Preparation of quinazolinone derivative as kinase inhibitor, and use thereof

Abstract

Provided are a compound represented by formula (I), a stereoisomer, a deuterated substance, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing same, as well as the use thereof as a BRAF regulator in the preparation of a drug for treating related diseases. Each group in formula (I) is as defined in the description.

Description

Preparation and use of quinazolinone derivatives as kinase inhibitors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority of Chinese patent application No. 202311563261.X filed on November 22, 2023, Chinese patent application No. 202311807306.3 filed on December 26, 2023, Chinese patent application No. 202410163788.1 filed on February 5, 2024, Chinese patent application No. 202410497576.7 filed on April 24, 2024, and Chinese patent application No. 202410785177.0 filed on June 18, 2024, and the entire contents of the above applications are incorporated herein by reference. Technical Field

[0003] The present invention provides quinazolinone derivatives, pharmaceutical compositions comprising such compounds, and methods of using such compounds or compositions, such as methods of treating proliferative diseases, cancers or tumors, or in some embodiments, diseases or conditions associated with dysregulation of kinases (such as, but not limited to, B-Raf kinase). Background Art

[0004] Kinases are enzymes that catalyze the transfer of a phosphate group from a high-energy, phosphate-donating molecule to a specific substrate. This process, called phosphorylation, involves the substrate acquiring the phosphate group and the high-energy ATP molecule donating the phosphate group. Kinases are classified into the following broad categories based on the substrates they target: protein kinases, lipid kinases, and carbohydrate kinases. Kinases are found in a wide variety of species, from bacteria to fungi to worms to mammals. Over 500 different kinases have been identified in humans.

[0005] MAP kinases (MAPKs) 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 triggers a signaling cascade whereby the Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which in turn activates MEK (MAPKK).

[0006] The BRAF protein is a member of the RAF family of serine / threonine kinases that participates in the Ras-Raf-MEK-extracellular signal-regulated kinase (ERK) pathway or the mitogen-activated protein kinase (MAPK) / ERK signaling pathway that affects cell division and differentiation. BRAF gene mutations 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 its metastatic cancers, and primary brain tumors. Although some BRAF inhibitors produce excellent extracranial responses, cancer may still develop brain metastases during or subsequently with BRAF inhibitor therapy. An estimated 20% of subjects with cancer will develop brain metastases, with the majority of brain metastases occurring in those subjects 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, radiotherapy, chemotherapy, immunotherapy, and / or targeted therapies, the prognosis remains poor.

[0007] Despite advances in multimodality treatment, which includes combinations of surgery, radiotherapy, chemotherapy, immunotherapy, and / or targeted therapies, the prognosis remains poor.

[0008] In addition, 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: Schindler et al. analyzed 1,320 central nervous system (CNS) tumors; and Behling et al. analyzed 969 CNS tumors in pediatric and adult populations. These studies, combined with other studies, have reported the presence of BRAF-V600E mutations in various cancers, including papillary craniopharyngioma, pleomorphic xanthomatous astrocytoma (PXA), ganglioglioma, astroblastoma, etc.

[0009] 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 many peripherally administered agents to be delivered 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, radiotherapy, and / or chemotherapy using agents such as temozolomide and / or bevacizumab. However, surgical treatment of brain cancer is not always possible, for example, the tumor may not be accessible, or the subject may not be able to withstand neurosurgical trauma. In addition, known radiotherapy and treatment with cytotoxic agents 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 black box 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 of 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.

[0010] Given that both P-gp and BCRP are expressed in the endothelial cells lining the blood and brain capillaries, the activity of both P-gp and BCRP in the BBB plays a key role in preventing most kinase inhibitors from distributing to 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 is still a need for the 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

[0011] The present invention provides a small molecule compound with BRAF regulatory activity, its stereoisomers, deuterated products or pharmaceutically acceptable salts. The compound can better penetrate the blood-brain barrier, has a higher brain-blood ratio, and has good activity, few side effects, excellent pharmacokinetics and high bioavailability.

[0012] The present invention provides compounds of the following formulas I, II, III, and IV, and their stereoisomers, deuterated compounds, or pharmaceutically acceptable salts.

[0013] Wherein, Cy is selected from 8-15 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-5 members selected from halogen, CN, OH, =O, NH2, -SF5, -COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-4 Alkyl-C 3-6 Cycloalkyl, 4-12 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, 5-9 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted by 1-3 halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl radical substitution;

[0014] In some embodiments, Cy is selected from 8-15 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-5 groups selected from halogen, CN, OH, ═O, NH 2 , -SF 5 , -COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, 5-9 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted by 1-3 halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl radical substitution;

[0015] In some embodiments, Cy is selected from 8-12 membered bicyclic heterocyclic groups, 10-15 membered tricyclic heterocyclic groups, and the heterocyclic groups are optionally substituted by 1-5 groups selected from halogen, CN, OH, =O, NH2, -SF5, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-12 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, 5-9 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted by 1-3 halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl radical substitution;

[0016] In some embodiments, Cy is selected from P1, P2, P3, or P4;

[0017] Ring A is a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl or heteroaryl is optionally substituted by 1-3 heteroatoms 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 radical substitution;

[0018] In some embodiments, Ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heteroaryl group is optionally substituted by 1-3 heteroatoms 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 radical substitution;

[0019] In some embodiments, ring A is a 5-membered or 6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, or a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl group or heteroaryl group is optionally substituted by 1-3 halogens, C 1-4 Alkoxy, -NHC 1-4Alkyl, -N(C 1-4 Alkyl)2, CN, C 1-4 Alkyl, halogenated C 1-4 Alkoxy and halogenated C 1-4 In some embodiments, ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl, wherein the heterocycloalkyl or heteroaryl 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 In some embodiments, the heterocycloalkyl group is selected from pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, etc. In some embodiments, the heteroaryl group is selected from pyrazolyl, oxazolyl, imidazolyl, triazole, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyridyl, pyrimidinyl, etc., and the heterocycloalkyl or 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 radical substitution;

[0020] In some embodiments, Ring A is a 5-membered or 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1-3 heteroatoms 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 In some embodiments, ring A is a 5-membered heteroaryl group, which 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 In some embodiments, the heteroaryl is selected from pyrazolyl, oxazolyl, imidazolyl, triazole, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyridyl, pyrimidinyl, etc., and the heteroaryl is optionally substituted by 1-2 groups selected from halogen, C 1-4 Alkoxy, -NHC1-4 Alkyl, -N(C 1-4 Alkyl)2, CN, C 1-4 Alkyl, halogenated C 1-4 Alkoxy and halogenated C 1-4 Alkyl radical substitution;

