAF inhibitor and its application in medicine Technical Field

The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises a therapeutically effective amount of an active ingredient M and a pharmaceutical excipient, wherein the active ingredient M is selected from the compound of general formula (I) or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the pharmaceutical composition or pharmaceutical preparation comprises 1-1000 mg of the active ingredient M. The present invention also relates to the use of the pharmaceutical composition or pharmaceutical preparation in preparing drugs for treating cancer.

Background Art

A kinase is an enzyme that catalyzes the transfer of a phosphate group from a high-energy, phosphate-donating molecule to a specific substrate. This process is called phosphorylation, where the substrate acquires the phosphate group and the high-energy ATP molecule donates the phosphate group. Kinases are divided into the following broad categories based on the substrates they act on: protein kinases, lipid kinases, carbohydrate kinases. Kinases are found in a variety of species, from bacteria to molds to worms to mammals. More than five hundred different kinases have been identified in humans.

MAP kinases (MAPK) are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all thought to participate in mitogenic stimulation of the MAPK pathway. Activation of this pathway at the receptor level initiates a signaling cascade whereby Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which in turn activates MEK (MAPKK).

The BRAF protein is a member of the RAF family of serine/threonine kinases that participates in cascades of the Ras Raf MEK extracellular signal-regulated kinase (ERK) pathway or the mitogen-activated protein kinase (MAPK)/ERK signaling pathway that affect cell division and differentiation. Mutations in the BRAF gene can lead to uncontrolled growth 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, and ovarian cancer and their metastatic cancers, and primary brain tumors. Although some BRAF inhibitors produce excellent extracranial responses, cancers may still develop brain metastases during or following BRAF inhibitor therapy. An estimated 20% of subjects with cancer will develop brain metastases, with the majority of brain metastases occurring in those with melanoma, colorectal cancer, lung cancer, and renal cell carcinoma. Brain metastases remain a substantial contributor to overall cancer mortality in subjects with advanced cancer, and despite multimodality treatment and advances in systemic therapy, which includes combinations of surgery, radiation therapy, chemotherapy, immunotherapy, and/or targeted therapies, the prognosis remains poor.

Additionally, BRAF has been identified as a potential target for the treatment of primary brain tumors. The prevalence of BRAF V600E mutations in primary brain tumors has been reported by Schindler et al. in their analysis of 1,320 central nervous system (CNS) tumors and Behling et al. in their analysis of 969 CNS tumors in pediatric and adult populations. These studies, combined with other studies, have reported the presence of BRAF V600E mutations in various cancers, including papillary craniopharyngioma, pleomorphic xanthomatous astrocytoma (PXA), ganglioglioma, astroblastoma, and others.

The blood-brain barrier (BBB) is a highly selective physical transport and metabolic barrier that separates the CNS from the blood. The BBB prevents certain drugs from entering brain tissue and is a limiting factor for the delivery of many peripherally administered agents to the CNS. Many drugs commonly used to treat cancer cannot cross the blood-brain barrier. This means that these drugs cannot penetrate the brain and therefore cannot effectively kill cancer cells in the brain. Current treatments for subjects with brain tumors include surgical resection, radiation therapy, and/or chemotherapy using agents such as temozolomide and/or bevacizumab. However, it is not always possible to treat brain cancer by surgery, for example, the tumor may be inaccessible or the subject may not be able to withstand the trauma of neurosurgery. In addition, radiation therapy and treatment with cytotoxic agents are known to have undesirable side effects. For example, there is increasing evidence that the use of temozolomide itself can induce mutations and worsen prognosis in a large proportion of subjects, and the bevacizumab label has a boxed warning for gastrointestinal perforation, surgical and wound healing complications, and bleeding. Kinase inhibitors are used to treat many peripheral cancers. However, due to their structural properties, many kinase inhibitors such as BRAF inhibitors (e.g., vemurafenib and dabrafenib) are substrates for active transporters such as P-glycoprotein (P gp) or breast cancer resistance protein (BCRP). For example, dabrafenib was reported to have an MDR1 efflux ratio of 11.4, a BCRP efflux ratio of 21.0, and a total brain to plasma ratio of 0.023, whereas vemurafenib was reported to have an MDR1 efflux ratio of 83, a BCRP efflux ratio of 495, and a total brain to plasma ratio of 0.004.

Given that both P gp and BCRP are expressed in endothelial cells lining the blood-brain capillaries, the activity of both P gp and BCRP in the BBB plays a key role in preventing most kinase inhibitors from distributing into the brain parenchyma. Therefore, kinase inhibitors are generally not suitable for the treatment of tumors or cancers in the brain, which is protected by the BBB. Therefore, there remains a need for treatment of tumors with BRAF mutations. In addition, there remains an unmet need for the treatment of CNS tumors, including CNS tumors with BRAF mutations.

Summary of the invention

The object of the present invention is to provide a pharmaceutical composition or pharmaceutical preparation, the pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of an active ingredient M and a pharmaceutical excipient, the active ingredient M being selected from the compound described in the general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the pharmaceutical composition or pharmaceutical preparation having a formulation specification of 1-1000 mg. The present invention also relates to the use of the pharmaceutical composition or pharmaceutical preparation in the preparation of drugs related to the treatment of cancer.

The pharmaceutical composition or pharmaceutical preparation of the present invention has the advantages of good oral performance, good efficacy, low toxicity and side effects, good safety, high selectivity, good pharmacokinetics, high bioavailability, and no inhibition of CYP enzymes.

The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of an active ingredient M and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation.

The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises an active ingredient M and a pharmaceutical excipient, wherein the active ingredient M is selected from the compounds of general formula I and II or stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof,

wherein Cy is selected from P1, P2, P3, P4, P5, P6, P7 or P8;

Ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1-2 groups selected from halogen, C _1-4 alkoxy, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, halogenated C _1-4 alkoxy, and halogenated C _1-4 alkyl. In some embodiments, it is a 5-membered heteroaryl group. In some embodiments, the heteroaryl group is selected from pyrazolyl, oxazolyl, imidazolyl, triazole, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyridinyl, pyrimidinyl, etc., and the heteroaryl group is optionally substituted by 1-2 groups selected from halogen, C _1-4 alkoxy, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, halogenated _{C 1-4 alkoxy} , and halogenated C Ring B is a 5-membered heterocyclic ring containing _1-3 heteroatoms selected from N, S, and O, and the heterocyclic ring is optionally substituted by 1-3 groups selected from =O, halogen, C _1-4 alkyl, halo-substituted C _1-4 alkyl, C _1-4 alkoxy, OH, and halo-substituted C _1-4 alkoxy;

# means to select a point to connect with Y;

n is selected from 0 or 1;

Each X ₁ is independently N or C; in some embodiments, each X ₁ is independently C;

X ₂ is N or CR ₃ ; in some embodiments, X ₂ is N; in some embodiments, X ₂ is CR ₃ ;

X ₃ is N or CR ₃₁ ; in some embodiments, X ₃ is N or CH;

X ₄ is N or CR ₃₂ ; In some embodiments, X ₄ is N or CH;

X ₅ is N or CR ₃₃ ; in some embodiments, X ₅ is N or CH;

X ₆ is C(O), S(O) or S(O) ₂ ; in some embodiments, X ₆ is C(O) or S(O) ₂ ; in some embodiments, X ₆ is S(O) ₂ ;

X ₇ is CR ₇ or N; in some embodiments, X ₇ is N; in some embodiments, X ₇ is CH;

R ₁ , R ₂ and R ₄ are independently H, halogen, OH, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogenated C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl; the -NHC _1-4 alkyl includes -NH methyl, -NH ethyl, -NH isopropyl, -NH propyl, -NH butyl, the -N(C _1-4 alkyl) ₂ includes dimethylamino, diethylamino, etc.;

R ₃ , R ₃₁ , R ₃₂ , and R ₃₃ are independently H, halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, C _{2-4 alkenyl, C 2-4 alkynyl} , C _1-4 alkoxy, halogenated C _1-4 alkoxy, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, or C _3-6 cycloalkyl. In some embodiments, R ₃ , R ₃₁ , R ₃₂ , and R ₃₃ are independently H, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C 1-4 alkoxy, halogenated C _1-4 alkoxy, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , or CN; in some embodiments, R ₃ is C 1-4 alkyl, halogenated C _1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, -NHC _1-4 alkyl, -N(C _1-4 alkyl) 2 , or CN. In some embodiments, R ₃ is H, C _1-4 alkyl, halo-substituted C _1-4 alkyl, C _1-4 alkoxy, halo-substituted C _1-4 alkoxy, C 2-4 alkenyl, C _{2-4 alkynyl, -NHC 1-4 alkyl} , -N(C _1-4 alkyl) ₂ , or CN; in some embodiments, R 3 is C _1-4 alkyl, halo-substituted C _1-4 alkyl, C 1-4 alkoxy, halo-substituted C _1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ ; in some embodiments, R ₃ is H, C _1-4 alkyl, halo-substituted C _1-4 alkyl, _{C 1-4} alkoxy, halo-substituted C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , or CN;

or R ₃₁ and R ₃₂ , or R ₃₂ and R ₃₃ and the atoms to which they are connected, together form a C _3-6 carbocyclic ring or a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, OH, NH ₂ , and CN; in some embodiments, optionally substituted with 1-3 groups selected from halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, C _1-4 haloalkoxy, and CN; in some embodiments, R 31 and R ₃₂ , or R ₃₂ and R ₃₃ and the atoms to which they are connected, together form a C _3-6 carbocyclic ring or a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, halogenated C 1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, and CN; _3-6 membered cycloalkyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, or forming a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, such as azetidinyl, oxetidinyl, azocyclopentenyl, oxecyclopentenyl, azocyclohexenyl, oxecyclohexenyl, the cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, halo-substituted C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkoxy and CN;

R ₅ is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C _1-4 alkoxy, halogenated C _1-4 alkoxy or C _3-6 cycloalkyloxy, the cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the heterocycloalkyl includes but is not limited to aziridine, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, oxirane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, etc., and is optionally substituted by 1-3 groups selected from halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogenated C _1-4 alkyl, CN, C _1-4 alkyl and =O; in some embodiments, R ₅ is C In some embodiments, R 5 is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C _1-4 alkoxy, halogenated C _1-4 alkoxy or C _3-6 cycloalkyloxy, and is optionally substituted by 1-3 groups selected from halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogenated C _1-4 alkyl, CN and C _1-4 alkyl; in some embodiments, R ₅ is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C _1-4 alkoxy, halogenated C _1-4 alkoxy or _{C 3-6 cycloalkyloxy} , and is optionally substituted by 1-3 groups selected from halogen, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN and _{C 1-4} alkyl groups; in some embodiments, optionally substituted by 1-3 groups selected from halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , C _1-4 alkoxy, halo-C _1-4 alkoxy, halo-C _1-4 alkyl, CN and C _1-4 alkyl groups; in some embodiments, R ₅ is substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, substituted or unsubstituted C _3-6 cycloalkyloxy, substituted or unsubstituted C _1-4 alkoxy or substituted or unsubstituted halo-C _1-4 alkoxy, and the substituents are as described above; in some embodiments, R ₅ is C _1-2 alkyl, CN substituted C _1-2 alkyl, halo-C 1-2 alkyl, C _1-2 alkyl _{In some embodiments , R 5 is} selected _{from C 1-2 alkyl , C 1-2 alkyl substituted with CN , ...}

R ₆ is H, halogen, C _1-4 alkyl or halogenated C _1-4 alkyl; in some embodiments, R ₆ is H;

or R ₅ and R ₆ and their connecting atoms together form a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocyclic ring is optionally substituted by 1-3 groups selected from halogen, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, and C _1-4 alkyl; the heterocyclic ring includes heteroaryl and heterocycloalkyl; in some embodiments, a 5-membered heterocyclic ring is formed; in some embodiments, a 5-membered heterocycloalkyl is formed and is optionally substituted by 1-3 groups selected from halogen, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, and C _1-4 alkyl;

R ₇ , R ₈ , and R ₉ are independently H, halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo-C _1-4 alkyl, _{C 1-4 alkoxy} , or halo-C _1-4 alkoxy; in some embodiments, R ₇ , R ₈ , and R ₉ are independently H, halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halo- _{C 1-4} alkyl, C _1-4 alkoxy, or halo-C _1-4 alkoxy; in some embodiments, R ₇ is H or halogen; in some embodiments, R ₈ is halogen, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkoxy or halogenated C _1-4 alkoxy; in some embodiments, R ₈ is halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkoxy or halogenated C _1-4 alkoxy; in some embodiments, R ₉ is H or halogen;

Y is C _1-2 alkylene, O or NR _y ; in some embodiments, Y is O; in some embodiments, Y is NH; in some embodiments, Y is methylene or ethylene;

R _y is H or C _1-4 alkyl; in some embodiments, R _y is H; in some embodiments, R _y is methyl, ethyl, propyl or isopropyl, etc.;

M is C _1-2 alkylene, O or NR _m ; in some embodiments, M is NH; in some embodiments, M is methylimino, ethylimino, propylimino or isopropylimino;

W is a bond, O, or NR _w ; in some embodiments, W is a bond, O, NH, or NC _1-4 alkyl;

R _m and R _w are independently H or C _1-4 alkyl; in some embodiments, R _m and R _w are independently H, methyl, ethyl, propyl or isopropyl;

R is selected from C _1-4 alkyl, C _3-8 cycloalkyl, a 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, or -OC _3-6 cycloalkyl, wherein the alkyl, cycloalkyl and heterocycle are optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halo-substituted C _1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ and halo-substituted C _1-4 alkyl; in some embodiments, R is selected from C _1-4 alkyl, C _3-8 cycloalkyl or a 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl and heterocycle are optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halo-substituted C _1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) In some embodiments, R is selected from _{C 3-8 cycloalkyl} or a 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , and halogenated C _1-4 alkyl groups; In some embodiments, R is C _{3-4 cycloalkyl} or a 4-membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, a 6-8 membered monocyclic heterocycloalkyl, a 5-6 membered monocyclic heteroaryl, a 5-10 membered heterocyclic heterocycloalkyl, a 5-10 membered bridged heterocycloalkyl, or a 6-10 membered spirocyclic heterocycloalkyl, and is optionally substituted by 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, OH, NH 2 , In some embodiments, R is selected from C _1-4 alkyl, C _{3-8 cycloalkyl} or _{4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy , halo} -substituted C 1-4 alkoxy, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 and halo-substituted C 1-4 alkyl; in some embodiments, R is selected from C _1-4 alkyl, C _3-8 cycloalkyl or 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ and halo-substituted C _1-4 alkyl; in some embodiments, R is selected from C _1-4 alkyl, C substituted with 1-3 groups selected from halogen, C _1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N (C _1-4 alkyl) 2 and halo-substituted C 1-4 alkyl; in some embodiments, R is a saturated _4-7 membered monocyclic heterocycloalkyl, a saturated 5-10 membered cyclic heterocycloalkyl, _a saturated _5-10 membered bridged heterocycloalkyl or a saturated 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halo-substituted C _1-4 alkyl, OH, NH 2 , -NHC 1-4 alkyl, -N (C _1-4 alkyl) 2 and halo-substituted C 1-4 alkyl. In some embodiments, R is selected from C _3-8 cycloalkyl, a _{saturated 4-7} -membered _monocyclic heterocycloalkyl containing _1-3 heteroatoms selected from N, S, and O, a _5-10 -membered heterocycloheterocycloalkyl, _a 5-10-membered bridged heterocycloalkyl, or a 6-10-membered spirocyclic heterocycloalkyl, wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc., the monocyclic heterocycloalkyl is selected from aziridine, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, oxirane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, etc., and the heterocycloheterocycloalkyl is selected from etc., the bridged heterocycloalkyl group is selected from etc., the spirocyclic heterocycloalkyl group is selected from:

etc.; the above groups are optionally substituted by 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halo-C _1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ and halo-C _1-4 alkyl;

When Cy is P2, R is a 4-10 membered saturated heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halo-substituted C _1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , and halo-substituted C _1-4 alkyl;

The pharmaceutical composition or pharmaceutical preparation comprises 1-1000 mg of active ingredient M, and the excipient comprises one or more of a filler, a binder, a glidant, a lubricant, and a disintegrant;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 5-800 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 5-600 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 5-400 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 20-800 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 20-600 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 20-400 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 5 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 10 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 20 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 50 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 60 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 70 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 80 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 90 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 100 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 150 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 200 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 400 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 600 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 800 mg of active ingredient M;

In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 1000 mg of active ingredient M;

In some embodiments, R ₆ and R ₉ are H; Y is O, M is NH, X ₂ is CR ₃ , X ₃ is CR ₃ , X ₄ is CR ₃₂ , X ₅ is CH, X ₆ is SO ₂ , X ₇ is CH,