[0021] Ring B is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from ═O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH, halogenated C 1-4 Alkoxy, 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, or -C 1-4 Alkyl-C 3-6 The cycloalkyl group is substituted, wherein the heterocyclic group, cycloalkyl group is optionally further substituted Ring B is a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, the heteroaryl being optionally substituted by 1-2 heteroatoms selected from =O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-2 Alkyl-C 3-6 Cycloalkyl or a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the heterocyclic group or cycloalkyl is optionally further substituted by In some embodiments, ring B is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from =O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl and a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, wherein the heterocyclic group is optionally further substituted In some embodiments, ring B is a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted by 1-2 heteroatoms selected from =O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl and a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the heterocyclic group is optionally further substituted In some embodiments, ring B is a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted by 1-2 heteroatoms selected from =O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl and 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the heterocyclic group is optionally further substituted by The group substitution;

[0022] Ring D is a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic group is optionally substituted by 1-3 heteroatoms 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 radical substitution;

[0023] In some embodiments, ring D is a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic group is optionally substituted by 1-2 heteroatoms selected from halogen, CN, C 1-4 Alkyl and halogenated C 1-4 In some embodiments, ring D is a 5-membered heterocyclic group or a 6-membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic group is optionally substituted by 1-2 heteroatoms selected from halogen, CN, C 1-4 Alkyl and halogenated C 1-4 Alkyl radical substitution;

[0024] Each n is independently selected from 0, 1, 2, 3, 4 or 5; in some embodiments, each n is independently selected from 0, 1, 2 or 3; in some embodiments, each n is independently selected from 0, 1 or 2; in some embodiments, each n is independently selected from 1 or 2;

[0025] Each X1 is independently selected from N, NR 11 , CR 11 or CR 11 R 12 In some embodiments, each X1 is independently selected from N or CR 11 In some embodiments, each X1 is independently selected from N; In some embodiments, each X1 is independently selected from CR 11 ;

[0026] Each X2 is independently selected from N, C or CR 21In some embodiments, each X2 is independently selected from N, C or CR 21 ; In some embodiments, each X2 is independently selected from N or C; In some embodiments, each X2 is independently selected from N; In some embodiments, each X2 is independently selected from C;

[0027] X3 selected from NR 31 , O or CR 31 R 32 In some embodiments, X3 is selected from NR 31 Or O; In some embodiments, X3 is selected from NR 31 ; In some embodiments, X3 is selected from O;

[0028] In some embodiments, Cy is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: or selected from 6-membered heterocycloalkyl groups optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH3, cyclopropyl, 1-3 groups selected from N, S, O heteroatoms, Substituted groups: Or selected from the following groups optionally substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: or selected from 1-3 selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, Substituted groups: In some embodiments, Cy is selected from In some embodiments, Cy is selected from

[0029] Y is C 1-2 Alkyl, O, C=O or NR y ;

[0030] In some embodiments, Y is O, C=O, or NH;

[0031] In some embodiments, Y is O or C=O;

[0032] In some embodiments, Y is O or NH; in some embodiments, Y is O;

[0033] R y H or C 1-4 Alkyl; in some embodiments, R y is H; in some embodiments, R y is methyl or ethyl;

[0034] M is C 1-2 Alkyl, O or NR m ; In some embodiments, M is NR m ;

[0035] W is a bond, O or NR w ; In some embodiments, W is a bond; In some embodiments, W is NR w ;

[0036] R m and R w are independently H or C 1-4 Alkyl; in some embodiments, R m and R w are independently H; in some embodiments, R m is H; in some embodiments, R w is H or CH3; in some embodiments, R w is CH3;

[0037] X4 is selected from C(O), S(O) or S(O)2; in some embodiments, X4 is selected from S(O)2;

[0038] X5 is selected from N or CR x5 In some embodiments, X5 is selected from CR x5 ;

[0039] X6 is selected from N or CR x6 In some embodiments, X6 is selected from CR x6 ;

[0040] X7 is selected from N or CR x7 In some embodiments, X7 is selected from CR x7 ;

[0041] X8 is selected from N or CR x8 In some embodiments, X8 is selected from CR x8 ;

[0042] R1, R2, R3 and R4 are each independently selected from H, halogen, OH, ═O, —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, C 2-4 Alkynyl, 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, said alkyl, heterocycloalkyl, aryl are optionally substituted by 1-3 halogen, OH, NH2, CN and C 1-4 In some embodiments, R1, R2, R3 and R4 are each independently selected from H, halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, said alkyl, heterocycloalkyl, aryl are optionally substituted by 1-3 heteroatoms selected from halogen, CN and C 1-4 In some embodiments, R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, a 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O,

[0043] R x5 、R x6 、R x7 、R x8 are independently selected from H, halogen, CN, 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, C 3-6 Cycloalkyl, 5-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and 6-9 membered aryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycle or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C1-4 Alkoxy, OH, NH2 and CN group substitution;

[0044] R 11 、R 12 、R 21 、R 31 、R 32 are independently selected from H, halogen, CN, 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, C 3-6 Cycloalkyl, 5-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and 6-9 membered aryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycle or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2 and CN group substitution;

[0045] In some embodiments, R 11 、R 21 、R 31 、R x5 、R x6 、R x7 、R x8 are independently selected from H, halogen, CN, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, 5-6 membered heterocyclic ring and 6 membered aryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, heterocyclic ring or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl radical substitution;

[0046] In some embodiments, R x5 、R x6 、R x7 、R x8 Each is independently selected from H, F, Cl, Br, CN, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3; in some embodiments, R x5 、Rx6 、R x7 、R x8 Each is independently selected from H, F, Cl, Br, CN, -CH3, -CH2CH3; in some embodiments, R x5 、R x6 、R x7 、R x8 are each independently selected from H, F, CN; in some embodiments, R x5 Selected from CN; in some embodiments, R x6 is selected from F or Cl; in some embodiments, R x6 is selected from F; in some embodiments, R x7 、R x8 are each independently selected from H;

[0047] Alternatively, R 11 With R 31 and its connected atoms together form C 3-6 A 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 by 1-3 heteroatoms selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH, NH2 and CN group substitution;

[0048] R is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, heterocyclic group is optionally substituted by 1-3 halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 Alkyl radical substitution;

[0049] In some embodiments, R is selected from C 5-10 Bicyclic cycloalkyl, C 3-6 Monocyclic cycloalkyl, 5-10 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the bicyclic cycloalkyl, bicyclic heterocycloalkyl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl and monocyclic heterocycloalkyl groups are optionally further substituted by 1-3 groups selected from halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl group substituted; provided that: the monocyclic cycloalkyl, monocyclic heterocycloalkyl is at least one selected from The group substitution;

[0050] In some embodiments, R is selected from 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-5 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the spirocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl group is optionally further substituted by one selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3; provided that: the monocyclic heterocycloalkyl group is substituted with at least one selected from The group substitution;

[0051] In some embodiments, R is selected from C 6-10 Spirocyclic cycloalkyl, C 4-5 Monocyclic cycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl group is optionally further substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3; provided that: the monocyclic cycloalkyl group is substituted with at least one selected from The group substitution;

[0052] In some embodiments, R is selected from 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-5 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, C 6-10 Spirocyclic cycloalkyl, C 4-5 Monocyclic cycloalkyl, the spirocyclic heterocycloalkyl, spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl and monocyclic cycloalkyl groups are optionally further substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3; provided that: the monocyclic heterocycloalkyl group, the monocyclic cycloalkyl group is substituted by at least one selected from The group substitution;

[0053] In some embodiments, R is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0054] In some embodiments, R is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0055] In some embodiments, R is selected from the group consisting of 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 substituted with the following groups: And at least one selected The group substitution;

[0056] In some embodiments, R is selected from the group consisting of 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 substituted with the following groups: And at least one selected The group substitution;

[0057] In some embodiments, R is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, heterocyclic group is optionally substituted by 1-3 halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 Alkyl radical substitution;

[0058] In some embodiments, R is selected from a 4-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocyclic group is optionally substituted by 1-3 heteroatoms selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 Alkyl radical substitution;

[0059] In some embodiments, R is selected from C 5-10 Bicyclic cycloalkyl, C 3-6 Monocyclic cycloalkyl, 5-10 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the bicyclic cycloalkyl, bicyclic heterocycloalkyl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl and monocyclic heterocycloalkyl groups are further substituted by The group substitution;

[0060] In some embodiments, R is selected from a 5-10 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, a 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, and O, wherein the bicyclic heterocycloalkyl is optionally substituted by 1-3 heteroatoms selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl group is further substituted by The group substitution;

[0061] In some embodiments, R is selected from 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the spirocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl group is further substituted by The group substitution;

[0062] In some embodiments, R is selected from 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-5 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the spirocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl group is further substituted by The group substitution;

[0063] In some embodiments, R is selected from C 6-10 Spirocyclic cycloalkyl, C 4-6 Monocyclic cycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl group is further substituted by The group substitution;

[0064] In some embodiments, R is selected from C 6-10 Spirocyclic cycloalkyl, C 4-5 Monocyclic cycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl group is further substituted by The group substitution;

[0065] In some embodiments, R is selected from 6-8 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the spirocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl group is further substituted by In some embodiments, R is selected from 6-membered spirocyclic heterocycloalkyl or 7-membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, or 4, 5, or 6-membered monocyclic heterocycloalkyl containing 1 heteroatom selected from N, S, and O, and the spirocyclic heterocycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, methoxy, ethoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, OH, NH2, -NHCH3, or -N(CH3)2, and the monocyclic heterocycloalkyl is further substituted by In some embodiments, R is selected from a 6-membered spirocyclic heterocycloalkyl or a 7-membered spirocyclic heterocycloalkyl containing 1 N heteroatom, a 4-, 5-, or 6-membered monocyclic heterocycloalkyl containing 1 N heteroatom, the spirocyclic heterocycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, the monocyclic heterocycloalkyl is further substituted by The group substitution;

[0066] In some embodiments, R is selected from C 6-8 Spirocyclic cycloalkyl, C 4-6 Monocyclic cycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl group is further substituted by In some embodiments, R is selected from C6 spirocyclic cycloalkyl or C7 spirocyclic cycloalkyl, C4 monocyclic cycloalkyl, C5 monocyclic cycloalkyl or C6 monocyclic cycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, methoxy, ethoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, OH, NH2, -NHCH3, -N(CH3)2, and the monocyclic cycloalkyl is further substituted by In some embodiments, R is selected from C6 spirocyclic cycloalkyl or C7 spirocyclic cycloalkyl, C4 monocyclic cycloalkyl, C5 monocyclic cycloalkyl or C6 monocyclic cycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, the monocyclic cycloalkyl is further substituted by The group substitution;

[0067] In some embodiments, R is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: The following groups substituted by 1-2 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0068] In some embodiments, R is selected from the following groups optionally substituted with 1-2 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0069] In some embodiments, R is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: The following groups substituted by 1-2 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0070] In some embodiments, R is selected from cyclobutyl, The cyclobutyl group, 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, and cyclobutyl, At least one selected The group substitution;

[0071] In some embodiments, R is selected from

[0072] In some embodiments, R is selected from

[0073] In some embodiments, R is selected from

[0074] In some embodiments, P1 is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0075] In some embodiments, P1 is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0076] In some embodiments, P2 is selected from 6-membered heterocycloalkyl optionally substituted by 1-3 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH3, cyclopropyl, 1-3 selected from N, S, O heteroatoms, Substituted groups:

[0077] In some embodiments, P2 is selected from 6-membered heterocycloalkyl optionally substituted by 1-3 selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, containing 1-3 heteroatoms selected from N, S, O, Substituted groups:

[0078] In some embodiments, P2 is selected from In some embodiments, P2 is selected from In some embodiments, P2 is selected from In some embodiments, P2 is selected from

[0079] In some embodiments, P3 is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0080] In some embodiments, P4 is selected from the group consisting of F, Cl, Br, ═O, —CH3, —CH2CH3, —CH2F, —CHF2, —CF3, —CH2CH2F, —CH2CHF2, —CH2CF3, Substituted groups:

[0081] As a specific first technical solution of the present invention, the present invention provides a compound represented by Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts,

[0082] Wherein, Cy is selected from 8-15 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-5 members selected from halogen, CN, OH, =O, NH2, -SF5, -COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-4 Alkyl-C 3-6 Cycloalkyl, 4-12 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, 5-9 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted by 1-3 halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl radical substitution; or

[0083] Cy is selected from 8-15 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-5 groups selected from halogen, CN, OH, =O, NH2, -SF5, -COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6Cycloalkyl, 4-12 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, 5-9 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted by 1-3 halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl radical substitution;

[0084] Y is C 1-2 Alkyl, O, C=O or NR y ;

[0085] R y H or C 1-4 alkyl;

[0086] M is C 1-2 Alkyl, O or NR m ;

[0087] W is a bond, O or NR w ;

[0088] R m and R w are independently H or C 1-4 alkyl;

[0089] X4 is selected from C(O), S(O) or S(O)2;

[0090] X5 is selected from N or CR x5 ;

[0091] X6 is selected from N or CR x6 ;

[0092] X7 is selected from N or CR x7 ;

[0093] X8 is selected from N or CR x8 ;

[0094] R x5 、R x6 、R x7 、R x8 are independently selected from H, halogen, CN, 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(C1-4 Alkyl)2, C 3-6 Cycloalkyl, 5-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and 6-9 membered aryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycle or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2 and CN group substitution;

[0095] R is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, heterocyclic group is optionally substituted by 1-3 halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 Alkyl radical substitution; or

[0096] R is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, heterocyclic group is optionally substituted by 1-3 halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 In some embodiments, R is selected from a 4-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic group is optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 Alkyl groups are substituted.