_R3 is _C1-2 alkyl, halogenated _C1-2 alkyl, _C1-2 alkoxy, halogenated _C1-2 alkoxy, _C2-4 alkenyl, _{C2-4 alkynyl} , _-NHC1-2 alkyl, -N( _C1-2 alkyl) ₂ or CN,

R ₃₁ and R ₃₂ are each independently H, F, Cl, C _1-2 alkyl, halogenated C _1-2 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-2 alkoxy, halogenated C _1-2 alkoxy, -NHC _1-2 alkyl, -N(C _1-2 alkyl) _2, CN or C _3-6 cycloalkyl,

_R5 is _C1-2 alkyl, _C1-2 alkyl substituted by CN or =O, halogenated _C1-2 alkyl, _C3-4 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, _C1-2 alkoxy, halogenated _C1-2 alkoxy or _C3-4 cycloalkyloxy,

_R8 is selected from H, F, Cl, CN, _C1-2 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, halogenated _C1-2 alkyl, _C1-2 alkoxy or halogenated _C1-2 alkoxy,

R is a 4-5 membered monocyclic heterocycloalkyl, a 6-8 membered monocyclic heterocycloalkyl, a 5-6 membered monocyclic heteroaryl, a 5-10 membered cyclic heterocycloalkyl, a 5-10 membered bridged heterocycloalkyl, a 6-10 membered spirocyclic heterocycloalkyl or -OC 3-6 cycloalkyl containing _1-3 heteroatoms selected from N, S and O, wherein the 4 membered monocyclic heterocycloalkyl is substituted by 1-3 groups selected from F, Cl, C _1-2 alkyl, C _1-2 alkoxy, OH, NH ₂ , -NHC _1-2 alkyl, -N(C _1-2 alkyl) ₂ and halogenated C _1-2 alkyl, and the 6-8 membered monocyclic heterocycloalkyl, the 5-6 membered monocyclic heteroaryl, the 5-10 membered cyclic heterocycloalkyl, the 5-10 membered bridged heterocycloalkyl, the 6-10 membered spirocyclic heterocycloalkyl or C _3-6 cycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, C 1-2 alkyl, C 1-2 alkoxy, OH, NH 2 , -NHC 1-2 alkyl, -N(C _1-2 alkyl) 2 and halogenated C 1-2 alkyl. substituted with _-1-2 alkoxy, OH, NH ₂ , -NHC _1-2 alkyl, -N(C _1-2 alkyl) ₂ and halogenated C _1-2 alkyl;

In some embodiments, _R3 is CN,

R ₃₁ and R ₃₂ are each independently H, F, Cl or C _3-6 cycloalkyl,

_R5 is selected from _C1-2 alkyl, halogenated _C1-2 alkyl, _C1-2 alkoxy, or _C1-2 alkyl substituted by CN or =O,

_R8 is H,

R is a 6-10 membered spirocyclic heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, a 4-5 membered monocyclic heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or a -OC _3-6 cycloalkyl group, wherein the 6-10 membered spirocyclic heterocycloalkyl group, the 4-5 membered monocyclic heterocycloalkyl group, and the C _3-6 cycloalkyl group are optionally substituted by 1-3 groups selected from F, Cl, C _1-2 alkyl, or C _1-2 alkoxy groups;

In some embodiments, _R3 is CN,

R ₃₁ and R ₃₂ are each independently H, F, Cl, cyclopropane, cyclobutane, cyclopentane or cyclohexane,

R ₅ is selected from -CH ₃ , -CH ₂ CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CHFCH ₂ F, -CHFCHF ₂ , -CHFCF ₃ , -CF ₂ CH ₂ F, -CF ₂ CHF ₂ , -CF ₂ CF. _3. -CH ₂ Cl, -CHCl ₂ , -CCl ₃ , -CH ₂ CH ₂ Cl, -CH ₂ CHCl ₂ , -CH ₂ CCl ₃ , -CHClCH ₂ Cl, -CHClCHCl ₂ , -CHClCCl ₃ , -CCl ₂ CH ₂ Cl, -CCl ₂ CHCl ₂ , -CCl ₂ CCl ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CH ₂ CN, -CH ₂ CH ₂ CN, -CH(CN)CH ₃ , -COCH ₃ , -COCH ₂ CN, R ₈ is H,

R is a 6-10 membered spirocyclic heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, a 4-5 membered monocyclic heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or a -OC _3-6 cycloalkyl group, wherein the 6-10 membered spirocyclic heterocycloalkyl group, the 4-5 membered monocyclic heterocycloalkyl group, and the C _3-6 cycloalkyl group are optionally substituted with 1-3 groups selected from F, Cl, C _1-2 alkyl, or C _1-2 alkoxy groups.

As a specific technical solution of the present invention, the compound of the present invention, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, the compound is selected from one of the structures in Table 1,

Table 1:

As a specific technical solution of the present invention, the compound of the present invention, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, the compound is selected from one of the structures in Table 2,

Table 2:

In some embodiments, the active ingredient M is selected from the following structures:

The pharmaceutical composition or pharmaceutical preparation of any one of the embodiments of the present invention comprises the active ingredient M and a pharmaceutical excipient in any of the foregoing embodiments, wherein the content of the active ingredient M is 0.5%-99%; in some embodiments, 1%-90%; in some embodiments, 1%-80%; in some embodiments, 1%-70%; in some embodiments, 1%-60%; in some embodiments, 1%-50%; in some embodiments, 1%-40%; in some embodiments, 1%-30%; in some embodiments, 1%-20%; in some embodiments, 1%-10%; in some embodiments, 5%-90%; in some embodiments, 5%-80%; in some embodiments, 5%-70%; in some embodiments, 5 %-60%; in some embodiments, 5%-45%; in some embodiments, 5%-40%; in some embodiments, 5%-30%; in some embodiments, 5%-20%; in some embodiments, 5%-10%; in some embodiments, 10%-90%; in some embodiments, 10%-80%; in some embodiments, 10%-70%; in some embodiments, 10%-60%; in some embodiments, 10%-50%; in some embodiments, 10%-45%; in some embodiments, 10%-40%; in some embodiments, 10%-30%; in some embodiments, 10%-25%; in some embodiments, 25%; in some embodiments, 10%.

Any pharmaceutical composition or pharmaceutical preparation of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises one or more of a filler, a binder, a glidant, a lubricant, and a disintegrant.

Any pharmaceutical composition or pharmaceutical preparation of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, and a disintegrant.

Any pharmaceutical composition or pharmaceutical preparation described in the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further contains one or more of a solubilizer, a pH adjuster, and a surfactant.

Any pharmaceutical composition or pharmaceutical preparation of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and a solubilizer.

Any pharmaceutical composition or pharmaceutical preparation of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and a pH regulator.

Any pharmaceutical composition or pharmaceutical preparation described in the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and a surfactant.

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, silicified microcrystalline cellulose, sucrose, sorbitol, dextran, calcium dihydrogen phosphate or starch; in some embodiments, the filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose or sorbitol; in some embodiments, the filler is selected from microcrystalline cellulose.

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the binder is selected from one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose or sodium carboxymethyl cellulose; in some embodiments, the binder is selected from one or more of hydroxypropyl methylcellulose, methylcellulose or sodium carboxymethyl cellulose; in some embodiments, the binder is selected from hydroxypropyl methylcellulose.

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the glidant is selected from one or more of talc, silicon dioxide, micro-powder silica gel, polyethylene glycol or magnesium dodecyl sulfate; in some embodiments, the glidant is selected from one or more of silicon dioxide or micro-powder silica gel; in some embodiments, the glidant is selected from colloidal silicon dioxide.

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate; in some embodiments, the lubricant is selected from sodium stearyl fumarate.

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or calcium carboxymethyl cellulose; in some embodiments, the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or calcium carboxymethyl cellulose; in some embodiments, the disintegrant is selected from cross-linked polyvinylpyrrolidone.

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the solubilizer is selected from one or more of oxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, polyethylene glycol 15-hydroxystearic acid, poloxamer, cyclodextrin, hydroxypropyl beta-cyclodextrin, docusate sodium or vitamin E polyethylene glycol succinate; in some embodiments, the solubilizer is selected from one or more of cyclodextrin or hydroxypropyl beta-cyclodextrin; in some embodiments, the solubilizer is selected from cyclodextrin; in some embodiments, the solubilizer is selected from hydroxypropyl beta-cyclodextrin.

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation. The surfactant is selected from sodium lauryl sulfate.

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the pH regulator is selected from magnesium oxide.

The pharmaceutical composition or pharmaceutical preparation of any one of the embodiments of the present invention comprises the active ingredient M of any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the content of the active ingredient M is 0.5%-99%; in some embodiments, 1%-90%; in some embodiments, 1%-80%; in some embodiments, 1%-70%; in some embodiments, 1%-60%; in some embodiments, 1%-50%; in some embodiments, 1%-40%; in some embodiments, 1%-30%; in some embodiments, 1%-20%; in some embodiments, 1%-10%; in some embodiments, 5%-90%; in some embodiments, 5%- 80%; in some embodiments, 5%-70%; in some embodiments, 5%-60%; in some embodiments, 5%-45%; in some embodiments, 5%-40%; in some embodiments, 5%-30%; in some embodiments, 5%-20%; in some embodiments, 5%-10%; in some embodiments, 10%-90%; in some embodiments, 10%-80%; in some embodiments, 10%-70%; in some embodiments, 10%-60%; in some embodiments, 10%-50%; in some embodiments, 10%-45%; in some embodiments, 10%-40%; in some embodiments, 10%-30%; in some embodiments, 10%-25%; in some embodiments, 25%; in some embodiments, 10%.

The pharmaceutical composition or pharmaceutical preparation of any one of the embodiments of the present invention comprises the active ingredient M of any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the filler content is 10%-90%; in some embodiments, the content is 10%-80%; in some embodiments, the content is 10%-75%; in some embodiments, the content is 10%-70%; in some embodiments, the content is 10%-60%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 10%-30%; in some embodiments, the content is 10%-20%; in one In some embodiments, the content is 20%-80%; in some embodiments, the content is 20%-75%; in some embodiments, the content is 20%-70%; in some embodiments, the content is 20%-60%; in some embodiments, the content is 20%-50%; in some embodiments, the content is 30%-80%; in some embodiments, the content is 30%-75%; in some embodiments, the content is 30%-70%; in some embodiments, the content is 40%-80%; in some embodiments, the content is 40%-75%; in some embodiments, the content is 40%-70%; in some embodiments, the content is 37%; in some embodiments, the content is 40%; in some embodiments, the content is 72.5%; in some embodiments, the content is 80%.

The pharmaceutical composition or pharmaceutical preparation described in any one of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the binder content is 1%-50%; in some embodiments, the content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-10%; in some embodiments, in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-4%; in some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2.5%; in some embodiments, the content is 1.5%-2.5%; in some embodiments, the content is 2%-2.5%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%.

The pharmaceutical composition or pharmaceutical preparation of any one of the embodiments of the present invention comprises the active ingredient M of any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the content of the glidant is 0.5%-10%; in some embodiments, the content is 0.5%-8%; in some embodiments, the content is 0.5%-6%; in some embodiments, the content is 0.5%-5%; in some embodiments, the content is 0.5%-4%; in some embodiments, the content is 0 .5%-3%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-4%; in some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 1%-2.5%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 3%.

The pharmaceutical composition or pharmaceutical preparation described in any one of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the lubricant content is 0.1%-10%; in some embodiments, the content is 0.1%-8%; in some embodiments, the content is 0.1%-6%; in some embodiments, the content is 0.1%-5%; in some embodiments, the content is 0.5%-8%; in some embodiments, the content is 0.5%-6%; in some embodiments, the content is 0.5%-5%; in some embodiments, the content is 0.5%-4%; in some embodiments, the content is 0 .5%-3%; in some embodiments, the content is 0.5%-2.0%; in some embodiments, the content is 0.5%-1%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 0.5%; in some embodiments, the content is 0.6%; in some embodiments, the content is 0.7%; in some embodiments, the content is 0.8%; in some embodiments, the content is 0.9%; in some embodiments, the content is 1.0%; in some embodiments, the content is 2%.

The pharmaceutical composition or pharmaceutical preparation of any one of the embodiments of the present invention comprises the active ingredient M of any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the disintegrant content is 0.5%-10%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-9%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-7%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-4%; in one In some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 2%-10%; in some embodiments, the content is 2%-8%; in some embodiments, the content is 2%-7%; in some embodiments, the content is 2%-6%; in some embodiments, the content is 3%-7%; in some embodiments, the content is 4%-7%; in some embodiments, the content is 5%-7%; in some embodiments, the content is 2%; in some embodiments, the content is 3%; in some embodiments, the content is 5%; in some embodiments, the content is 6%; in some embodiments, the content is 7%; in some embodiments, the content is 10%.

The pharmaceutical composition or pharmaceutical preparation described in any one of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further contains a solubilizer, wherein the solubilizer content is 5%-50%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 30%-50%; in some embodiments, the content is 30%-45%; in some embodiments, the content is 10%; in some embodiments, the content is 20%; in some embodiments, the content is 30%; in some embodiments, the content is 32%; in some embodiments, the content is 40%; in some embodiments, the content is 42.5%; in some embodiments, the content is 45%.

The pharmaceutical composition or pharmaceutical preparation described in any one of the above embodiments comprises the active ingredient M and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further comprises a surfactant, wherein the surfactant content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-20%; in some embodiments, the content is 5%-20%; in some embodiments, the content is 10%-20%; in some embodiments, the content is 10%-15%; in some embodiments, the content is 5%; in some embodiments, the content is 10%; in some embodiments, the content is 15%; in some embodiments, the content is 20%.

The pharmaceutical composition or pharmaceutical preparation of any one of the embodiments of the present invention comprises the active ingredient M of any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further comprises a pH adjuster, wherein the content of the pH adjuster is 1%-50%; in some embodiments, the content is 1%-9%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%; in some embodiments, the content is 4%; in some embodiments, the content is 5%;

The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, comprising:

(i) active ingredient M, in an amount of 0.5%-99%; in some embodiments, 1%-90%; in some embodiments, 1%-80%; in some embodiments, 1%-70%; in some embodiments, 1%-60%; in some embodiments, 1%-50%; in some embodiments, 1%-40%; in some embodiments, 1%-30%; in some embodiments, 1%-20%; in some embodiments, 1%-10%; in some embodiments, 5%-90%; in some embodiments, 5%-80%; in some embodiments, 5%-70%; in some embodiments, 5%-60%; in some embodiments, 5%-45%; in some embodiments, 5%-40 %; in some embodiments, 5%-30%; in some embodiments, 5%-20%; in some embodiments, 5%-10%; in some embodiments, 10%-90%; in some embodiments, 10%-80%; in some embodiments, 10%-70%; in some embodiments, 10%-60%; in some embodiments, 10%-50%; in some embodiments, 10%-40%; in some embodiments, 10%-30%; in some embodiments, 10%-25%; in some embodiments, 25%-40%; in some embodiments, 25%-50%; in some embodiments, 42%; in some embodiments, 25%; in some embodiments, 10%;

(ii) a filler, wherein the filler is one or more of microcrystalline cellulose, silicified microcrystalline cellulose or sorbitol, and the content is 10%-90%; in some embodiments, the content is 10%-80%; in some embodiments, the content is 10%-70%; in some embodiments, the content is 10%-60%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 10%-30%; in some embodiments, the content is 10%-20%; in some embodiments, the content is 30%-80%; in some embodiments, the content is 40%-80%; in some embodiments, the content is 37%; in some embodiments, the content is 40%; in some embodiments, the content is 72.5%; in some embodiments, the content is 80%;

(iii) a binder, wherein the binder is one or more of hydroxypropyl methylcellulose, methylcellulose or sodium carboxymethylcellulose, and the content is 1%-50%; in some embodiments, the content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-20%; in some embodiments, the content is 1%-15%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-4%; in some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2.5%; in some embodiments, the content is 1.5%-2.5%; in some embodiments, the content is 2%-2.5%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%;

(iv) a glidant, which is one or more of silicon dioxide or micro-powdered silica gel, and has a content of 0.5%-10%; in some embodiments, the content is 0.5%-5%; in some embodiments, the content is 0.5%-4%; in some embodiments, the content is 0.5%-3%; in some embodiments, the content is 0.5%-2%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 0.5%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 3%;

(v) lubricant, the lubricant is sodium stearyl fumarate, the content is 0.1%-10%; in some embodiments, the content is 0.1%-8%; in some embodiments, the content is 0.1%-6%; in some embodiments, the content is 0.1%-5%; in some embodiments, the content is 0.5%-2.0%; in some embodiments, the content is 0.5%-1%; in some embodiments, the content is 0.5%; in some embodiments, the content is 0.6%; in some embodiments, the content is 0.7%; in some embodiments, the content is 0.8%; in some embodiments, the content is 0.9%; in some embodiments, the content is 1.0%.