[0097] As a specific second technical solution of the present invention, the compound shown in Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts,

[0098] wherein Cy is selected from P1, P2, P3 or P4;

[0099] Ring A is a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl or heteroaryl is optionally substituted by 1-3 heteroatoms 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 In some embodiments, ring A is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted with 1-3 heteroatoms 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 radical substitution;

[0100] Ring B is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, O, and the heteroaryl is optionally substituted by 1-3 heteroatoms selected from ═O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, or -C 1-4 Alkyl-C 3-6 The cycloalkyl group is substituted, wherein the heterocyclic group, cycloalkyl group is optionally further substituted In some embodiments, ring B is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, which is optionally substituted by 1-3 heteroaryls selected from =O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH, halogenated C 1-4 Alkoxy and containing 1-3 selected from N, S, O heteroatoms 5-6 membered heterocyclic group substituted, wherein the heterocyclic group is optionally further substituted In some embodiments, ring B is a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted by 1-2 heteroatoms selected from =O, halogen, C 1-4 Alkyl, C 1-4Alkoxy, halogenated C 1- 4 alkyl, C 3-6 Cycloalkyl, -C 1-2 Alkyl-C 3-6 Cycloalkyl or a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the heterocyclic group or cycloalkyl is optionally further substituted by The group substitution;

[0101] Ring D is a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic group is optionally substituted by 1-3 heteroatoms 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 radical substitution;

[0102] Each n is independently selected from 0, 1, 2, 3, 4 or 5;

[0103] Each X1 is independently selected from N, NR 11 , CR 11 or CR 11 R 12 ;

[0104] Each X2 is independently selected from N, C or CR 21 ;

[0105] X3 selected from NR 31 , O or CR 31 R 32 ;

[0106] R1, R2, R3 and R4 are each independently selected from H, halogen, OH, ═O, —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, C 2-4 Alkynyl, 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, said alkyl, heterocycloalkyl, aryl are optionally substituted by 1-3 halogen, OH, NH2, CN and C 1-4 Alkyl radical substitution;

[0107] R 11 、R 12 、R21 、R 31 、R 32 are independently selected from H, halogen, CN, 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, C 3-6 Cycloalkyl, 5-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O and 6-9 membered aryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycle or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2 and CN group substitution;

[0108] Alternatively, R 11 With R 31 and its connected atoms together form C 3-6 A 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 by 1-3 heteroatoms selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH, NH2 and CN group substitution;

[0109] R is selected from C 5-10 Bicyclic cycloalkyl, C 3-6 Monocyclic cycloalkyl, 5-10 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the bicyclic cycloalkyl, bicyclic heterocycloalkyl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl and monocyclic heterocycloalkyl groups are optionally further substituted by 1-3 groups selected from halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4Alkyl radical substitution;

[0110] The condition is that the monocyclic cycloalkyl group or the monocyclic heterocycloalkyl group is at least one selected from or

[0111] R is selected from C 5-10 Bicyclic cycloalkyl, C 3-6 Monocyclic cycloalkyl, 5-10 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the bicyclic cycloalkyl, bicyclic heterocycloalkyl are optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl and monocyclic heterocycloalkyl groups are further substituted by In some embodiments, R is selected from a 5-10 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, a 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, and O, the bicyclic heterocycloalkyl being optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl group is further substituted by The group substitution;

[0112] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0113] As a specific third technical solution of the present invention, the compound shown in Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts,

[0114] Wherein, Ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl or heteroaryl is optionally substituted by 1-2 heteroatoms 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 C1-4 In some embodiments, ring A is a 5-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted with 1-2 heteroatoms 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 radical substitution;

[0115] Ring B is a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted by 1-2 heteroatoms selected from ═O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-2 Alkyl-C 3-6 Cycloalkyl or a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the heterocyclic group or cycloalkyl is optionally further substituted by In some embodiments, ring B is a 6-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl is optionally substituted by 1-2 heteroatoms selected from =O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl and a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the heterocyclic group is optionally further substituted The group substitution;

[0116] Ring D is a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic group is optionally substituted by 1-2 heteroatoms selected from halogen, CN, C 1-4 Alkyl and halogenated C 1-4 Alkyl radical substitution;

[0117] R1, R2, R3 and R4 are each independently selected from H, halogen, ═O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, said alkyl, heterocycloalkyl, aryl are optionally substituted by 1-3 heteroatoms selected from halogen, CN and C 1-4 Alkyl radical substitution;

[0118] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0119] As a specific fourth technical solution of the present invention, the compound shown in Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts,

[0120] wherein each n is independently selected from 0, 1, 2 or 3;

[0121] Each X1 is independently selected from N or CR 11 ;

[0122] Each X2 is independently selected from N, C or CR 21 ;

[0123] X3 selected from NR 31 or O;

[0124] X4 is selected from S(O)2;

[0125] X5 selected from CR x5 ;

[0126] X6 selected from CR x6 ;

[0127] X7 selected from CR x7 ;

[0128] X8 selected from CR x8 ;

[0129] R 11 、R 21 、R 31 、R x5 、R x6 、R x7 、R x8 are independently selected from H, halogen, CN, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, 5-6 membered heterocyclic ring and 6 membered aryl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, alkoxy, heterocyclic ring or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl radical substitution;

[0130] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0131] As a specific fifth technical solution of the present invention, the compound shown in Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts are further shown in Formula II and III,

[0132] Wherein, the definitions of Cy, Y, M, W, X4 and R are the same as those in any of the aforementioned technical solutions.

[0133] As a specific sixth technical solution of the present invention, the compound shown in Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts,

[0134] wherein Y is O, C=O or NH; in some embodiments, Y is O or C=O, preferably Y is O;

[0135] M is NR m ;

[0136] W is a key;

[0137] R m is H;

[0138] R is selected from 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-5 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the spirocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl group is optionally further substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3; provided that: the monocyclic heterocycloalkyl group is substituted with at least one selected from or

[0139] R is selected from 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-5 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the spirocyclic heterocycloalkyl is optionally substituted by 1-3 halogens, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl group is further substituted by The group substitution;

[0140] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0141] As a specific seventh technical solution of the present invention, the compound represented by Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts,

[0142] Wherein, Y is O or C=O, preferably Y is O;

[0143] M is NR m ;

[0144] W is NR w ;

[0145] R m is H;

[0146] R w is H or CH3;

[0147] R is selected from C 6-10 Spirocyclic cycloalkyl, C 4-5 Monocyclic cycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl, C 1- 4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl group is optionally further substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3;

[0148] Provided that: the monocyclic cycloalkyl group is at least one selected from or

[0149] R is selected from C 6-10 Spirocyclic cycloalkyl, C 4-5 Monocyclic cycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl, C 1- 4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl group is further substituted by The group substitution;

[0150] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0151] As a specific eighth technical solution of the present invention, the compounds represented by Formula I, Formula II and Formula III, their stereoisomers, deuterated substances or pharmaceutically acceptable salts,

[0152] Wherein, R is selected from the following groups optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: Optionally substituted by 1-2 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: Optionally substituted by 1-2 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: In some embodiments, R is selected from the following groups optionally substituted with 1-2 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: In some embodiments, R is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: Optionally substituted by 1-2 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0153] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0154] As a specific ninth technical solution of the present invention, the compounds represented by Formula I, Formula II and Formula III, their stereoisomers, deuterated substances or pharmaceutically acceptable salts,

[0155] Wherein, R is selected from the following groups optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0156] Alternatively, R is selected from the group consisting of 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 substituted with the following groups: and At least one selected The group substitution;

[0157] Alternatively, R is selected from the group consisting of 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 substituted with the following groups: and At least one selected The group substitution;

[0158] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0159] As a specific tenth technical solution of the present invention, the compounds represented by Formula I, Formula II and Formula III, their stereoisomers, deuterated substances or pharmaceutically acceptable salts, wherein

[0160] P1 is selected from the following groups optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: In some embodiments, P1 is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0161] P2 is selected from 6-membered heterocycloalkyl optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH3, cyclopropyl, 1-3 groups selected from N, S, O heteroatoms, Substituted groups: In some embodiments, P2 is selected from 6-membered heterocycloalkyl optionally substituted by 1-3 selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, containing 1-3 heteroatoms selected from N, S, O, Substituted groups:

[0162] P3 is selected from the following groups optionally substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0163] P4 is selected from the group consisting of optionally 1-3 selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, Substituted groups:

[0164] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0165] As a specific eleventh technical solution of the present invention, the compound shown in Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts, wherein

[0166] Y is O or NH; in some embodiments, Y is O;

[0167] M is NH;

[0168] W is a key;

[0169] X4 is selected from S(O)2;

[0170] X5 selected from CR x5 ;

[0171] X6 selected from CR x6 ;

[0172] X7 selected from CR x7 ;

[0173] X8 selected from CR x8 ;

[0174] R x5 、R x6 、R x7 、R x8Each independently selected from H, F, Cl, CN, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3;

[0175] Cy is selected from the group consisting of 1-3 groups selected from F, Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH3, cyclopropyl, Substituted groups: In some embodiments, Cy is selected from the following groups optionally substituted with 1-3 groups selected from F, Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0176] R is selected from or optionally 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 substituted with the following groups: and At least one selected The group substitution;

[0177] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0178] As a specific twelfth technical solution of the present invention, the compound shown in Formula I, its stereoisomers, deuterated substances or pharmaceutically acceptable salts, wherein

[0179] X5 selected from CR x5 ; X6 selected from CR x6 ;X7 is selected from CR x7 ;X8 selected from CR x8 ; R x5 Selected from CN; R x6 Selected from F, Cl;

[0180] R x7 、R x8 are each independently selected from H;

[0181] Cy is selected from the following groups optionally substituted by 1-3 groups selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0182] R is selected from 1-2 selected from F, -CH3, -CH2CH3 substituted with the following groups: and At least one selected The group substitution;

[0183] The definitions of the remaining groups are the same as those in any of the above technical solutions.

[0184] As a specific thirteenth technical solution of the present invention, the compound represented by formula I, II, III, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, wherein

[0185] Cy is selected from the following groups substituted with one selected from CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3:

[0186] R is selected from 1-2 The following groups substituted by groups:

[0187] As a specific fourteenth technical solution of the present invention, the compounds represented by Formula I, II, and III, and their stereoisomers, deuterated substances, or pharmaceutically acceptable salts, have a structure of Formula IV:

[0188] Among them, R cy Selected from C 1-2 Alkyl, halogenated C 1-4 alkyl;

[0189] R is selected from a 4-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl group is further substituted by 1-2 heteroatoms selected from Group substitution.

[0190] As a specific fifteenth technical solution of the present invention, the compound shown in formula IV, its stereoisomers, deuterated substances or pharmaceutically acceptable salts, wherein R cy Selected from CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3;

[0191] R is selected from 1-2 The following groups substituted by groups:

[0192] 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,

[0193] Table 1

[0194] The present invention also provides a composition or pharmaceutical formulation comprising a compound according to any of the foregoing embodiments, a stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (a unit dosage form is also referred to as a "dose strength").

[0195] Furthermore, the composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any one of the aforementioned schemes, its stereoisomers, deuterated substances or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0196] The present invention also provides the use of a compound according to any of the aforementioned embodiments, or a stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating / preventing a BRAF-mediated disease. Furthermore, the BRAF-mediated disease is a tumor, and more preferably, the tumor is a brain tumor, melanoma, colorectal cancer, non-small cell lung cancer, glioma, papillary thyroid carcinoma, or skin cancer.

[0197] The present invention also provides a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound as described in any of the preceding schemes, a stereoisomer, a deuterated form thereof, or a pharmaceutically acceptable salt thereof, wherein the disease is preferably a tumor, and the therapeutically effective amount is preferably 1-1500 mg. In some embodiments, the mammal of the present invention includes a human.

[0198] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses 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, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0199] 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 50-100mg; 100-1500mg, 100-1000mg, 100-900 mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0200] -200mg, 50-150mg, 50-125mg, 50-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800 mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0201] In some embodiments, the pharmaceutical composition or formulation of the present invention contains the above-mentioned therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, or pharmaceutically acceptable salt;

[0202] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, or pharmaceutically acceptable salt thereof, and a carrier and / or excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength"). In some embodiments, the pharmaceutical composition includes but is not limited to 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 40 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present invention or a stereoisomer, deuterated substance or pharmaceutically acceptable salt thereof.