(vi) a disintegrant, which is one or more of hydroxypolypyrrolidone, cross-linked sodium carboxymethylcellulose, or calcium carboxymethylcellulose, and has a content of 0.5%-10%; in some embodiments, a content of 1%-10%; in some embodiments, a content of 1%-9%; in some embodiments, a content of 1%-8%; in some embodiments, a content of 1%-7%; in some embodiments, a content of 1%-6%; in some embodiments, a content of 1%-5%; in some embodiments, a content of 1%-4%; in some embodiments, a content of 1%-3%; in some embodiments, a content of 1%-2%; in some embodiments, a content of In some embodiments, the content is 1.5%-10%; in some embodiments, the content is 2%-10%; in some embodiments, the content is 2%-8%; in some embodiments, the content is 2%-7%; in some embodiments, the content is 2%-6%; in some embodiments, the content is 3%-7%; in some embodiments, the content is 4%-7%; in some embodiments, the content is 5%-7%; in some embodiments, the content is 2%; in some embodiments, the content is 3%; in some embodiments, the content is 4%; in some embodiments, the content is 6%; in some embodiments, the content is 8%; in some embodiments, the content is 10%;

(vii) In some embodiments, the composition may further comprise one or more of a solubilizer, a surfactant, and a pH adjuster, preferably one of a solubilizer, a surfactant, and a pH adjuster;

The solubilizer is one or more of cyclodextrin or hydroxypropyl beta-cyclodextrin, and the content is 5%-50%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-45%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 30%-50%; in some embodiments, the content is 30%-45%; in some embodiments, the content is 10%; in some embodiments, the content is 20%; in some embodiments, the content is 30%; in some embodiments, the content is 32%; in some embodiments, the content is 40%; in some embodiments, the content is 42.5%; in some embodiments, the content is 45%;

The surfactant is sodium dodecyl sulfate, and the content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-20%; in some embodiments, the content is 5%-20%; in some embodiments, the content is 10%-20%; in some embodiments, the content is 10%-15%; in some embodiments, the content is 5%; in some embodiments, the content is 10%; in some embodiments, the content is 15%; in some embodiments, the content is 20%;

The pH adjuster is magnesium oxide, and the content is 1%-50%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-9%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%; in some embodiments, the content is 4%; in some embodiments, the content is 5%.

Optionally, the pharmaceutical preparation as described above is characterized in that the binder can be added in a solution state or in a powder state; the disintegrant can be added internally, externally, or both internally and externally.

The present invention also provides an application of a pharmaceutical composition or a pharmaceutical preparation in preparing drugs related to treating cancer.

The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound or pharmaceutical composition disclosed in the present application, preferably 1-1000 mg, wherein the disease is preferably cancer, such as BRAF-mediated cancer, such as solid tumors.

"Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., cancer) being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1000 mg, 2-1000 mg, 3-1000 mg, 4-1000 mg, 5-1000 mg, 6-1000 mg, 10-1000 mg, 20-1000 mg, 25-1000 mg, 30-1000 mg, 40-1000 mg, 50-1000 mg, 60-1000 mg, 70-1000 mg, 75-1000 mg, 80-1000 mg, 90-1000 mg, 100-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg, 1-900 mg, 2-90 0mg, 3-900mg, 4-900mg, 5-900mg, 6-900mg, 10-900mg, 20-900mg, 25-900mg, 30-900mg, 40-900mg, 50-900mg, 60-900mg, 70-900mg, 75-900mg, 80-900mg, 90-900mg, 100-900mg, 200-900mg, 300-900mg, 400-900mg 1-800mg, 2-800mg, 3-800mg, 4-800mg, 5-800mg, 6-800mg, 10-800mg, 20 -800mg, 25-800mg, 30-800mg, 40-800mg, 50-800mg, 60-800mg, 70-800mg, 75-800mg, 80-800mg, 90-800mg, 100-800mg, 200-800mg, 300-800mg , 400-800mg 1-700mg, 2-700mg, 3-700mg, 4-700mg, 5-700mg, 6-700mg, 10-700mg, 20-700mg, 25-700mg, 30-700mg, 40-700mg, 50-700mg, 60-7 00mg, 70-700mg, 75-700mg, 80-700mg, 90-700mg, 100-700mg, 200-700mg, 300-700mg, 400-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-60 0mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-50 0mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-3 00mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300 mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-2 00mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 1-100mg, 2-100mg, 5-100mg, 10-100mg, 15-100mg, 20-100mg, 25-100mg, 30-100mg, 40-100mg, 50-100mg, 60-100mg, 70-100mg, 75-100mg, 80-100mg, 90-100mg; in some embodiments, the therapeutically effective Examples of amounts include, but are not limited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 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, 300 mg, 350 mg, 400 mg, 600 mg, 800 mg.

In some embodiments, the formulation specifications of the pharmaceutical composition or pharmaceutical preparation of the present invention include but are not limited to 1-1000 mg, 2-1000 mg, 3-1000 mg, 4-1000 mg, 5-1000 mg, 6-1000 mg, 10-1000 mg, 20-1000 mg, 25-1000 mg, 30-1000 mg, 40-1000 mg, 50-1000 mg, 60-1000 mg, 70-1000 mg, 75-1000 mg, 80-1000 mg, 90-1000 mg, 100-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg, 1000mg, 1-900mg, 2-900mg, 3-900mg, 4-900mg, 5-900mg, 6-900mg, 10-900mg, 20-900mg, 25-900mg, 30-900mg, 40-900mg, 50-900mg, 60-900mg, 70-900mg, 75-900mg, 80-900mg, 90-900mg, 100-900mg, 200-900mg, 300-900mg, 400-900mg, 1-800mg, 2-800mg, 3-800mg, 4-800mg, 5-800mg, 6-8 00mg, 10-800mg, 20-800mg, 25-800mg, 30-800mg, 40-800mg, 50-800mg, 60-800mg, 70-800mg, 75-800mg, 80-800mg, 90-800mg, 100-800mg, 200- 800mg, 300-800mg, 400-800mg, 1-700mg, 2-700mg, 3-700mg, 4-700mg, 5-700mg, 6-700mg, 10-700mg, 20-700mg, 25-700mg, 30-700mg, 40-700mg, 50-700mg, 60-700mg, 70-700mg, 75-700mg, 80-700mg, 90-700mg, 100-700mg, 200-700mg, 300-700mg, 400-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-50 0mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-4 00mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg , 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg , 40-200 mg, 50-200 mg, 60-200 mg, 70-200 mg, 75-200 mg, 80-200 mg, 90-200 mg, 100-200 mg, 125-200 mg, 150-200 mg, 1-100 mg, 2-100 mg, 5-100 mg, 10-100 mg, 15-100 mg, 20-100 mg, 25-100 mg, 30-100 mg, 40-100 mg, 50-100 mg, 60-100 mg, 70-100 mg, 75-100 mg, 80-100 mg, 90-100 mg; in some embodiments, treatment Examples of effective amounts include, but are not limited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 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, 300 mg, 350 mg, 400 mg, 600 mg, 800 mg.

In some embodiments, the amount of the active ingredient M in a unit preparation of the pharmaceutical composition or pharmaceutical preparation of the present invention includes but is not limited to 1-1000 mg, 2-1000 mg, 3-1000 mg, 4-1000 mg, 5-1000 mg, 6-1000 mg, 10-1000 mg, 20-1000 mg, 25-1000 mg, 30-1000 mg, 40-1000 mg, 50-1000 mg, 60-1000 mg, 70-1000 mg, 75-1000 mg, 80-1000 mg, 90-1000 mg, 100-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg, 1-900 mg, 2-1000 mg, 300-1000 mg, 400-1000 mg, 1-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg, 1-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg, 1-1000 mg, 200-1000 mg, 300-1000 mg, 400 900mg, 3-900mg, 4-900mg, 5-900mg, 6-900mg, 10-900mg, 20-900mg, 25-900mg, 30-900mg, 40-900mg, 50-900mg, 60-900mg, 70-900mg, 75-900mg, 80-900mg, 90 -900mg, 100-900mg, 200-900mg, 300-900mg, 400-900m, 1-800mg, 2-800mg, 3-8 00mg, 4-800mg, 5-800mg, 6-800mg, 10-800mg, 20-800mg, 25-800mg, 30-800mg, 4 0-800mg, 50-800mg, 60-800mg, 70-800mg, 75-800mg, 80-800mg, 90-800mg, 100 -800mg, 200-800mg, 300-800mg, 400-800mg, 1-700mg, 2-700mg, 3-700mg, 4-70 0mg, 5-700mg, 6-700mg, 10-700mg, 20-700mg, 25-700mg, 30-700mg, 40-700mg, 50-700mg, 60-700mg, 70-700mg, 75-700mg, 80-700mg, 90-700mg, 100-700mg, 20 0-700mg, 300-700mg, 400-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 300-600mg, 400-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500m g, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg , 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400m g, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 8 0-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400m g, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30 -300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-3 00mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-2 00mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200m g, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200m g, 150-200mg, 1-100mg, 2-100mg, 5-100mg, 10-100mg, 15-100mg, 20-100mg, 25 -100mg, 30-100mg, 40-100mg, 50-100mg, 60-100mg, 70-100mg, 75-100mg, 80-10 0 mg, 90-100 mg; in some embodiments, examples of therapeutically effective amounts include, but are not limited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 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, 300 mg, 350 mg, 400 mg, 600 mg, 800 mg.

A method for treating a disease in a mammal, the method comprising administering the active ingredient M to a subject at a daily dose of 1-1200 mg/day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-3600 mg/day, 25-3600 mg/day, 50-3600 mg/day, 100-3600 mg/day, 200-3600 mg/day, 10-2400 mg/day, 25-2400 mg/day, 50-2400 mg/day, 100-2400 mg/day, 200-2400 mg/day, 10-1200 mg/day, 25-1200 mg/day, 50-1200 In some embodiments, the daily dose includes but is not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 100 mg/day, 120 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 300 mg/day, 240 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1000 mg/day, 1200 mg/day, 2400 mg/day, 3600 mg/day.

The present invention relates to a kit, which may include a pharmaceutical composition or a pharmaceutical preparation in a single-dose or multi-dose form. The kit contains an amount of the active ingredient M in the pharmaceutical composition of the present invention, including but not limited to 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 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, 300 mg, 350 mg, 400 mg, 600 mg, 800 mg, 1200 mg.

Unless stated otherwise, the terms used in this specification and claims have the following meanings.

"Preparation specifications" refers to the weight of the main drug (active ingredient M) contained in each vial, tablet or other unit preparation.

Synthetic route

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

the term

Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

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

"Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

"Halo" or "halogen substitution" means substitution by one or more halogens selected from F, Cl, Br, I, or isotopes thereof. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they can be substituted by the same or different halogens. It usually includes 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

"Deuterium" refers to the isotope of hydrogen (H).

"Deuterated" or "deuterated substance" refers to the situation where the hydrogen atoms on groups such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl, etc. are replaced by at least one deuterium atom, and the upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced in the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and the upper limit, for example, 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms or 1 deuterium atom.

A "C _xy " group refers to a group containing x to y carbon atoms, for example, a "C _1-6 alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms.

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

"Alkylene" refers to a divalent straight chain or branched chain saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and the like.

"Haloalkyl" refers to a situation where one or more hydrogen atoms in an alkyl group are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine or their isotopes). The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Usually, the alkyl group is substituted by 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, they can be substituted by _the same or different halogens. Specific examples include, but are not limited to, _-CF3 , _-CH2Cl , _-CH2CF3 , _-CCl2 , _CF3 , etc.

"Alkoxy" or "alkyloxy" refers to -O-alkyl. For example, -OC _1-8 alkyl, -OC _1-6 alkyl, -OC _1-4 alkyl or -OC _1-2 alkyl. Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy, etc.; the alkoxy group may be optionally substituted with a substituent.

"Haloalkoxy" refers to -O-haloalkyl. For example, -O-halo C _1-8 alkyl, -O-halo C _1-6 alkyl, -O-halo C _1-4 alkyl or -O-halo C _1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, 1 halogen substitutions; when the number of halogen substituents is greater than 1, they can be substituted by the same or different halogens; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

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

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

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

"Alkyne" refers to a straight or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C≡C), typically containing 2-6 carbon atoms, further containing 2-4 carbon atoms, non-limiting examples include ethynylene, propynylene, butynylene, and the alkynylene group may be optionally substituted with a substituent.

"Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain ring heteroatoms. Cycloalkyl can be monocyclic, bicyclic or polycyclic. The bicyclic or polycyclic rings can be cyclic, spirocyclic, bridged or a combination thereof. The bicyclic or polycyclic rings can include one or more aromatic rings, but the ring system as a whole is not aromatic, and the connection site can be on the aromatic ring or on the non-aromatic ring. Usually, the cycloalkyl contains 3 to 20 carbon atoms, further contains 3-8 carbon atoms, and further contains 3-6 carbon atoms; when it is a monocyclic cycloalkyl, it contains 3-15 carbon atoms, or 3-10 carbon atoms, or 3-8 carbon atoms, or 3-6 carbon atoms; when it is a bicyclic or polycyclic cycloalkyl, it contains 5-12 carbon atoms, or 5-11 carbon atoms, or 6-10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, The cycloalkyl group may be optionally substituted with a substituent.

"Cycloalkylene" refers to a divalent radical of a cycloalkyl group.

"Aryl" refers to a carbocyclic ring having aromaticity and not containing heteroatoms, including monocyclic aromatic groups and condensed aromatic groups. It usually contains 6 to 13 carbon atoms, further contains 6 to 9 carbon atoms, further is phenyl, non-limiting examples include phenyl, naphthyl, anthracenyl, phenanthrenyl, and the aryl group may be optionally substituted by a substituent.

"Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic carbocycle, including aryl and cycloalkyl. The carbocycle can be monocyclic, bicyclic or polycyclic, including bridged rings, cyclocyclic rings and spirocyclic rings and their combinations. The carbocycle usually has 3 to 12 carbon atoms, or 3-10 carbon atoms, or 3-6 carbon atoms. In non-limiting examples, monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, and bicyclic bridged rings include etc., double ring and ring include etc., bicyclic spiro ring includes The carbocyclic ring may be optionally substituted with a substituent.

"Heterocycloalkyl" refers to a saturated or partially unsaturated non-aromatic carbocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, S, and O. Heterocycloalkyl can be monocyclic, bicyclic, or polycyclic. The bicyclic or polycyclic ring can be a bridged ring, a cyclic ring, a spirocyclic ring, or a combination thereof. The bicyclic or polycyclic ring can include one or more aromatic or heteroaromatic rings, but the ring system as a whole does not have aromaticity, and the connection site can be on the aromatic ring or on the non-aromatic ring. Usually, the heterocycloalkyl group is a 3-20-membered ring. When it is a monocyclic heterocycloalkyl group, it is usually a 3-15-membered ring, or a 3-10-membered ring, or a 3-8-membered ring, or a 3-6-membered ring; when it is a bicyclic or polycyclic heterocycloalkyl group, it is usually a 5-12-membered ring, or a 5-11-membered ring, or a 6-9-membered ring. The heteroatoms N and S therein include their oxidation states. Non-limiting examples of heterocycloalkyl include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azocycloolyl, azocyclohexenyl, oxolyl, oxenyl, and the like, and the heterocycloalkyl may be optionally substituted with a substituent.

"Heteroaromatic ring" or "heteroaryl" when not specifically stated, refers to a ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states and having aromaticity, which may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic ring may be a bridged ring, a fused ring, a spirocyclic ring and a combination thereof; when it is bicyclic or polycyclic, it may be a condensation of a heteroaryl and an aryl, or a condensation of a heteroaryl and a heteroaryl, wherein either the heteroaryl or the aryl may be a connection site. Non-limiting examples include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, The heteroaryl group may be optionally substituted by a substituent.

"Heterocycle" or "heterocyclyl" 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, and its meaning includes heteroaryl and heterocycloalkyl. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiro heterocycles or their combinations. It is usually a 3-12 membered heterocycle or a 5-12 membered heterocycle, or a 5-7 membered heterocycle. The heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl , dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, The heterocyclic ring may be optionally substituted with a substituent.

"Heterocyclylene" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include wait.