[0203] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer, a deuterated form, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg. The disease is preferably a tumor, particularly brain tumor, melanoma, colorectal cancer, non-small cell lung cancer, glioma, papillary thyroid carcinoma, and skin cancer.

[0204] A method for treating a disease in a mammal, the method comprising administering a compound of the present invention, a stereoisomer, a deuterated substance or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day, the daily dose being a single dose or a divided dose. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 1 In some embodiments, the daily dose includes but is not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1500 mg / day.

[0205] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated substance or pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

[0206] The amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0207] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0208] Synthesis route

[0209] Patent documents such as WO2021116050A1 describe methods for preparing BRAF modulators. Those skilled in the art can combine this document with known organic synthesis techniques to prepare the compounds of the present invention, starting with commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0210] Specific and similar reactants can be selectively identified by indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis facilities, many of which standard chemical supply facilities (e.g., those listed above) offer custom synthesis services.

[0211] the term

[0212] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:

[0213] The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon 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, an isotope of fluorine 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0214] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.

[0215] "Halo" or "halogen-substituted" refers to substitution with 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 hydrogen atoms that can be replaced 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 may be the same or different halogens. Typical examples include 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.

[0216] "Deuterium" refers to the isotope deuterium of hydrogen (H).

[0217] "Deuterated" or "deuterated compound" refers to a situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl or other group is replaced by at least one deuterium atom. The upper limit of the number of deuterated groups is equal to the sum of the number of replaceable hydrogen atoms in the substituted group. Unless otherwise specified, the number of deuterated groups 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.

[0218] “C x-y " group refers to a group containing x to y carbon atoms, such as "C 1-6 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0219] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group. Typically, it is an alkyl group having 1 to 20 carbon atoms, or an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. The alkyl group may be further substituted with a substituent.

[0220] "Alkylene" refers to a divalent straight-chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and the like.

[0221] "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 replaceable hydrogen atoms in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. Typically, an alkyl group is substituted with 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen. When the number of halogen substituents is greater than 1, they can be the same or different halogens. Specific examples include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, etc.

[0222] "Alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, -OC 1-8 Alkyl, -OC 1-6 Alkyl, -OC 1-4 Alkyl or -OC 1-2 Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy, and cyclobutyloxy, and the like; the alkoxy groups may be optionally substituted with substituents.

[0223] "Haloalkoxy" refers to an -O-haloalkyl group. For example, -O-haloC 1-8 Alkyl, -O-halogenated C 1-6 Alkyl, -O-halogenated C 1-4 Alkyl or -O-halogenated C 1-2 Alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms 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, or 1 halogen substitution; when the number of halogen substituents is greater than 1, they may be the same or different halogen substitutions; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.

[0224] "Alkenyl" refers to a straight or branched chain 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-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -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 with a substituent.

[0225] "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.

[0226] "Alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, and 4-decynyl. The alkynyl group may be optionally substituted with a substituent.

[0227] "Alkynylene" 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 of which include ethynylene, propynylene, and butynylene, and the alkynylene group may be optionally substituted with a substituent.

[0228] "Cycloalkyl" refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group containing no ring heteroatoms. Cycloalkyl can be monocyclic, bicyclic or polycyclic. Bicyclic or polycyclic rings can be cyclic, spirocyclic, bridged or a combination thereof. Bicyclic or polycyclic rings can include one or more aromatic rings, but the ring system as a whole does not have aromaticity. The attachment site can be on the aromatic ring or on the non-aromatic ring. Usually, the cycloalkyl group 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 group, 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 group, 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.

[0229] "Cycloalkylene" refers to a divalent radical of a cycloalkyl group.

[0230] "Aryl" refers to a carbocyclic ring having aromaticity and containing no heteroatoms, including monocyclic aryl and condensed ring aryl. It generally contains 6 to 13 carbon atoms, further contains 6 to 9 carbon atoms, and is further phenyl. Non-limiting examples include phenyl, naphthyl, anthracenyl, and phenanthrenyl. Aryl may optionally be substituted with a substituent.

[0231] "Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic carbocycle, including aryl and cycloalkyl. Carbocycles can be monocyclic, bicyclic, or polycyclic, including bridged, fused, and spirocyclic rings and combinations thereof. Carbocycles typically have 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.

[0232] "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. Bicyclic or polycyclic rings can be bridged, fused, spirocyclic, or a combination thereof. Bicyclic or polycyclic rings can include one or more aromatic or heteroaromatic rings, but the ring system as a whole is not aromatic. The attachment point can be on the aromatic ring or on the non-aromatic ring. Heterocycloalkyl groups are usually 3 to 20-membered rings. When they are monocyclic heterocycloalkyl groups, they are usually 3 to 15-membered rings, or 3-10-membered rings, or 3-8-membered rings, or 3-6-membered rings; when they are bicyclic or polycyclic heterocycloalkyl groups, they are usually 5-12-membered rings, or 5-11-membered rings, or 6-9-membered rings. The heteroatoms N and S include their oxidation states. Non-limiting examples of heterocycloalkyl groups include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azolidinyl, azohexenyl, oxolanyl, oxetan ... The heterocycloalkyl group may be optionally substituted with a substituent.

[0233] "Heteroaromatic ring" or "heteroaryl" unless otherwise specified refers to a ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states and having aromatic properties. "Heteroaromatic ring" or "heteroaryl" may contain =O and may be monocyclic, bicyclic or polycyclic. Bicyclic or polycyclic rings may be bridged, parallel, spirocyclic or combinations thereof. When bicyclic or polycyclic, it may be a fusion of heteroaryl and aryl, or a fusion of heteroaryl and heteroaryl, wherein either heteroaryl or 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.

[0234] "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 includes heteroaryl and heterocycloalkyl. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles, and bicyclic spiro heterocycles, or combinations thereof. Heterocycles are typically 3- to 12-membered heterocycles, 5- to 12-membered heterocycles, or 5- to 7-membered heterocycles. 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]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl, The heterocyclic ring may be optionally substituted with a substituent.

[0235] "Heterocyclylene" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include wait.

[0236] "Spiro" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the 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. Typically, the spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Typically, the spiro ring is a trispirotri (representing a three-membered ring spirotricycle), 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.