"Spiro" refers to a polycyclic group that shares a carbon atom (called spiro atom) between rings, which may contain 0 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 6-14-membered ring, or a 6-12-membered ring, or a 6-10-membered ring. Usually, the spiro ring is a trispirotri (indicating a three-membered ring spirotricyclic ring), a trispirotetra, a trispiropenta, a trispirohexa, a tetraspirotetra, a tetraspiropenta, a tetraspirohexa, a pentaspiropenta or a pentaspirohexa. Non-limiting examples of spiro rings include The spiro ring may be optionally substituted with a substituent.

"Parallel ring" refers to a polycyclic group in which the rings share two adjacent ring atoms and a chemical bond, and may contain one or more double bonds or triple bonds, and the rings may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Usually, the ring is a 5-20-membered ring, or a 5-14-membered ring, or a 5-12-membered ring, or a 5-10-membered ring. Usually, the ring is a three-to-four ring (indicates a ring formed by a three-membered ring and a four-membered ring. According to the IUPC naming rules, it may be a three-membered ring as the basic ring or a four-membered ring as the basic ring. The same applies below), a three-to-five ring, a three-to-six ring, a four-to-four ring, a four-to-five ring, a four-to-six ring, a five-to-five ring, a five-to-six ring, and a six-to-six ring. Non-limiting examples of parallel rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, The cyclic ring may be optionally substituted by a substituent.

"Bridged ring" means two non-adjacent ring atoms shared between two rings, and may contain one or more double bonds or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Usually the ring atoms of the bridged ring are 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings include adamantane,

"Substitution" or "substituent" unless otherwise specified refers to any substitution at a position permitted by chemical theory, and the number of substituents complies with the chemical bonding rules. Exemplary substituents include, but are not limited to, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heteroalkyl, C _5-12 aryl, 5-12 membered heteroaryl, hydroxy, C _{1-6 alkoxy, C 5-12 aryloxy} , thiol, C _1-6 alkylthio, cyano, halogen, C _1-6 alkylthiocarbonyl, C _1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, amino, phosphonic acid, -CO ₂ (C _{1-6 alkyl), -OC(=O)(C 1-6 alkyl} ), -OCO ₂ ( _{C 1-6 alkyl} ), -C(=O)NH ₂ , -C(=O)N(C _1-6 alkyl) ₂ , -OC(＝O)NH(C _1-6 alkyl), -NHC(＝O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(＝O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(＝O)N(C _1-6 alkyl) ₂ , -HC(＝O)NH(C _1-6 alkyl), _-NHC (＝O)NH ₂ , -NHSO ₂ (C 1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, _and the like.

"Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

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

A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically/pharmaceutically acceptable carriers and/or excipients.

"Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

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

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

"Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers and conformational isomers.

"Solvate" refers to a substance formed by a stoichiometric or non-stoichiometric amount of a solvent that is bound to the compound or salt of the present invention by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

"Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

DETAILED DESCRIPTION

The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

Detection Methods

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^{- 6} (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF ₂₅₄ or Qingdao GF ₂₅₄ silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

RuPhos-Pd-G3: Catalyst with CAS No. 1445085-77-7.

Example 1

Step 1: In a 50 mL reaction bottle, 1A (800 mg, 5.99 mmol), triethylamine (1.82 g, 17.97 mmol) and dichloromethane (10 mL) were added in sequence. After the addition, the mixture was stirred at 0°C for 20 minutes, and a dichloromethane (7 mL) solution of aminosulfonyl chloride (692 mg, 5.99 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction solution was diluted with dichloromethane (50 mL), washed with water (30 mL × 1) and saturated brine (30 mL × 1) in sequence, 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%).

Step 2: In a 50 mL reaction bottle, 1C (250 mg, 0.8 mmol, preparation method refer to WO2021116050A1), 1B (160 mg, 0.9 mmol), cesium carbonate (310 mg, 0.96 mmol) and N, N-dimethylformamide (10 mL) were added in sequence. After the addition, the mixture was stirred at 80 ° C for 18 hours. Ethyl acetate (50 mL) was added to the reaction solution, and then washed with water (40 mL × 2). The organic layer was washed with The residue was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 1 (86 mg, yield 23%).

LCMS m/z=470.5 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.36(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

Step 1: In a 50 mL reaction bottle, 2A (520 mg, 4.34 mmol), triethylamine (2.19 g, 21.64 mmol) and dichloromethane (10 mL) were added in sequence. After the addition, the mixture was stirred at 0°C for 20 minutes, and a solution of aminosulfonyl chloride (500 mg, 4.34 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction solution was diluted with dichloromethane (50 mL), washed with water (50 mL × 1) and saturated brine (50 mL × 1) in sequence, 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 2B (450 mg, yield 32%).

Step 2: Referring to the reaction operation of step 2 of Example 1, compound 2 (60 mg, yield 16%) was obtained by separation and purification.

LCMS m/z=456.2 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.26(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

Step 1: In a 50 mL reaction bottle, add aminosulfonyl chloride (1.0 g, 8.68 mmol), triethylamine (2.63 g, 26.04) and dichloromethane (10 mL) in sequence, stir at 0 ° C for 20 minutes, slowly add cyclopropanol (1.11 g, 17.36 mmol) dropwise, and stir at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure to obtain 3B, which is used directly in the next step without purification.

Step 2: Referring to the second step synthesis reaction of Example 1, compound 3 (100 mg, yield 14.5%) was obtained by separation and purification.

LCMS m/z=431.1 [M+H] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD)δ8.26(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

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

83%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.49 (s, 1H), 9.84 (s, 1H), 7.24–7.18 (m, 2H), 7.03 (dd, 1H).

Step 2: In a 250 mL single-mouth bottle, 4B (3.85 g, 21.51 mmol) was dissolved in an aqueous solution (60 mL) of sodium hydroxide (1.03 g, 25.75 mmol), and methoxyamine hydrochloride (2.69 g, 32.27 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in a mixed solvent of dichloromethane (200 mL) and methanol (10 mL), dried over anhydrous sodium sulfate, and filtered through diatomaceous earth pad. 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] ⁺ ;

Step 3: In a 50 mL single-necked bottle, 4C (2.6 g, 14.27 mmol) was dissolved in trimethyl orthoformate (54 mL), and the mixture was stirred at 105°C for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by slurrying with petroleum ether. The solid was filtered and dried to obtain 4D (2.4 g, yield 88%).

LCMS m/z＝193.1[M+H] ⁺ ;

Step 4: In a 100 mL single-mouth bottle, 4D (2.4 g, 12.49 mmol) was dissolved in dry N, N-dimethylformamide (40 mL). Cesium carbonate (4.88 g, 14.99 mmol) was slowly added under an ice bath. After the addition, the mixture was stirred at room temperature for 0.5 h. 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 the addition, the mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into ice water (250 mL), stirred for 30 min, filtered, and the obtained solid was dried and purified by slurrying 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 (400MHz, DMSO-d ₆ ) 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 (377MHz, DMSO-d ₆ ) δ -107.70 (s), -128.37 (s).

Step 5: Compound 4 (32 mg, yield 7%) was obtained by synthesis, separation and purification according to the second step of Example 1.

LCMS m/z＝478.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.33(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -127.22(s), -172.76(s).

Example 5

Step 1: In a 50 mL reaction bottle, 5A (720 mg, 6.04 mmol), triethylamine (1.83 g, 18.12 mmol) and dichloromethane (10 mL) were added in sequence. After the addition, the mixture was stirred at 0°C for 20 minutes, and a solution of aminosulfonyl chloride (700 mg, 6.04 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1-2 h. The reaction solution was diluted with dichloromethane (100 mL), washed with water (40 mL × 1) and saturated brine (40 mL × 1) in sequence, 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 = 12/1) to obtain 5B (600 mg, yield 61%).

Step 2: Referring to the second step of Example 1, compound 5 (12 mg, yield 1%) was obtained by synthesis, separation and purification.

LCMS m/z＝456.30[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ8.33(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-134.36 (s).

Example 6

Step 1: In a 50 mL reaction bottle, add 6A (synthesis method reference: WO2017/1660, 2017, A1) (620 mg, 5.38 mmol), triethylamine (1633.21 mg, 16.14 mmol) and dichloromethane (20 mL) in sequence, stir at 0 ° C for 20 minutes after addition, slowly drop aminosulfonyl chloride (622 mg, 5.38 mmol) in dichloromethane (10 mL) solution, and stir at room temperature for 1-2 hours. The reaction solution was diluted with dichloromethane (100 mL), washed with water (40 mL × 1) and saturated brine (40 mL × 1) in sequence, 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 = 20/1) to obtain 6B (500 mg, yield 48%).

Step 2: Referring to the second step of Example 1, compound 6 (8 mg, yield 1%) was obtained by synthesis, separation and purification.

LCMS m/z＝488.20[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.42(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

Step 1: Refer to step 2 of Example 1 for synthesis, separation and purification to obtain compound 7 (58 mg, yield: 8%).

LCMS m/z＝486.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.38(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-127.26 (s).

Example 8

Step 1: Refer to step 2 of Example 1 for synthesis, separation and purification to obtain compound 8 (0.3 g, yield: 42%).

LCMS m/z=472.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.48(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-127.15 (s).

Example 9

Step 1: Add 9A (25 g, 184.46 mmol) and sodium formate (15.55 g, 21.51 mmol) into a 250 mL single-necked bottle and react at 130° C. for 2 hrs. After the reaction is complete, cool to room temperature and filter to obtain 9B (22.0 g, yield 94%).

LCMS m/z＝128.2[M+H] ⁺ ;

Step 2: In a 250 mL single-necked bottle, 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 hrs. After the reaction was complete, it was cooled to room temperature and filtered. The filter cake was washed twice with ethyl acetate (1 mL), and then the filter cake was concentrated to obtain 9C (1.3 g, yield 82%).

LCMS m/z＝245.2[M+H] ⁺ ;

Step 3: In a 25mL single-mouth bottle, 9C (0.60g, 2.46mmol) was dissolved in dry N,N-dimethylformamide (6mL). Cesium carbonate (1.6g, 4.91mmol) was slowly added under ice bath. After the addition, the reaction was stirred at room temperature for 0.5h. In an ice bath, 2,3,6-trifluorobenzonitrile (0.41g, 2.61mmol) was slowly added dropwise. After the addition, the reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (10mL) was added to the reaction system to dilute the reaction, and water (20mL) was added to quench the reaction, and extracted with ethyl acetate (20mLx2). The organic phase was washed with water (20mLx2), and the organic phase was concentrated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain 9E (0.75g, yield 80%).

LCMS m/z=382.0 [M+H] ⁺ ;

Step 4: Referring to the second step of Example 1, the synthesis, separation and purification were performed to obtain 100 mg of solid, which 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] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.36(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -127.30 (s), -67.08 (s).

Example 10

Step 1: Add 10A (20 g, 184.46 mmol) to ethyl formate (20 mL) and react overnight at 55° C. After the reaction is complete, cool to room temperature and concentrate the reaction solution to obtain the residue 10B (3.1 g, yield 12%).

LCMS m/z=100.2[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ 8.23 (s, 1H), 6.32 (s, 1H), 6.01–5.67 (m, 1H), 3.71–3.60 (m, 2H).

Step 2: In a 25 mL single-mouth bottle, 2-amino-5-hydroxybenzoic acid (0.5 g, 3.31 mmol) was added to 10B (3.1 mL, 28.4 mmol) and reacted at 150°C for 21 hours. After the reaction was complete, it was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (0.5 mL × 2), and then the filter cake was concentrated to obtain 10C (0.70 g, yield 94%).

LCMS m/z＝227.2[M+H] ⁺ ;

Step 3: In a 25 mL single-mouth bottle, 10C (0.70 g, 3.09 mmol) was dissolved in dry N, N-dimethylformamide (6 mL). Cesium carbonate (2.01 g, 6.17 mmol) was slowly added under an ice bath. After the addition, the reaction was stirred at room temperature for 0.5 h. In an ice bath, 2,3,6-trifluorobenzonitrile (0.51 g, 3.20 mmol) was slowly added dropwise. After the addition, the reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (5 mL) was added to the reaction system to dilute the reaction, and water (20 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with water (20 mL × 2), and the organic phase was concentrated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain 10E (1.1 g, yield 98%).

LCMS m/z=364.2 [M+H] ⁺ ;

Step 4: In a 25 mL single-mouth bottle, 10E (0.50 g, 1.38 mmol) was dissolved in dry N, N-dimethylformamide (5 mL), and cesium carbonate (0.90 g, 2.76 mmol) and 1B (0.24 g, 1.38 mmol) were slowly added under an ice bath, and stirred at 100 ° C for 4 hours. After the reaction was complete, the reaction was filtered, and the filtrate was purified by preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to separate and purify compound 10 (150 mg, yield 21%).

LCMS m/z＝520.0[M+H] ⁺ ;

¹ H NMR(400MHz,DMSO-d6)δ10.37(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).

¹⁹ F NMR (377MHz, DMSO-d6) δ -127.22 (s), -120.46 (s).

Embodiment 11

Step 1: In a 100 mL reaction bottle, 11A (5.0 g, 87.62 mmol) and ethyl formate (40 mL) were added in sequence. After the addition, the mixture was stirred at 55 °C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 11B (7.0 g, yield 93%).

LCMS m/z＝86.20[M+H] ⁺ ;

Step 2: In a 100 mL reaction bottle, 11B (7.0 g, 82.26 mmol) and 4A (1.5 g, 9.83 mmol) were added in sequence, and stirred at 145 °C for 10 hours. After the reaction was completed, the mixture was filtered and the obtained solid was purified by slurrying with ethyl acetate. The solid was filtered and dried to obtain 11C (1.5 g, yield 75%).

LCMS m/z＝203.10[M+H] ⁺ ;

Step 3: In a 100 mL reaction bottle, 11C (1.5 g, 7.42 mmol) was dissolved in dry N,N-dimethylformamide (20 mL), and cesium carbonate (3.63 g, 11.13 mmol) was added under ice bath, and 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 ice bath, and the mixture was reacted at room temperature for 2 h. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL × 1) and saturated brine (50 mL × 1) in turn, the organic layer was dried over anhydrous sodium sulfate, filtered and 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] ⁺ ;

Step 4: In a 100 mL reaction bottle, 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 in sequence. After the addition, the mixture was stirred at 100 °C for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution, and then 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 chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 11 (150 mg, yield 52%).

LCMS m/z＝496.20[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.37(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

Step 1: In a 50 mL reaction bottle, 12A (100 mg, 0.75 mmol), triethylamine (150 mg, 1.50 mmol) and dichloromethane (10 mL) were added in sequence. After the addition, the mixture was stirred at 0°C for 20 minutes, and a dichloromethane (5 mL) solution of aminosulfonyl chloride (92 mg, 0.80 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction solution was diluted with dichloromethane (40 mL), washed with water (30 mL × 1) and saturated brine (30 mL × 1) in sequence, 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%).

Step 2: In a 50 mL reaction bottle, 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) were added in sequence. After the addition, the mixture was stirred at 100 °C for 12 hours. Ethyl acetate (40 mL) was added to the reaction solution, which was then 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 (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 12 (35 mg, yield 23%).

LCMS m/z=470.50 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.23(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).

Embodiment 13

Step 1: In a 50 mL reaction bottle, 13A (500 mg, 3.21 mmol), triethylamine (0.97 g, 9.59 mmol) and dichloromethane (10 mL) were added in sequence, stirred at 0°C for 20 minutes, and a solution of aminosulfonyl chloride (740 mg, 6.40 mmol) in dichloromethane (7 mL) was slowly added dropwise, and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain 13B (500 mg, crude product).

Step 2: In a 50 mL reaction bottle, 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) were added in sequence. After the addition, the mixture was stirred at 100 °C for 12 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 min) to obtain compound 13 (46.76 mg, yield 3.78%).

LCMS m/z=492.4 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ8.30(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).

Embodiment 14

Step 1: In a 50 mL reaction bottle, add aminosulfonyl chloride (0.18 g, 1.59 mmol), triethylamine (0.48 g, 4.74 mmol) and dichloromethane (5 mL) in sequence, stir at 0°C for 20 minutes, slowly add 14A (0.20 g, 1.59 mmol) dropwise, and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was used directly in the next step without purification.

Step 2: In a 50 mL reaction bottle, 1C (490 mg, 1.56 mmol), 14B (0.30 g crude product), cesium carbonate (1.52 mg, 4.67 mmol) and N,N-dimethylformamide (5 mL) were added in sequence. After the addition, the mixture was stirred at 100 °C for 18 hours. Ethyl acetate (50 mL) was added to the reaction solution, which was then 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 preparation (instrument: Biotage Isolera One; chromatographic column: C18 spherical 20-35um 100A80g (Agela Technologies); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water; gradient: 5%-90% acetonitrile isocratic elution; cycle time: 20 min; retention time: 7 min) to obtain compound 14 (28 mg, yield 3.89%).