[0237] "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 rings are 5 to 20-membered rings, or 5 to 14-membered rings, or 5 to 12-membered rings, or 5 to 10-membered rings. Usually, the rings are three-to-four rings (representing a ring formed by a three-membered ring and a four-membered ring. According to the IUPC naming rules, it is possible to have a three-membered ring as the basic ring or a four-membered ring as the basic ring. The same applies below), three-to-five rings, three-to-six rings, four-to-four rings, four-to-five rings, four-to-six rings, five-to-five rings, five-to-six rings, and six-to-six rings. Non-limiting examples of parallel rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, The cyclic ring may be optionally substituted with a substituent.

[0238] "Bridged ring" means two rings that share two non-adjacent ring atoms and may contain one or more double or triple bonds. A bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Typically, the number of ring atoms in a bridged ring is 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10. Non-limiting examples of bridged rings include adamantane, Indicates that two hydrogen atoms on the same carbon atom are replaced by alkenyl, such as cyclobutyl. Substitution can form

[0239] "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 bond 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, hydroxyl, 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, halo 1-6 Alkyl, halogenated C 1-6 Alkoxy, amino, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C1- 6-alkyl)2,-OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2,-HC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, etc.

[0240] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0241] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that retain the biological effectiveness and properties of the free acids or free bases, and the free acids are reacted with non-toxic inorganic or organic bases, or the free bases are reacted with non-toxic inorganic or organic acids.

[0242] 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.

[0243] "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 target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0244] An "excipient" is a substance that is not itself a therapeutic agent but serves as a diluent, adjuvant, binder, and / or vehicle that 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, and maltodextrin. 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.

[0245] , 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.

[0246] 19) ethanol; (20) pH buffer solution; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0247] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, and conformational isomers.

[0248] The compounds of the present invention also include their tautomers. For example, when the present invention describes a compound on the left side in which the pyrimidine ring is substituted with OH, it also includes the tautomer compound on the right side.

[0249] "Solvate" refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric amount of a solvent bound to the compound or salt thereof by non-covalent forces between the molecules. When the solvent is water, the solvate is a hydrate.

[0250] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate. DETAILED DESCRIPTION

[0251] The present invention will be described in detail below through examples. Where specific conditions are not specified in the examples, the experimental methods are carried out according to conventional conditions. The examples are provided to better illustrate the present invention, but it should not be understood that the present invention is limited to the examples. Any non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention are still within the scope of protection of the present invention.

[0252] Detection method

[0253] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0254] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0255] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0256] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0257] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0258] Intermediate 1: 2-Azaspiro[3.3]heptane-2-sulfonamide

[0259] first step:

[0260] To a 50 mL reaction flask, 1a (800 mg, 5.99 mmol), triethylamine (1.82 g, 17.97 mmol), and dichloromethane (10 mL) were added sequentially. After complete addition, the mixture was stirred at 0°C for 20 minutes. A solution of aminosulfonyl chloride (692 mg, 5.99 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane (50 mL), washed sequentially with water (30 mL × 1) and saturated brine (30 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 15 / 1) to provide intermediate 1 (180 mg, 17% yield).

[0261] Intermediate 2: 2-((3-(2,2-difluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-3,6-difluorobenzonitrile

[0262] first step:

[0263] 2a (20 g, 184.46 mmol) was added to ethyl formate (20 mL) and reacted at 55° C. overnight. After the reaction was complete, the mixture was cooled to room temperature and concentrated to afford the residue 2b (3.1 g, 12% yield).

[0264] LCMS m / z=100.2[M+H] + ;

[0265] 1 H NMR (400MHz, CDCl3) δ8.23(s,1H),6.32(s,1H),6.01–5.67(m,1H),3.71-3.60(m,2H).

[0266] Step 2:

[0267] In a 25 mL single-necked flask, 2-amino-5-hydroxybenzoic acid (0.5 g, 3.31 mmol) was added to 2b (3.1 mL, 28.4 mmol) and reacted at 150°C for 21 hr. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (0.5 mL x 2) and then concentrated to afford 2c (0.70 g, 94% yield).

[0268] LCMS m / z=227.2[M+H] + ;

[0269] Step 3:

[0270] In a 25 mL single-necked flask, 2c (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 ice-cooling and the reaction was stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (0.51 g, 3.20 mmol) was slowly added dropwise under ice-cooling and the reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (5 mL) was added to dilute the reaction system and quenched with water (20 mL). The reaction was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with water (20 mL x 2). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain intermediate 2 (1.1 g, 98% yield).

[0271] LCMS m / z=364.2[M+H] + .

[0272] Intermediate 3: 3,6-difluoro-2-((3-(2-fluoroethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)benzonitrile

[0273] first step:

[0274] In a 250 mL reaction flask, 2-fluoroethylamine hydrochloride (9.0 g, 90.53 mmol) was dissolved in water (80 mL). An aqueous solution of sodium hydroxide (3.3 g, 82.54 mmol) was added under ice-water bath. After stirring for 30 minutes, 3a (4.0 g, 22.29 mmol) was added and stirred at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of dichloromethane (100 mL) and methanol (50 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 1 / 1) to afford 3b (3.8 g, 86% yield).

[0275] LCMS m / z=199.10[M+H] + ;

[0276] Step 2:

[0277] In a 20 mL microwave tube, 3b (1.5 g, 8.58 mmol) was dissolved in triethyl orthoformate (10 mL). The reaction solution was heated to 185°C for 2 h. After the reaction was completed, the mixture was filtered and the filter cake was dried to give 3c (1.6 g, 89% yield).

[0278] LCMS m / z=209.10[M+H] + ;

[0279] Step 3:

[0280] In a 100 mL reaction flask, 3c (1.5 g, 7.20 mmol) was dissolved in N,N-dimethylformamide (20 mL). Cesium carbonate (3.52 g, 10.80 mmol) was slowly added under 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 under ice-water bath. After complete addition, the mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed sequentially with water (100 mL × 1) and saturated brine (100 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain intermediate 3 (1.35 g, 54% yield).

[0281] LCMS m / z=346.10[M+H] + ;

[0282] Intermediate 4:

[0283] Dissolve tert-butyl alcohol (388 ml, 4.24 mol) in dichloromethane (3.5 L). Slowly add chlorosulfonyl isocyanate (500 g, 3.53 mol) dropwise in an ice-water bath, maintaining the temperature below 5°C. After addition, warm the mixture to room temperature and allow to react for 1 hour. Slowly add 4-dimethylaminopyridine (863 g, 7.07 mol) in an ice-water bath, maintaining the temperature below 5°C. After addition, warm the mixture to room temperature and allow to react overnight. After completion of the reaction, concentrate the reaction mixture to one-third of its original volume. Add a mixture of saturated aqueous sodium bicarbonate (3 L) and ethyl acetate (0.5 L) with vigorous stirring, and stir at room temperature for 1 hour. Filter, and wash the filter cake with sodium bicarbonate until excess 4-dimethylaminopyridine is removed. Add a mixture of water (1 L) and ethyl acetate (1 L), filter, and dry the filter cake to obtain Intermediate 4 (1040 g, 97% yield).