LCMS m/z＝462.1[M+H] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD)δ8.22(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -146.12 (s), -220.65 (s).

Embodiment 15

Step 1: In a 100 mL single-necked bottle, 15A (0.25 g, 1.74 mmol) was dissolved in dry acetonitrile (15 mL), and 15B (0.53 g, 1.74 mmol) was added. After the addition, the mixture was stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was the crude compound 15C. The crude compound 15C was directly used for the next step without purification.

Step 2: Compound 15C (crude product) and dichloromethane (12 ml) were added to a single-necked bottle, and trifluoroacetic acid (3 ml) was added, and the mixture was reacted at room temperature for 2 hours. After concentration, compound 15D was obtained, which was directly used for the next step without purification.

Step 3: In a 100 mL single-mouth bottle, 15D (crude product) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (2.27 g, 6.97 mmol) and 1C (300 mg, 0.96 mmol) were slowly added under ice bath, and the mixture was stirred at 100 °C for 6 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid. The residue was separated and purified by medium pressure preparation (instrument: Biotage Isolera One; chromatographic 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 isocratic elution; cycle time: 20 min; retention time: 7 min) to obtain compound 15 (120 mg, total yield of three steps 14.4%).

LCMS m/z=480.4 [M+H] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD)δ8.25(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -121.73 (s), -145.77 (s).

Example 16

Step 1: In a 100 mL single-mouth bottle, 3-(trifluoromethyl)azetidine hydrochloride (16A) (0.25 g, 1.55 mmol) was dissolved in dry acetonitrile (15 mL), and 15B (0.47 g, 1.55 mmol) was added. After the addition, the mixture was stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was the crude compound 16C. No purification was required and the next step was carried out directly.

Step 2: Compound 16C (crude product) and dichloromethane (12 ml) were added to a single-necked bottle, and trifluoroacetic acid (3 ml) was added, and the mixture was reacted at room temperature for 2 hours. After concentration, compound 16D was obtained, which was directly used for the next step without purification.

Step 3: In a 100 mL single-mouth bottle, 16D (crude product) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (2.02 g, 6.20 mmol) and 1C (300 mg, 0.96 mmol) were slowly added under ice bath, and the mixture was stirred at 100 °C for 6 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid. The residue was separated and purified by medium pressure preparation (instrument: Biotage Isolera One; chromatographic 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 isocratic elution; cycle time: 20 min; retention time: 8 min) to obtain compound 16 (100 mg, total yield of three steps 12.9%).

LCMS m/z＝498.5[M+H] ⁺ ;

¹ H NMR (400MHz, CD ₃ OD)δ8.23(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -70.81 (s), -145.19 (s).

Embodiment 17

Step 1: In a 100 mL single-mouth bottle, 2-azabicyclo[3.1.0]hexane hydrochloride (17A) (0.47 g, 3.97 mmol) was dissolved in dry acetonitrile (25 mL), and 15B (1.2 g, 3.97 mmol) was added. After the addition, the mixture was stirred at 70°C for 4 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was the crude compound 17B. The crude compound 17B was directly used for the next step without purification.

Step 2: Compound 17B (680 mg, 2.59 mmol) and dichloromethane (12 ml) were added to a single-mouth bottle, trifluoroacetic acid (3 ml) was added, and the mixture was reacted at room temperature for 2 hours. 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%).

Step 3: In a 100 mL single-mouth bottle, 17C (217 mg, 1.34 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (655 mg, 2.01 mmol) was slowly added under ice bath, and the mixture was stirred at 50°C for 0.5 h. In an ice bath, a solution of 1C (420 mg, 1.34 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise, and the mixture was stirred at 100°C for 2 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain an oily liquid which was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-80% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 17 (56 mg, yield: 9%).

LCMS m/z＝456.5[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.39(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,3 H),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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-128.22 (s).

Embodiment 18

Step 1: In a 50 mL reaction bottle, 18A (500 mg, 5.08 mmol), triethylamine (1.54 g, 15.24 mmol) and dichloromethane (10 mL) were added in sequence, stirred at 0°C for 20 minutes, and a solution of aminosulfonyl chloride (1.17 g, 10.16 mmol) in dichloromethane (7 mL) was slowly added dropwise, and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain 18B (500 mg, crude product).

Step 2: In a 50 mL reaction bottle, 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 added in sequence. After the addition, the mixture was stirred at 100 °C for 12 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 min) to obtain compound 18 (22.34 mg, yield 1.7%).

LCMS m/z=472.5 [M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ )δ8.31(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).

Embodiment 19

Step 1: In a 50 mL reaction bottle, 19A (500 mg, 4.49 mmol), triethylamine (1.36 g, 13.47 mmol) and dichloromethane (10 mL) were added in sequence. After the addition, the mixture was stirred at 0°C for 20 minutes, and a solution of aminosulfonyl chloride (520 mg, 4.49 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1-2 h. The reaction solution was diluted with dichloromethane (100 mL), washed with water (40 mL × 1) and saturated brine (40 mL × 1) in sequence, 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 = 12/1) to obtain 19B (600 mg, yield 70%).

Step 2: In a 100 mL reaction bottle, 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) were added in sequence. After the addition, the mixture was stirred at 80 °C for 18 hours. Ethyl acetate (100 mL) was added to the reaction solution, and then 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 (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 min) to obtain compound 19 (12 mg, yield 1%).

LCMS m/z＝484.60[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.36(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-127.31 (s).

Example 20 and Example 21

Step 1: Take a 500mL reaction bottle, dissolve trimethyl sulfoxide iodide (100.45g, 456.62mmol) in tert-butanol (350mL) at room temperature, then add potassium tert-butoxide (45.0g, 401.83mmol), react at 50℃ for 1h, then cool to room temperature, slowly add 20A (40.0g, 182.65mmol), after the addition is complete, react at 50℃ for 48h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to quench, water (50 mL) was added, and ethyl acetate (150 mL×2) was used for extraction. The combined organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 2:1) to obtain 10.0 g of the racemate. The racemate was separated by chiral preparative HPLC to obtain peak 1 (3.0 g, retention time 8.45 min, set as 20B) and peak 2 (3.0 g, retention time 11.62 min, set as 21B), respectively. Preparative chromatographic separation conditions: instrument SFC Prep 150AP; chromatographic column: Daicel AD-H (19 mm×250 mm); mobile phase system: A for CO ₂ and B for MeOH; gradient: B 10%; 5. flow rate: 45 mL/min.

Step 2: Take a 100 mL reaction bottle, 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 hydrogen atmosphere. After the reaction is complete, filter and concentrate the filtrate to obtain the crude title compound 20C (1.1 g, 80%), which is directly used in the next step without purification.

LCMS m/z = 114.2 [M+H] ⁺ .

Step 3: Take a 50mL reaction bottle, dissolve compound 20C (1.1g, 9.72mmol) in 1,4-dioxane (15mL) at room temperature, add sulfonamide (0.78g, 8.11mmol), and react at 100°C for 12 hours. After the reaction is complete, add water (10mL), extract with ethyl acetate (15mL×2), wash the combined organic phase with saturated brine (10mL×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) = 1:1) to obtain the title compound 20D (1.3g, 70%).

LCMS m/z = 193.1 [M+H] ⁺ .

Step 4: In a 50mL reaction bottle, add 1C (407.4mg, 1.30mmol), 20D (500mg, 2.60mmol), cesium carbonate (813.8mg, 2.60mmol) and N,N-dimethylformamide (10mL) in sequence at room temperature, and stir at 100℃ for 12 hours after addition. After the reaction is complete, add water (10mL) and extract with ethyl acetate (30mL×2). The combined organic phase is washed with saturated brine (10mL×1), dried over anhydrous sodium sulfate, filtered, and the residue is prepared by preparative liquid phase after the filtrate is concentrated. HPLC separation method: 1. Instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×250mm). 2. The sample is filtered with a 0.45μm filter head to prepare a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 10% to 55%; c. Flow rate 12 mL/min; d. Elution time 20 min. Retention time 7.0 min to obtain compound 20 (230 mg, 18%).

LCMS m/z = 486.1 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.00(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).

Using 21B (3 g) as the starting material, the same synthesis method as compound 20 was used to obtain compound 21 (200 mg).

LCMS m/z = 486.1 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ8.01(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).

Embodiment 22

Step 1: In a 100 mL reaction bottle, 22A (0.8 g, 3.98 mmol) (synthesis reference patent WO2019/60611, 2019, A1 for compound 22A) was dissolved in acetonitrile (20 mL), and potassium permanganate (1.20 g, 7.61 mmol) and basic alumina (1.0 g, 9.79 mmol) were added in sequence. After the addition, the mixture was reacted at room temperature for 5 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated. The residue was separated and purified by column chromatography (PE/EA=1/1) to obtain 22B (0.65 g, yield 82%).

LCMS m/z＝200.10[M+H] ⁺ ;

Step 2: In a 100 mL reaction bottle, 22B (0.6 g, 3.01 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium ethanethiolate (0.50 g, 5.94 mmol) was added. The reaction solution was replaced with nitrogen three times, and then heated to 130 °C for 10 hours. After the reaction was completed, the solution was filtered and the filtrate was concentrated to obtain 22C (0.45 g, yield 80%).

LCMS m/z＝186.10[M+H] ⁺ ;

Step 3: In a 100 mL reaction bottle, 22C (0.45 g, 2.43 mmol) was dissolved in N, N-dimethylformamide (10 mL), and cesium carbonate (1.20 g, 3.75 mmol) was slowly added in an ice-water bath. After stirring at room temperature for 0.5 hours, a solution of 2,3,6-trifluorobenzonitrile (0.38 g, 2.43 mmol) in N, N-dimethylformamide (5 mL) was slowly added dropwise in an ice-water bath, and reacted at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (50 mL × 1) and saturated brine (50 mL × 1) in turn, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE/EA = 2/1) to obtain 22D (0.55 g, yield 70%).

LCMS m/z=323.30 [M+H] ⁺ ;

Step 4: In a 100 mL reaction bottle, 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) were added in sequence. After the addition, the mixture was stirred at 100 °C for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution, which was then 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 chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 10 min) to obtain compound 22 (150 mg, yield 40%).

LCMS m/z＝479.10[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.38(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).

Embodiment 23

Step 1: 23A (1.00 g, 9.11 mmol) and acetic acid (15 mL) were added to a single-mouth bottle, followed by 3-ethoxy-2-methyl-2-propenoic acid ethyl ester (2.88 g, 18.22 mmol), and heated under reflux for 16 hours. After the reaction was completed as monitored by LCMS, the acetic acid was removed by rotation, and the remaining solid was slurried with ethyl acetate (20 mL). The solid was filtered and dried to obtain the product 23B (1.2 g, 74.7%).

LC-MS (ESI): m/z=177.1[M+H] ⁺ .

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. 2,3,6-trifluorobenzonitrile (0.23 g, 1.48 mmol) was added under stirring at 0°C, and the temperature was slowly raised to room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (15 mL) to precipitate a large amount of solid, which was filtered and dried to obtain product 23C (0.12 g, 33.6%).

LC-MS (ESI): m/z=314.1[M+H] ⁺ .

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 added to a single-mouth bottle in sequence, and stirred at 80°C for 18 hours. After the reaction was completed, ethyl acetate (50 mL) was added to the reaction solution, and then 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((400MHz,DMSO-d ₆ )δ10.41(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] ⁺ .

Embodiment 24

Step 1: In a 50 mL reaction bottle, 24A (1.2 g, 10.95 mmol), triethylamine (3.32 g, 32.85 mmol) and acetonitrile (20 mL) were added in sequence, stirred for 30 minutes after the addition, 15B (4.97 g, 16.43 mmol) was slowly added dropwise, and stirred at 40 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure to obtain 24B (1 g, crude product).

Step 2: In a 50 mL reaction bottle, 24B (0.8 g, 3.17 mmol) and dichloromethane (6 mL) were added in sequence, trifluoroacetic acid (2 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 24C (0.8 g, crude product).

Step 3: In a 50 mL reaction bottle, 24C (0.8 g, 5.26 mmol), cesium carbonate (2.57 g, 7.89 mmol) and N,N-dimethylformamide (15 mL) were added in sequence, and the mixture was stirred at 50 °C for 2 hours, and then 4E (2.08 g, 6.31 mmol) was added, and the mixture was stirred at 80 °C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid phase (instrument: waters2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic 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 (400MHz, CDCl ₃ )δ8.26(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).

Embodiment 25

Step 1: In a 25 mL reaction bottle, compound 1 (180 mg, 0.38 mmol), Lawesson's reagent (768 mg, 1.90 mmol) and dry tetrahydrofuran (9 mL) were added in sequence. After the addition, the mixture was stirred at 80 ° C for 4 hours. 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 separated and purified by preparative liquid phase to obtain compound 25 (35 mg, yield 19%).

LCMS m/z＝486.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.41(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-127.24 (s).

Embodiment 26

Step 1: In a 250 mL reaction bottle, 2-fluoroethylamine hydrochloride (9.0 g, 90.53 mmol) was dissolved in water (80 mL), and an aqueous solution of sodium hydroxide (3.3 g, 82.54 mmol) was added under an ice-water bath, and 4B (4.0 g, 22.29 mmol) was added after stirring for 30 minutes, and stirred at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was dissolved in a mixed solvent of dichloromethane (100 mL) and methanol (50 mL). After filtration, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE/EA=1/1) to obtain 26A (3.8 g, yield 86%).

LCMS m/z＝199.10[M+H] ⁺ ;

Step 2: In a 20 mL microwave tube, 26A (1.5 g, 8.58 mmol) was dissolved in triethyl orthoformate (10 mL), the reaction solution was heated to 185 °C for 2 hours, and after the reaction was completed, the reaction mixture was filtered and the filter cake was dried to obtain 26B (1.6 g, yield 89%).

LCMS m/z＝209.10[M+H] ⁺ ;

Step 3: In a 100 mL reaction bottle, 26B (1.5 g, 7.20 mmol) was dissolved in N, N-dimethylformamide (20 mL), and cesium carbonate (3.52 g, 10.80 mmol) was slowly added in an ice-water bath. 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 in an ice-water bath. After the addition was complete, the mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (100 mL × 1) and saturated brine (100 mL × 1) in turn, the organic layer was dried over anhydrous sodium sulfate, filtered, and 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] ⁺ ;

Step 4: In a 100 mL reaction bottle, 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 in sequence, and the mixture was reacted at 100 °C for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution, and then 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 chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 10 min) to obtain compound 26 (320 mg, yield 55%).

LCMS m/z＝502.10[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.37(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).

Embodiment 27

Step 1: In a 100 mL single-mouth bottle, 27A (1.0 g, 8.96 mmol) was dissolved in dry acetonitrile (15 mL), and 15B (2.71 g, 8.96 mmol) and triethylamine (1.81 g, 17.96 mmol) were added and stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was compound 27C, which was directly used for the next step without purification.

Step 2: Compound 27C and dichloromethane (12 ml) were added to a single-mouth bottle, and trifluoroacetic acid (6 ml) was added, and the mixture was reacted at room temperature for 2 hours. 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 two steps 57.9%).

Step 3: In a 100 mL single-mouth bottle, 27D (0.45 g, 2.92 mmol) was dissolved in dry N, N-dimethylformamide (6 mL), and cesium carbonate (0.95 g, 2.92 mmol) and 4E (800 mg, 2.43 mmol) were slowly added and stirred at 80 ° C for 6 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid. The residue was separated and purified by medium pressure preparation (instrument: Biotage Isolera One; chromatographic column: C18 spherical 20-35um 100A 80g (Agela Technologies); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water; gradient: 5%-90% acetonitrile isocratic 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 (400MHz, DMSO-d ₆ )δ10.63(s,1H),7.96–7.78(m,2H),7.73(dd,1H),7.56(dd,1H),7.44(d,1 H),5.47-5.28(m,1H),4.25-4.16(m,2H),4.05(s,3H),4.04–3.95(m,2H).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -126.63 (s), -177.31 (s).

Embodiment 28

Step 1: In a 100 mL single-mouth bottle, 28A (1.0 g, 7.72 mmol) was dissolved in dry acetonitrile (15 mL), and 15B (2.33 g, 7.72 mmol) and triethylamine (1.56 g, 15.44 mmol) were added. After the addition, the mixture was stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was the crude compound 28C. No purification was required and the next step was carried out directly.

Step 2: Compound 28C (crude product) and dichloromethane (12 ml) were added to a single-mouth bottle, trifluoroacetic acid (6 ml) was added, and the mixture was reacted at room temperature for 2 hours. 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 two steps 56.30%).

Step 3: In a 100 mL single-mouth bottle, 28D (0.47 g, 2.74 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), and cesium carbonate (0.89 g, 2.74 mmol) and 4E (750 mg, 2.28 mmol) were slowly added and stirred at 80 ° C for 6 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid. The residue was separated and purified by medium pressure preparation (instrument: Biotage Isolera One; chromatographic column: C18 spherical 20-35um 100A 80g (Agela Technologies); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water; gradient: 5%-90% acetonitrile isocratic 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] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) 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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -90.00 (s), -126.12. (s).

Embodiment 29

Step 1: In a 100 mL single-mouth bottle, compound 29A (0.4 g, 2.64 mmol) was dissolved in acetonitrile (25 mL), and 15B (1.10 g, 3.64 mmol) was added, and the mixture was reacted at 40°C for 3 hours. After the reaction was complete, the reaction solution was concentrated to obtain compound 29B (1.5 g, crude product), which was directly subjected to the next step.

Step 2: In a 100 mL single-mouth bottle, compound 29B (1.5 g, 5.10 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added to react at room temperature for 2 hours. After the reaction, the residue was concentrated and purified by column chromatography (PE/EA=1/1) to obtain compound 29C (420 mg, yield 43%).

LCMS m/z＝502.10[M+H] ⁺ ;

Step 3: In a 100 mL single-mouth bottle, compound 4E (0.5 g, 1.52 mmol) was dissolved in dry N,N-dimethylformamide (20 mL), cesium carbonate (1.0 g, 3.07 mmol) was added, and the mixture was stirred at 50°C for 0.5 h. Then, a solution of 29C (0.42 g, 2.16 mmol) in N,N-dimethylformamide (5 mL) was added dropwise, and the reaction solution was stirred at 100°C for 12 h. After the reaction was completed, the product was filtered and the filtrate was concentrated. The residue was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isogradient elution; cycle time: 10 minutes) to obtain compound 29 (80 mg, yield 10%).

LCMS m/z=504.10 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.49(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).

Embodiment 30

Step 1: In a 250 mL single-mouth bottle, 4B (4 g, 22.29 mmol) was dissolved in an aqueous solution (40 mL) of sodium hydroxide (2.85 g, 71.33 mmol), 1-methylcyclopropylamine hydrochloride (8.39 g, 78.02 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and 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 pad, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM/MeOH=20/1) to obtain 30A (4.0 g, yield 87%).

Step 2: In a 50 mL single-mouth bottle, 30A (4.0 g, 19.39 mmol) was dissolved in trimethyl orthoformate (32 mL), and the mixture was stirred at 105°C for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by slurrying with petroleum ether. The solid was filtered and dried to obtain 30B (2.4 g, yield 57%).

LCMS m/z＝217.1[M+H] ⁺ ;

Step 3: In a 100 mL single-mouth bottle, 30B (2.0 g, 9.25 mmol) was dissolved in dry N, N-dimethylformamide (40 mL). Cesium carbonate (3.62 g, 11.1 mmol) was slowly added under an ice bath. After the 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 the addition, the mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into ice water (250 mL), stirred for 30 min, filtered, and the obtained solid was dried and purified by pulping with a mixed solvent of petroleum ether (100 mL) and ethyl acetate (10 mL). The solid was filtered and dried to obtain 30C (2.5 g, yield 76%).

LCMS m/z=354.1 [M+H] ⁺ ;

Step 4: In a 100 mL single-mouth bottle, compound 1B (240 mg, 1.36 mmol) was dissolved in dry N,N-dimethylformamide (8 mL), and cesium carbonate (552 mg, 1.69 mmol) was slowly added under ice bath, and stirred at 50°C for 0.5 h. In an ice bath, a solution of compound 30C (400 mg, 1.13 mmol) in N,N-dimethylformamide (2 mL) was slowly added dropwise, and stirred at 100°C for 6 h. After the reaction was complete, the reaction solution was poured into ice water (50 mL), stirred for 30 min, filtered, and the obtained solid was dried and separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 30 (240 mg, yield 42%).

LCMS m/z＝510.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.38(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-127.33 (s).

Embodiment 31

Step 1: In a 250 mL reaction bottle, 31A (10 g, 39.61 mmol), ammonia (20 mL) and 1,4-dioxane (100 mL) were added in sequence and stirred at 100 degrees Celsius for 24 hours. The reaction solution was extracted (ethyl acetate), washed and concentrated to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) gave 31B (8.5 g, yield 86.02%).

Step 2: In a 50 mL reaction bottle, 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 added in sequence, and stirred at 110 ° C for 12 hours. The reaction solution was extracted (ethyl acetate), washed, and concentrated to obtain a crude product. Column chromatography separation (petroleum ether: ethyl acetate = 1:0-0:1) gave 31C (500 mg, yield 17.28%).

Step 3: In a 50 mL reaction bottle, 31C (0.25 g, 0.73 mmol), copper bromide (0.49 g, 2.19 mmol), tert-butyl nitrite (0.23 g, 2.19 mmol) and acetonitrile (3 mL) were added in sequence, and the reaction was stirred at room temperature for 1 hour. The reaction solution was extracted (ethyl acetate), washed, and concentrated to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) gave 31D (250 mg, yield 83.81%).

Step 4: In a 50 mL reaction bottle, 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), Pd ₂ (dba) ₃ (56 mg, 0.06 mmol) and 1,4-dioxane (5 mL) were added in sequence, and the mixture was stirred at 120° C. for 5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid separation to obtain compound 31 (88.1 mg, yield 28.6%).

LCMS m/z＝504.8[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) 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).

Embodiment 32

Step 1: In a 50 mL reaction bottle, 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 added in sequence, and stirred at 110 ° C for 12 hours. The reaction solution was extracted (ethyl acetate), washed, and concentrated to obtain a crude product. Column chromatography separation (petroleum ether: ethyl acetate = 1:0-0:1) gave 32A (500 mg, yield 17.28%).

Step 2: In a 50 mL reaction bottle, 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 added in sequence, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted (ethyl acetate), washed and concentrated to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) gave 32B (90 mg, yield 58.88%).

Step 3: In a 50 mL reaction bottle, 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), Pd ₂ (dba) ₃ (19 mg, 0.02 mmol) and 1,4-dioxane (3 mL) were added in sequence and stirred at 120°C for 5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic 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 (400MHz, CDCl ₃ ) δ8.33(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).

Embodiment 33

Step 1: 33A (2.92 g, 39.98 mmol) and water (40 mL) were added to a 250 mL single-necked bottle, and 4B (2.10 g, 11.76 mmol) was added at 0-5°C and reacted at room temperature for 4 hrs. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol = 10/1) to give 33B (2.2 g, yield 89%).

LCMS m/z＝209.1[M+H] ⁺ ;

Step 2: In a 100 mL single-mouth bottle, 33B (2.0 g, 9.61 mmol) was added to trimethyl orthoformate (20 mL) and reacted at 105°C overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 1/2) to obtain 33C (870 mg, yield 41%).

LCMS m/z=219.1 [M+H] ⁺ ;

Step 3: In a 25 mL single-mouth bottle, 33C (0.87 g, 3.99 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (1.56 g, 4.79 mmol) was slowly added under an ice bath. After the addition, the reaction was stirred at room temperature for 0.5 h. In an ice bath, 2,3,6-trifluorobenzonitrile (0.66 g, 4.19 mmol) was slowly added dropwise. After the addition, the reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (15 mL) was added to the reaction system to dilute the reaction, and water (20 mL) was added to quench the reaction, and extracted with ethyl acetate (20 mL × 2). The organic phase was washed with water (20 mL × 2), and the organic phase was concentrated and 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] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ8.39(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).

Step 4: In a 25 mL single-necked bottle, 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), and reacted at 50 °C for 30 min. Then, 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, the mixture was stirred at 80 °C for 4 hrs. After the reaction was complete, the reaction was filtered and the filtrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain 220 mg of 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 H NMR (400MHz, DMSO-d ₆ )δ10.37(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-127.30 (s).

Embodiment 34

Step 1: 34A (2.00 g, 17.57 mmol) and water (20 mL) were added to a 250 mL single-mouth bottle, and a solution of sodium hydroxide (0.62 g, 15.62 mmol) in water (20 mL) was slowly added dropwise at 0-5°C, and reacted at 0-5°C for 10 min, then 4B (0.87 g, 4.88 mmol) was added at 0-5°C, and reacted at room temperature for 4 hrs. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol = 10/1) to obtain 34B (0.83 g, yield 80%).

LCMS m/z=213.1 [M+H] ⁺ ;

Step 2: In a 100 mL single-mouth bottle, 34B (0.72 g, 3.39 mmol) was added to trimethyl orthoformate (10 mL) and reacted at 105°C overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 1/2) to obtain 34C (280 mg, yield 37%).

LCMS m/z＝223.2[M+H] ⁺ ;

Step 3: In a 25 mL single-mouth bottle, 34C (0.28 g, 1.26 mmol) was dissolved in dry N,N-dimethylformamide (4 mL). Cesium carbonate (0.49 g, 1.51 mmol) was slowly added under an ice bath. After the addition, the reaction was stirred at room temperature for 0.5 h. In an ice bath, 2,3,6-trifluorobenzonitrile (0.22 g, 1.39 mmol) was slowly added dropwise. After the addition, the reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (10 mL) was added to the reaction system to dilute the reaction, and water (10 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL × 2). The organic phase was washed with water (10 mL × 2), and the organic phase was concentrated and 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 (400MHz, DMSO-d ₆ )δ8.44(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,1 H),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).

Step 4: In a 25 mL single-necked bottle, 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), and reacted at 50 °C for 30 min. Then, 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, the mixture was stirred at 80 °C for 4 hrs. After the reaction was complete, the reaction was filtered and the filtrate was purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to separate and purify compound 34 (110 mg, yield 30%).

LCMS m/z＝516.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.37(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -72.80 (s), -127.34 (s).

Embodiment 35

Step 1: 35A (2.50 g, 22.01 mmol) and water (25 mL) were added to a 250 mL single-mouth bottle, and a solution of sodium hydroxide (0.79 g, 19.78 mmol) in water (25 mL) was slowly added dropwise at 0-5°C, and reacted at 0-5°C for 10 min, then 4B (1.10 g, 6.18 mmol) was added at 0-5°C, and reacted at room temperature for 4 hrs. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol = 10/1) to obtain 35B (0.65 g, yield 49%).

LCMS m/z=213.1 [M+H] ⁺ ;

Step 2: In a 100 mL single-necked bottle, 35B (0.72 g, 3.39 mmol) was added to triethyl orthoformate (10 mL) and reacted at 180°C for 2.5 hrs under microwave. After the reaction was complete, the mixture was cooled to room temperature and concentrated to obtain crude 35C, which was directly used for the next step.

LCMS m/z＝223.2[M+H] ⁺ ;

Step 3: In a 25 mL single-mouth bottle, the crude product 35C was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (1.1 g, 3.41 mmol) was slowly added under an ice bath. After the addition, the reaction was stirred at room temperature for 0.5 h. In an ice bath, 2,3,6-trifluorobenzonitrile (0.49 g, 3.12 mmol) was slowly added dropwise. After the addition, the reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (20 mL) was added to the reaction system to dilute the reaction, and water (20 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with water (20 mL × 2), and the organic phase was concentrated and 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] ⁺ ;

Step 4: In a 25 mL single-necked bottle, 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), and reacted at 50 ° C for 30 min. Then, 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, the reaction was stirred at 80 ° C for 3 hrs. After the reaction was complete, the reaction was filtered and the filtrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to separate and purify compound 35 (105 mg, yield 45%).

LCMS m/z＝516.6[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.37(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),4.8 9-4.85(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -74.66 (s), -129.42 (s).

Example 36 and Example 37

Compound 17 (300 mg) was separated by chiral SFC to give P1 (retention time: 0.588 min, set as compound 36) and P2 (retention time: 0.694 min, set as compound 37). Separation method: Instrument name: Waters 150Prep-SFC F; Chromatographic column: Chiralcel AD-Column; Mobile phase: A for CO ₂ and B for 0.1% NH ₃ ·H ₂ O 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 at a concentration of 10 mg/mL; Injection: 2.0 mL per injection; Treatment: After separation, it was concentrated by rotary evaporator at 35°C, and then the solvent was dried by freeze dryer at -80°C to give compound 36 (86 mg, 29%) and compound 37 (74 mg, 25%).

Compound 36:

LCMS m/z=456.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.40(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-128.22 (s).

Compound 37:

LCMS m/z=456.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.42(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).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-128.22 (s).

Embodiment 38

Step 1: 38A (16.66 g, 119.37 mmol) and water (120 mL) were added to a 1000 mL single-necked bottle, and a solution of sodium hydroxide (4.29 g, 107.30 mmol) in water (120 mL) was slowly added dropwise at 0-5°C, and 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 reacted at room temperature for 4 hrs. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol=10/1) to obtain 38B (3.0 g, yield 37.56%).

LCMS m/z＝239.1[M+H] ⁺ ;

Step 2: In a 100 mL single-mouth bottle, 38B (2.7 g, 11.33 mmol) was added to dry N,N-dimethylformamide (30 mL), and triethyl orthoformate (30 mL) was added at room temperature, and the mixture was reacted at 150°C for 4 hrs. After the reaction was complete, the mixture was cooled to room temperature, and the reaction mixture was concentrated to obtain crude 38C, which was directly used for the next step.

LCMS m/z＝249.1[M+H] ⁺ ;

Step 3: In a 25 mL single-mouth bottle, 38C was dissolved in dry N,N-dimethylformamide (30 mL). Cesium carbonate (4.11 g, 13.54 mmol) was slowly added under an ice bath. After the addition, the mixture was stirred at room temperature for 0.5 h. 2,3,6-trifluorobenzonitrile (1.95 g, 12.41 mmol) was slowly added dropwise under an ice bath. After the addition, the mixture was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (100 mL) was added to the reaction system to dilute the reaction. Water (100 mL) was then 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 the organic phase was concentrated, 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] ⁺ ;

Step 4: In a 25 mL single-mouth bottle, 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), and reacted at 50°C for 30 min. Then, a solution of 38D (2.40 g, 6.23 mmol) in N, N-dimethylformamide (10 mL) was added dropwise at 50°C. After the addition, the mixture was stirred at 80°C overnight. After the reaction was complete, the reaction was filtered, and the organic phase of the filtrate was concentrated and 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] ⁺ ;

Step 5: In a 25 mL single-mouth bottle, add 38E (2.00 g, 3.69 mmol) to methanol (5 mL), and add ammonia methanol solution (7.0 M, 40 mL) dropwise at 0-5°C. After the addition, stir and react at room temperature overnight. After the reaction is complete, the reaction solution is concentrated to obtain compound 38F (crude product), which is directly used for the next step.

LCMS m/z＝513.1[M+H] ⁺ ;

Step 6: In a 25 mL single-mouth bottle, 38F (0.21 g, 0.41 mmol) was added to dry dichloromethane (6 mL), and Burgess reagent (195.41 g, 0.82 mmol) was added at 0-5 °C. After the addition, the reaction was stirred at room temperature overnight. The reaction was filtered and the filtrate was purified by preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to separate and purify compound 38 (35 mg, yield 17%).

LCMS m/z＝495.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.36(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＝2.9Hz,1H),5.08(s,2H),3.84(s,4H),2.11-2.08(t,4H),1.78–1.70(m,2H).

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-127.33 (s).

Embodiment 39

Step 1: In a 100 mL single-mouth bottle, 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), and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed twice with water (60 mL), washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA=1:1) to obtain compound 39C (800 mg, yield: 74%).

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

Step 3: In a 100 mL single-necked bottle, 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), allylpalladium chloride (71 mg, 0.20 mmol), and potassium carbonate (629 mg, 4.55 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70 °C for 5 h. After the reaction was completed, 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 chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 30%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 39 (210 mg, yield: 31%).

LCMS m/z＝520.50[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ8.34(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).

¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -121.46(s), -150.87(s), -222.31(s).

Example 40 and Example 41:

Step 1: In a 25 mL single-mouth bottle, 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), and reacted at 50 ° C for 30 min. Then, 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, the mixture was stirred at 100 ° C overnight. After the reaction was complete, the reaction solution was filtered, the filter cake was added with N, N-dimethylformamide (4 mL), the filtrate was concentrated, and then dissolved with water (15 mL) and ethyl acetate (10 mL). The aqueous phase was extracted once with ethyl acetate (10 mL), and the pH was adjusted to about 7 with a saturated ammonium chloride solution. Then, the aqueous phase was extracted with dichloromethane (20 mL × 3), and the organic phase was dried and concentrated with anhydrous sodium sulfate to obtain a crude product of 40A, which was directly used for the next step.

LCMS m/z＝538.5[M+H] ⁺ ;

Step 2: The crude product 40A was separated by chiral SFC to obtain P1 (retention time: 14.73 min, set as compound 40) and P2 (retention time: 24.02 min, set as compound 41). Separation method: Instrument name: Waters 150SFC; Chromatographic column: AD; Mobile phase: A for CO ₂ and B for IPA+MeOH (0.05% NH ₃ ·H ₂ O); 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 per injection; Treatment: After separation, it was concentrated by rotary evaporator at 35°C, and then the solvent was dried by freeze dryer at -80°C to obtain P1 and P2.

Compound 40: (P1: 120 mg, 11%), ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -120.44(s), -171.59(s), -216.41(s).

Compound 41: (P2: 140 mg, 13%), ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -120.44(s), -127.17(s), -171.59(s).

Embodiment 42

Step 1: Add 42A (420 mg, 1.70 mmol) and acetonitrile (5 mL) into a 25 mL single-necked bottle, and slowly add triethylamine (0.430 g, 4.25 mmol) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)yl)sulfonyl)amide (0.615 g, 2.04 mmol) at 0-5°C, and react overnight at room temperature. After the reaction is complete, concentrate the reaction mixture to obtain crude 42B, which is directly used for the next step.

LCMS m/z＝257.1[M+H] ⁺ ;

Step 2: In a 25 mL single-mouth bottle, the crude product 42B was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was slowly added dropwise at 0-5°C, and the mixture was reacted overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated, and the organic phase was concentrated and 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] ⁺ ;

Step 3: In a 25 mL single-necked bottle, add 42C (0.250 g, 1.18 mmol) and cesium carbonate (0.577 g, 1.77 mmol) to dry N,N-dimethylformamide (5 mL), and react at 50 ° C for 30 min. Then, add 10E (0.429 g, 1.18 mmol) in N,N-dimethylformamide (2 mL) dropwise at 50 ° C. After the addition, stir and react at 80 ° C overnight. After the reaction was complete, the reaction solution was filtered and the filtrate was purified by preparative liquid phase purification (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to separate and purify compound 42 (110 mg, yield 17%).

LCMS m/z = 556.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ10.57(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,1 H),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).

¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -98.98(s), -120.45(s), -126.75(s).

Embodiment 43

Step 1: In a 100 mL single-mouth bottle, 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), and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed twice with water (60 mL), washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA=1:1) to obtain compound 43C (830 mg, yield: 71%).

Step 2: Compound 43C (830 mg, 2.22 mmol), copper bromide (992 mg, 4.44 mmol), and acetonitrile (40 ml) were added to a single-mouth bottle, and tert-butyl nitrite (458 mg, 4.44 mmol) was slowly added dropwise under an ice bath, and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, diatomaceous earth was used for padding, and the mixture was filtered. After the filtrate was concentrated, the residue was separated by column chromatography (petroleum ether: ethyl acetate (v/v) = 1:0-0:1) to obtain compound 43D (800 mg, yield: 82%).

Step 3: In a 100 mL single-necked bottle, 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), allylpalladium chloride (99 mg, 0.27 mmol), and potassium carbonate (625 mg, 4.25 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70 °C for 5 h. After the reaction was completed, 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 chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 30%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 43 (56 mg, yield: 6%).

LCMS m/z＝538.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ8.35(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).

Embodiment 44

Step 1: 44A (4.5 g, 23.13 mmol) and isopropanol (50 mL) were added to a 250 mL single-mouth bottle, and then triethylamine (4.68 g, 46.26 mmol) and isopropanolamine (2.08 g, 27.76 mmol) were added, and the mixture was reacted at 80°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated, slurried 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] ⁺ ;

Step 2: In a 250 mL single-mouth bottle, add phosphorus oxychloride (60 mL), slowly add 44B (5.3 g, 22.72 mmol) in batches at 0-5°C, and react at 110°C for 5 hrs. After the reaction is complete, the reaction solution is concentrated, and water (100 mL) is slowly added at 0-5°C to quench the reaction, and extracted with ethyl acetate (100 mL×2). After the organic phase is concentrated, it is 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] ⁺ ;

Step 3: Add 4C (2.80 g, 13.01 mmol) and acetonitrile (30 mL) into a 100 mL single-mouth bottle, then add alumina (2.65 g, 25.99 mmol) and potassium permanganate (3.08 g, 19.49 mmol), and stir at room temperature overnight. After the reaction is complete, filter the reaction solution, concentrate the filtrate, and purify it 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 (400MHz, DMSO-d6) δ9.01(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).

Step 4: 4D (0.88 g, 4.13 mmol) and N,N-dimethylformamide (10 mL) were added to a 50 mL single-mouth bottle, and sodium ethanethiolate (1.04 g, 12.35 mmol) was added. After the addition, nitrogen was used for protection, and the reaction was stirred at 130°C overnight. After the reaction was complete, the reaction solution was concentrated, and dilute hydrochloric acid was added to adjust the pH value to acidic. After concentration, the residue was obtained, and 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] ⁺ ;

Step 5: In a 25 mL single-mouth bottle, 44E (0.30 g, 1.51 mmol) was dissolved in dry N,N-dimethylformamide (8 mL). Cesium carbonate (0.74 g, 2.26 mmol) was slowly added under an ice bath. After the addition, the mixture was stirred at room temperature for 0.5 h. In an 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. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated and 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] ⁺ ;

Step 6: In a 25 mL single-necked bottle, 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), and reacted at 50 ° C for 30 min. Then, 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 hrs. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with N,N-dimethylformamide (2 mL). The filtrate was concentrated and dissolved with ethyl acetate (15 mL) and water (15 mL). The aqueous phase was separated and the pH value was adjusted to neutral with saturated ammonium chloride, and extracted with dichloromethane (20 mL×3). The organic phases were combined, 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] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.44(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).

¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-127.37 (s).

Embodiment 45

Step 1: 45A (10 g, 61.33 mmol) and N,N-dimethylformamide (100 mL) were added to a 250 mL single-mouth bottle, and N,N-diisopropylethylamine (15.85 g, 122.64 mmol) and 1-fluoro-2-iodoethane (12.80 g, 73.63 mmol) were slowly added dropwise at 0-5°C, and reacted 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 minutes, the mixture was filtered, and the filter cake was washed with water (100 mL) and petroleum ether (50 mL), and the filter cake was concentrated to obtain 45B (10.0 g, yield 78%).

LCMS m/z=210.2 [M+H] ⁺ ;

Step 2: In a 500 mL single-mouth bottle, 45B (10 g, 47.81 mmol) was dissolved in dichloromethane (260 mL) and methanol (26 mL), and hydrazine hydrate (5.98 g, 95.62 mmol) was slowly added dropwise at room temperature. After the addition, the mixture was reacted at room temperature for 2.5 hrs. After the reaction was complete, the reaction solution was filtered, the filtrate was washed with 5N ammonia water (200 mL), extracted with dichloromethane (200 mL×2), the organic phase was dried over anhydrous sodium sulfate and concentrated, the residue was dissolved in ethanol (50 mL), concentrated hydrochloric acid (8 mL) was added, stirred for 30 min and concentrated, the residue was slurried with ethyl acetate (30 mL), and filtered to obtain 45C (1.90 g, yield 34%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.25(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).

Step 3: 45C (0.49 g, 3.23 mmol) and water (10 mL) were added to a 250 mL single-necked bottle, and a solution of sodium hydroxide (0.12 g, 3.04 mmol) in water (10 mL) was slowly added dropwise at 0-5°C, and reacted at 0-5°C for 10 min, and 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 reacted at room temperature overnight. After the reaction was complete, 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] ⁺ ;

Step 4: In a 100 mL single-necked bottle, 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 the reaction was complete, the mixture was cooled to room temperature and the reaction solution was concentrated to obtain crude 45E, which was directly used for the next step.

LCMS m/z＝225.1[M+H] ⁺ ;

Step 5: In a 25 mL single-mouth bottle, 45E (0.31 g, 1.38 mmol) was dissolved in dry N,N-dimethylformamide (5 mL), and cesium carbonate (0.54 g, 1.66 mmol) was added under ice bath, and 2,3,6-trifluorobenzonitrile (0.24 g, 1.52 mmol) was slowly added dropwise, and the reaction was stirred at room temperature overnight. After the reaction was complete, the reaction was filtered, and the filtrate was concentrated and 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] ⁺ ;

Step 6: In a 25 mL single-necked bottle, add 1B (0.21 g, 1.20 mmol) and cesium carbonate (0.49 g, 1.5 mmol) to dry N,N-dimethylformamide (8 mL), and react at 50 ° C for 30 min. Then, add 45F (0.36 g, 1.00 mmol) in N,N-dimethylformamide (2 mL) dropwise at 50 ° C. After the addition, stir the reaction at 80 ° C overnight. After the reaction was complete, the reaction solution was filtered and the filtrate was purified by preparative liquid phase purification (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to separate and purify compound 45 (83.0 mg, yield 16%).

LCMS m/z＝518.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.38(s,1H),8.58(s,1H),7.91–7.83(m,2H),7.74-7.71(dd,1H),7.56-7.53(dd,1H),7.42-7.4 1(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).

¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ -127.24 (s), -220.60 (s).

Embodiment 46

Step 1: In a 25 mL single-mouth bottle, 22C (1.35 g, 7.29 mmol) was dissolved in dry N,N-dimethylformamide (30 mL). Cesium carbonate (4.75 g, 14.58 mmol) was slowly added under ice bath. After the addition, the mixture was stirred at room temperature for 0.5 h. In an ice bath, 39A (1.51 g, 8.75 mmol) was slowly added dropwise. After the addition, the mixture was stirred at 30°C overnight. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated and 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] ⁺ ;

Step 2: In a 25 mL single-mouth bottle, 46A (2.30 g, 6.82 mmol) was dissolved in dry acetonitrile (50 mL), and tert-butyl nitrite (0.71 g, 6.89 mmol) and copper bromide (1.54 g, 6.90 mmol) were slowly added in sequence at 0-5°C, and the reaction was stirred overnight at room temperature after the addition was completed. After the reaction was complete, the reaction solution was concentrated, and saturated sodium bicarbonate (100 mL) was added to quench the reaction, and dissolved with ethyl acetate (100 mL), then filtered, and the filtrate was extracted with ethyl acetate (100 mL×2), and the organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and 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] ⁺ ;

Step 3: Add 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) and tris(dibenzyl-BASE acetone)dipalladium (0.11 g, 0.19 mmol) to dry 1,4-dioxane (16 mL), blow with nitrogen for 2 min and then react in microwave at 120 °C for 1 hr. After the reaction was complete, the filtrate was concentrated, ethyl acetate (20 mL) and water (20 mL) were added to dissolve, the aqueous phase was separated and the pH value was adjusted to neutral with saturated ammonium chloride, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3/2), and then separated by chiral SFC to obtain compound 46 (retention time: 2.08 min). Separation method: Instrument name: Waters 150Prep-SFC F; Chromatographic column: Chiralcel AD column; Mobile phase: A for CO ₂ and B for MeOH (0.1% NH ₃ ·H ₂ O); 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 injected each time; treatment: after separation, it was concentrated by rotary evaporator at 35°C, and then the solvent was dried by freeze dryer at -80°C to obtain compound 46 (0.18 mg, yield 18%).

LCMS m/z＝497.8[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ9.28(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).

Embodiment 47

Step 1: In a 250 mL single-mouth bottle, compound 5B (0.55 g, 3.39 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), cesium carbonate (1.42 g, 4.36 mmol) was added, and the mixture was reacted at 50°C for 0.5 h. Then, a solution of 26C (1 g, 2.90 mmol) in N,N-dimethylformamide (10 mL) was added dropwise, and the reaction solution was stirred at 85°C for 12 h. After the reaction, ethyl acetate (100 mL) was added, and then 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 chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 25%-65% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 47 (700 mg, yield 49%).

LCMS m/z＝488.30[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ10.47(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).

Embodiment 48

Step 1: In a 250 mL single-mouth bottle, compound 5B (8.2 g, 50.55 mmol) was dissolved in dry N,N-dimethylformamide (50 mL), cesium carbonate (16.6 g, 7.41 mmol) was added, and the mixture was stirred at 50°C for 0.5 h. Then, a solution of 9E (2.5 g, 6.88 mmol) in N,N-dimethylformamide (15 mL) was added dropwise, and the reaction solution was stirred at 85°C for 12 h. After the reaction was completed, the product was filtered and the filtrate was concentrated. The residue was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isogradient elution; cycle time: 10 minutes) to obtain compound 48 (250 mg, yield 7%).

LCMS m/z＝506.90[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ8.34(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).

Embodiment 49

Step 1: Dissolve the raw material 5B (0.45 g, 2.77 mmol) in DMF (10 mL), add cesium carbonate (0.91 g, 2.79 mmol), heat the reaction solution to 50 ° C and stir for 30 min, then add the 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 with diatomaceous earth, concentrate the filtrate, and purify the residue with EA to obtain 0.50 g of white solid. Then purify with 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 (400MHz, DMSO-d ₆ ) δ9.27(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).

Embodiment 50

Step 1: In a 100 mL single-necked bottle, 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), allylpalladium chloride (65 mg, 0.18 mmol), and potassium carbonate (571 mg, 4.13 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70 °C for 5 h. After the reaction was completed, 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 chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 30%-80% acetonitrile isocratic elution; cycle time: 20 minutes) to obtain compound 50 (72 mg, yield: 12%).

LCMS m/z＝506.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ8.33(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).

Embodiment 51

Step 1: In a 100 mL single-necked bottle, 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 the addition, nitrogen was replaced and the reaction was stirred at 70 °C for 5 h. After the reaction was completed, 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 chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19mm×150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-80% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 51 (210 mg, yield: 31%).

LCMS m/z=512.1 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ )δ8.34(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).

Embodiment 52

Step 1: Dissolve 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), and potassium carbonate (876 mg, 6.33 mmol) in dry 1,4-dioxane (40 mL), add allylpalladium chloride (33 mg, 0.09 mmol), replace nitrogen after addition, and stir at 85°C for 10 h. After the reaction is complete, monitor by TLC (dichloromethane: methanol = 20:1 (v/v)), filter the reaction solution, concentrate the filtrate, and purify the crude product 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 (400MHZ, DMSO-d ₆ )δ8.35(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).

Embodiment 53

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), and allylpalladium chloride (33 mg, 0.09 mmol) was added. After the addition, nitrogen was replaced and the mixture was stirred at 85°C for 10 h. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated. 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 (400MHZ, DMSO-d ₆ )δ8.35(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).

Preparation of formulations:

1. Preparation 1-1: Specification 20 mg/tablet:

2. Preparation 1-2; Specification: 20 mg/tablet

3. Preparation 1-3; Specification: 20 mg/tablet

4. Preparation 1-4: Specification 200 mg/tablet:

5. Preparation 1-5: Specification 1000 mg/tablet:

Preparation method of the above prescription preparation:

1). API-excipient micronized product: Compound 10 and surfactant (if any) or pH adjuster (if any) are weighed and mixed according to the prescription ratio, and then micronized after mixing evenly.

2) Weighing: weigh the API-excipient micronized material, filler, adhesive, glidant, disintegrant, lubricant according to the prescription;

3). Mixing: Mix the API-excipient micronized powder, filler, binder, glidant, and disintegrant for 5 minutes, and add the lubricant and mix for 2 minutes.

4). Tabletting: The powder in 3) is tableted using a die of suitable specifications, and the tablet weight and hardness are controlled during the tableting process.

Other compounds of the present invention such as the example compounds were prepared by referring to the above preparation methods to prepare corresponding preparations.

Biological test cases

1. BRAF _V600E enzyme activity test

BRAF _V600E (ABCAM, ab204154) and MEMK1 _K97R (USBio, M2865-06J) proteins were diluted to appropriate multiples using 1×Assay buffer (pH=7.4Tris-HCl buffer, supplemented with 10mM MgCl ₂ ) to make the final concentration of BRAF _V600E 10ng/μL and the final concentration of substrate MEMK1 _K97R 1μM. 1μL BRAF _V600E , 1μL compound serial dilution (final concentration 2μM starting, 5-fold dilution, 8 concentrations), and 6μL Assay buffer were respectively pipetted into a 20μL 384-well reaction plate and pre-incubated in a constant temperature incubator at 37°C for 30min. 1μL 200μM ATP and 1μM MEK1 _K97R were then added to the reaction wells corresponding to the compound incubation, oscillated to mix, and pre-incubated in a constant temperature incubator at 37°C for 60min for enzymatic reaction. After the reaction is completed, 5 μL of the above reaction product is transferred to another 384-well plate, and 5 μL of the prepared ADP-GloTM Reagent (Promega, V9101) is added and mixed by pipetting, and placed at room temperature for 40 minutes. 10 μL of Kinase Detection Reagent is added to the 384-well plate and incubated at room temperature for 40 minutes. Finally, the Luminescence module is selected to detect each well using an ELISA reader (BMG LRBTECH) (Gain value is fixed at 3600), and the LUM fluorescence value is calculated by the formula

The inhibition rate of the compound on BRAF _V600E was calculated. The Graphpad software log (inhibitor) vs. response--Variable slope (four parameters) equation was used for fitting analysis to calculate the IC ₅₀ value of the sample.

The compounds of the present invention, such as the compounds in the examples, have very good enzyme activity, with IC ₅₀ ≤ 100 nM. The inhibitory activity of some compounds on BRAF _V600E is shown in Table 1.

Table 1 Inhibitory activity of compounds against BRAFV600E

A indicates IC ₅₀ ≤10 nM, B indicates 10 nM＜IC ₅₀ ≤50 nM, and C indicates 50 nM＜IC ₅₀ ≤100 nM.

Conclusion: The compounds of the present invention, such as the compounds of the examples, show high inhibitory activity against BRAF _V600E .

2. Inhibition of A375 cell proliferation

A375 cells (ATCC, CRL-1619) were cultured in a _CO2 incubator at 37°C for 48 h using DMEM complete medium (+10% FBS). The cells were trypsinized and counted, and then the density was adjusted to 1.67× ¹⁰⁴ /mL. 90 μL (1500) of cells were inoculated into each well of a 96-well plate with a transparent bottom, and transferred to a _CO2 incubator and cultured overnight at 37°C. After the cells were incubated overnight, 10 μL of the diluted compound (starting at a final concentration of 10 μM, 3-fold dilution, 11 concentrations) was added to each well using a spray gun. The positive control was a serum-free medium containing DMSO. After mixing evenly, the cells were placed in a _CO2 incubator at 37°C for 72 h. After the incubation, remove the cells. The kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 μL CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a sealing film, and the plate was placed on an oscillator for 15 minutes (the whole process must be kept away from light), and the Luminescence module of the microplate reader (BMG LRBTECH) was used to detect the fluorescence signal value LUM of each well.

Calculate the inhibition rate of the compound. Use Graphpad software log (inhibitor) vs. response--Variable slope (four parameters) equation for fitting analysis and calculate the IC ₅₀ value of the sample. The vertical axis of the data is the percentage of inhibition rate, and the horizontal axis is the logarithm of the sample concentration (Log ₁₀ ).

The compounds of the present invention, such as the compounds in the examples, have very good cell activity, with IC ₅₀ ≤100 nM. The inhibitory activity of some compounds on A357 cells is shown in Table 2.

Table 2 Inhibitory activity of compounds on A375 cells

A indicates IC ₅₀ ≤10 nM, B indicates 10 nM＜IC ₅₀ ≤50 nM, and C indicates 50 nM＜IC ₅₀ ≤100 nM.

Conclusion: The compounds of the present invention, such as the compounds in the examples, show high inhibitory activity at the cellular level.

3. Pharmacokinetic test in mice

1.1 Experimental animals: Male ICR mice, 20-25 g, 12 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

1.2 Experimental design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

Table 3. Dosing Information

Note: Reference compound 1 is compound Example 1 in document WO2021116055A1;

Intravenous administration solvent: 5% DMA + 5% HS-15 + 90% NS; intragastric administration solvent: 0.5% MC

Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Table 4. Pharmacokinetic parameters of test compounds in mouse plasma


Note: Reference compound 1 is compound Example 1 in document WO2021116055A1; -: not applicable.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in mice and have better brain penetration properties than the control compounds.

4. Beagle dog pharmacokinetic test

Experimental animals: Male beagle dogs, about 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

Test method: On the test day, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration. Administration was performed according to Table 5.

Table 5. Dosing Information

Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC

(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose solution;)

Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Table 6. Pharmacokinetic parameters of test compounds in beagle dog plasma

Note: Reference compound 1 is compound Example 1 in document WO2021116055A1;

-:not applicable.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.

5. Pharmacokinetic test in rats

5.1 Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

5.2 Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours one day before administration and were fed 4 hours after administration.

Table 7 Dosage information

Dosing solvent: 0.5% MC

Before and after drug administration, 0.1 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The time points for blood collection in the venous group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h; the time points for blood collection in the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. All samples were stored at -80°C before analysis and testing.

Table 8 Pharmacokinetic parameters of test compounds in rat plasma


Note: Reference compound 1 is compound Example 1 in document WO2021116055A1; -: not applicable.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good bioavailability and pharmacokinetic characteristics in rats.

6. Preparation stability study

6.1 High temperature (60°C) test

The bare chips of the preparations 1-4 were placed at a high temperature of 60°C for inspection, and samples were taken for testing after 5 days and 10 days. The test results are shown in the following table.

Table 9 High temperature test results

Note: RRT: Relative Retention Time

6.2 High humidity (RH92.5%) test

The bare chips of the samples of preparations 1-4 were placed in a high humidity environment (RH 92.5%) for inspection, and samples were taken for testing after 5 days and 10 days. The test results are shown in the following table.

Table 10 High humidity test results

6.3 Accelerated test

Samples of preparations 1-4 were placed in a simulated commercial packaging at 40°C ± 2°C and RH 75% ± 5% for testing. The test results are shown in the following table.

Table 11 Accelerated test results

Conclusion: The compound preparations of the present invention have good high temperature, high humidity and accelerated stability.

Claims (14)

A pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises an active ingredient M and a pharmaceutical excipient, wherein the active ingredient M is selected from a compound of formula I or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof,
wherein Cy is selected from P1, P2, P3, P4, P5, P6, P7 or P8;
Ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1-2 groups selected from halogen, C _1-4 alkoxy, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, halo-substituted C _1-4 alkoxy, and halo-substituted C _1-4 alkyl; Ring B is a 5-membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic ring is optionally substituted by 1-3 groups selected from =O, halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, OH, and halogenated C _1-4 alkoxy; # means to select a point to connect with Y; n is selected from 0 or 1; Each _X1 is independently N or C; X ₂ is N or CR ₃ ; X ₃ is N or CR ₃₁ ; X ₄ is N or CR ₃₂ ; _X5 is N or _CR33 ; X ₆ is C(O), S(O) or S(O) ₂ ; X ₇ is CR ₇ or N; R ₁ , R ₂ and R ₄ are independently H, halogen, OH, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogenated C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl; R ₃ , R ₃₁ , R ₃₂ , and R ₃₃ are independently H, halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, or C _3-6 cycloalkyl, 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 carbocyclic ring or a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and the carbocyclic ring or heterocyclic ring is optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, OH, NH ₂ , and CN; R ₅ is C _1-4 alkyl, halogenated C _1-4 alkyl, C _3-6 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C _1-4 alkoxy, halogenated C _1-4 alkoxy or C _3-6 cycloalkyloxy, and is optionally substituted by 1-3 groups selected from halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , C _1-4 alkoxy, halogenated C _1-4 alkoxy, halogenated C _1-4 alkyl, CN, C _1-4 alkyl or =O; _R6 is H, halogen, _C1-4 alkyl or halogenated _C1-4 alkyl; or R ₅ and R ₆ and their connecting atoms together form a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocyclic ring is optionally substituted by 1-3 groups selected from halogen, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, and C _1-4 alkyl; R ₇ , R ₈ , and R ₉ are independently H, halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogenated C _1-4 alkyl, _{C 1-4 alkoxy} , or halogenated C _1-4 alkoxy; Y is C _1-2 alkylene, O or NR _y ; R _y is H or C _1-4 alkyl; M is C _1-2 alkylene, O or NR _m ; W is a bond, O or NR _w ; _Rm and _Rw are independently H or _C1-4 alkyl; R is selected from C _1-4 alkyl, C _3-8 cycloalkyl, 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O or -OC _3-6 cycloalkyl, wherein the alkyl, cycloalkyl and heterocycle are optionally substituted with 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halo-substituted C _1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ and halo-substituted C _1-4 alkyl; When Cy is P2, R is a 4-10 membered saturated heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 groups selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, halo-substituted C _1-4 alkoxy, OH, NH ₂ , -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , and halo-substituted C _1-4 alkyl; The pharmaceutical composition or pharmaceutical preparation contains 1-1000 mg of active ingredient M, and the excipient contains one or more of a filler, a binder, a glidant, a lubricant, and a disintegrant. The pharmaceutical composition or pharmaceutical preparation according to claim 1, wherein the pharmaceutical composition or pharmaceutical preparation comprises 5-800 mg, 5-600 mg or 5-400 mg of active ingredient M. The pharmaceutical composition or pharmaceutical preparation according to claim 2, wherein the pharmaceutical composition or pharmaceutical preparation comprises 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg of active ingredient M. The pharmaceutical composition or pharmaceutical preparation according to claim 1, wherein the pharmaceutical composition or pharmaceutical preparation comprises an active ingredient M and a pharmaceutical excipient, wherein the active ingredient M is selected from a compound of formula I or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, having a structure of formula II:
in, R ₆ and R ₉ are H; Y is O; M is NH; _X2 is _CR3 ; _X3 is _CR31 ; _X4 is _CR32 ; _X5 is CH; _X6 is _SO2 ; _X7 is CH; R ₃ is C _1-2 alkyl, halogenated C _1-2 alkyl, C _1-2 alkoxy, halogenated C _1-2 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, -NHC _{1- 2} alkyl, -N(C _1-2 alkyl) ₂ or CN; R ₃₁ and R ₃₂ are each independently H, F, Cl, C _1-2 alkyl, halogenated C _1-2 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-2 alkoxy, halogenated C _1-2 alkoxy, -NHC _1-2 alkyl, -N(C _1-2 alkyl) _2, CN or C _3-6 cycloalkyl; _R5 is _C1-2 alkyl, _C1-2 alkyl substituted by CN or =O, halogenated _C1-2 alkyl, _C3-4 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, _C1-2 alkoxy, halogenated _C1-2 alkoxy or _C3-4 cycloalkyloxy; R ₈ is selected from H, F, Cl, CN, C _1-2 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, halogenated C _1-2 alkyl, C _1-2 alkoxy or halogenated C _1-2 alkoxy; R is a 4-5 membered monocyclic heterocycloalkyl, a 6-8 membered monocyclic heterocycloalkyl, a 5-6 membered monocyclic heteroaryl, a 5-10 membered cyclic heterocycloalkyl, a 5-10 membered bridged heterocycloalkyl, a 6-10 membered spirocyclic heterocycloalkyl or -OC 3-6 cycloalkyl containing _1-3 heteroatoms selected from N, S and O, wherein the 4 membered monocyclic heterocycloalkyl is substituted by 1-3 groups selected from F, Cl, C _1-2 alkyl, C _1-2 alkoxy, OH, NH ₂ , -NHC _1-2 alkyl, -N(C _1-2 alkyl) ₂ and halogenated C _1-2 alkyl, and the 6-8 membered monocyclic heterocycloalkyl, the 5-6 membered monocyclic heteroaryl, the 5-10 membered cyclic heterocycloalkyl, the 5-10 membered bridged heterocycloalkyl, the 6-10 membered spirocyclic heterocycloalkyl or C _3-6 cycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, C 1-2 alkyl, C 1-2 alkoxy, OH, NH 2 , -NHC 1-2 alkyl, -N(C _1-2 alkyl) 2 and halogenated C 1-2 alkyl. The alkyl group may be substituted with _{-C 1-2} alkoxy, OH, NH ₂ , -NHC _1-2 alkyl, -N(C _1-2 alkyl) ₂ and halogenated C _1-2 alkyl. The pharmaceutical composition or pharmaceutical preparation according to claim 1, wherein the pharmaceutical composition or pharmaceutical preparation comprises an active ingredient M and a pharmaceutical excipient, wherein the active ingredient M is selected from the compound of formula I or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein _R3 is CN; R ₃₁ and R ₃₂ are each independently H, F, Cl or C _3-6 cycloalkyl; R ₅ is selected from C _1-2 alkyl, halogenated C _1-2 alkyl, C _1-2 alkoxy, or C _1-2 alkyl substituted by CN or ＝O; _R8 is H; R is a 6-10 membered spirocyclic heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, a 4-5 membered monocyclic heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or a -OC _3-6 cycloalkyl group, wherein the 6-10 membered spirocyclic heterocycloalkyl group, the 4-5 membered monocyclic heterocycloalkyl group, and the C _3-6 cycloalkyl group are optionally substituted with 1-3 groups selected from F, Cl, C _1-2 alkyl, or C _1-2 alkoxy groups. According to the pharmaceutical composition or pharmaceutical preparation of claim 1, the active ingredient M is selected from one of the structures in Table 1 or Table 2. A pharmaceutical composition or pharmaceutical preparation comprising the active ingredient M according to any one of claims 1 to 6 and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and preferably further comprises one or more of a solubilizer, a pH adjuster, and a surfactant. The pharmaceutical composition or pharmaceutical preparation according to claim 7, wherein the content of the active ingredient M is 0.5%-99%, preferably 5%-60%. The pharmaceutical composition or pharmaceutical preparation according to claim 7, wherein the filler is one or more of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, silicified microcrystalline cellulose, sucrose, sorbitol, dextran, calcium dihydrogen phosphate or starch, preferably one or more of microcrystalline cellulose, silicified microcrystalline cellulose or sorbitol, and the content of the filler is preferably 10%-90%, preferably 10-80%, more preferably 10%-50%, or/and The binder is one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose or sodium carboxymethyl cellulose, preferably one or more of hydroxypropyl methylcellulose, methylcellulose or sodium carboxymethyl cellulose, and the binder content is preferably 1%-10%, preferably 1%-5%, more preferably 1%-2.5%, or/and The glidant is one or more of talc, silicon dioxide, micro-powdered silica gel, polyethylene glycol or magnesium dodecyl sulfate, preferably one or more of silicon dioxide or micro-powdered silica gel, and the content of the glidant is preferably 0.5%-10%, preferably 0.5%-5%, more preferably 0.5%-3%, or/and The lubricant is one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, preferably sodium stearyl fumarate, and the lubricant content is preferably 0.1%-10%, preferably 0.1%-5%, more preferably 0.5%-2.0%, or/and The disintegrant is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or calcium carboxymethyl cellulose, preferably one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or calcium carboxymethyl cellulose, and the disintegrant content is preferably 0.5%-10%, preferably 2%-10%. The pharmaceutical composition or pharmaceutical preparation according to claim 7, wherein the solubilizer is one or more of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, polyethylene glycol 15-hydroxystearic acid, poloxamer, cyclodextrin, hydroxypropyl beta-cyclodextrin, docusate sodium or vitamin E polyethylene glycol succinate, preferably one or more of cyclodextrin or hydroxypropyl beta-cyclodextrin, and the solubilizer content is preferably 5%-50%, preferably 10%-50%. The pharmaceutical composition or pharmaceutical preparation according to claim 7, comprising: (i) active ingredient M, in an amount of 0.5% to 99%, preferably 5% to 60%; (ii) a filler, which is one or more of microcrystalline cellulose, silicified microcrystalline cellulose or sorbitol, with a content of 10%-90%, preferably 10%-70%, more preferably 10%-50%; (iii) a binder, which is one or more of hydroxypropyl methylcellulose, methylcellulose or sodium carboxymethylcellulose, and has a content of 1% to 10%, preferably 1% to 5%, and more preferably 1% to 2.5%; (iv) a glidant, which is one or more of silicon dioxide or micro-powdered silica gel, with a content of 0.5%-10%, preferably 0.5%-5%, more preferably 0.5%-3%; (v) a lubricant, wherein the lubricant is sodium stearyl fumarate, and the content thereof is 0.1%-10%, preferably 0.1%-5%, and more preferably 0.5%-2.0%; (vi) a disintegrant, which is one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose or calcium carboxymethylcellulose, and the content thereof is 0.5%-10%, preferably 2%-10%. The pharmaceutical composition or pharmaceutical preparation according to claim 11, further comprising one or more of a solubilizer, a surfactant, and a pH regulator; the solubilizer is one or more of cyclodextrin or hydroxypropyl beta-cyclodextrin, and the content is 5%-50%, preferably 10%-50%; the surfactant is sodium dodecyl sulfate, and the content is 1%-40%, preferably 10%-20%; the pH regulator is magnesium oxide, and the content is 1%-50%, preferably 1%-5%. Use of the pharmaceutical composition or pharmaceutical preparation according to any one of claims 1 to 12 for preparing drugs for treating cancer. A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of an active ingredient M, preferably 1-1000 mg of the therapeutically effective amount, wherein the disease is preferably cancer.