[0284] LCMS m / z=302.1[M+1] +

[0285] 1 H NMR (400MHz, DMSO-d6) δ8.46(d,2H),6.98(d,2H),3.23(s,6H),1.26(s,9H).

[0286] Example 1

[0287] first step:

[0288] Compound 1A (5 g, 20.53 mmol) was dissolved in ethanol (30 mL) and acetonitrile (30 mL). Hydrazine hydrate (3 mL) was added and stirred at room temperature for 2 hours. Clear solids formed. The solids were filtered, washed with ethanol, and dried to obtain compound 1B (4 g, 81%).

[0289] LC-MS (ESI): m / z = 240.1 [M+H] + .

[0290] Step 2:

[0291] Compound 1B (2 g, 8.36 mmol) was dissolved in trimethyl orthoacetate (20 mL), and p-toluenesulfonic acid monohydrate (200 mg, 1.04 mmol) was added. The mixture was refluxed and stirred overnight. The reaction mixture was cooled to room temperature, concentrated to dryness, and diluted with dichloromethane (40 mL). The mixture was washed and extracted with saturated sodium bicarbonate solution (8 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain compound 1C (1 g, 45%).

[0292] LC-MS (ESI): m / z = 263.1 [M+H] + .

[0293] Step 3:

[0294] Compound 1C (650 mg, 2.48 mmol), pinacol diboronate (945 mg, 3.72 mmol), and potassium acetate (486 mg, 4.96 mmol) were added sequentially to 1,4-dioxane (20 mL) solvent. The atmosphere was purged with nitrogen three times. [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.18 g, 0.25 mmol) was added and the atmosphere was purged with nitrogen again three times. The temperature was raised to 90°C and the reaction mixture was reacted for 16 hours. After cooling, ethyl acetate (60 mL) was added to the reaction mixture, which was then washed with water (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain compound 1D (600 mg, 78%), which was directly used in the next step.

[0295] LC-MS(ESI):m / z=229.2[M-82+H] + .

[0296] Step 4:

[0297] Compound 1D (600 mg, 1.93 mmol) was dissolved in ethyl acetate (10 mL), cooled to 0°C, and 30% aqueous hydrogen peroxide (1.2 mL) was slowly added. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, saturated sodium thiosulfate solution (10 mL) was slowly added to quench the reaction. The mixture was then separated and extracted with ethyl acetate (10 mL x 3). The organic phase was dried, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain compound 1E (250 mg, 45%).

[0298] LC-MS (ESI): m / z = 201.1 [M+H] + .

[0299] Step 5:

[0300] 1E (200 mg, 1 mmol) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of cesium carbonate (0.65 g, 2 mmol). 1F (0.23 g, 1.5 mmol) was added with stirring at 0°C. After addition, the temperature was slowly raised to room temperature and allowed to react for 1 h. After completion of the reaction, monitored by LCMS, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated brine, dried, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain compound 1G (150 mg, 44%).

[0301] LC-MS (ESI): m / z = 338.4 [M+H] + .

[0302] Step 6:

[0303] Intermediate 1 (100 mg, 0.57 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium carbonate (286 mg, 0.88 mmol) was added. After stirring at room temperature for 30 minutes, 1G (150 mg, 0.44 mmol) was added, and the reaction was stirred at 50°C for 16 hours. After completion of the reaction, LCMS monitoring was performed, 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 (dichloromethane:methanol = 10:1 (v / v)) to obtain compound 1 (8 mg, 3.7%).

[0304] LC-MS (ESI): m / z = 494.0 [M+H] + .

[0305] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.50(s,1H),8.14(d,1H),7.98–7.70(m,2 H),7.65–7.35(m,2H),3.81(s,4H),2.54(s,3H),2.08(t,4H),1.77-1.66(m,2H).

[0306] Example 2:

[0307] first step:

[0308] 2A (0.93 g, 5.15 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Morpholine (897.34 mg, 10.30 mmol) and potassium carbonate (2.49 g, 18.11 mmol) were added at room temperature and allowed to react overnight at 100°C. After the reaction was complete and cooled to room temperature, water (50 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate (100 mL x 2). The organic phases were combined, concentrated, and purified by column chromatography (dichloromethane / methanol = 97 / 3, v / v) to afford 2B (1.2 g, 100% yield).

[0309] LCMS m / z=232.2[M+H] + ;

[0310] Step 2:

[0311] 2B (1.20 g, 5.19 mmol) was dissolved in dry N,N-dimethylformamide (20 mL). Cesium carbonate (4.23 g, 12.98 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (0.98 g, 6.23 mmol) was slowly added dropwise under ice-cooling. The reaction 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 = 2 / 1, v / v) to afford 2C (0.85 g, 44% yield).

[0312] LCMS m / z=369.1[M+H] + ;

[0313] Step 3:

[0314] In a 25 mL single-necked flask, intermediate 1 (0.32 g, 1.83 mmol) and cesium carbonate (1.59 g, 4.88 mmol) were added to dry N,N-dimethylformamide (15 mL) and reacted at 50°C for 30 min. Then, 2C (0.45 g, 1.22 mmol) was added at 50°C and stirred at 85°C for 5 hr. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed with N,N-dimethylformamide (2 mL). The filtrate was purified by HPLC to afford compound 2 (220 mg, 34% yield).

[0315] LC-MS (ESI): m / z = 525.5 [M+H] + .

[0316] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.74(s,1H),7.91–7.84(m,2H),7.55-7.51(dd,1H),7.2 9-7.25(dd,1H),6.79(d,1H),3.84(s,4H),3.72(s,8H),2.12-2.08(t,4H),1.77–1.70(m,2H).

[0317] Example 3:

[0318] first step:

[0319] Dissolve crude product 3A (2.00 g, 11.82 mmol) in dichloromethane (21 mL) and slowly add trifluoroacetic acid (7 mL) dropwise at 0-5°C. Allow to react overnight at room temperature. After completion of the reaction, concentrate the reaction mixture to obtain crude product 3B, which was directly used in the next step.

[0320] Step 2:

[0321] 3B (0.82 g, 11.87 mmol) and acetonitrile (20 mL) were added to a 50 mL single-necked flask. Triethylamine (6.01 g, 59.35 mmol) and intermediate 4 (4.31 g, 14.24 mmol) were slowly added at 0-5°C and allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was concentrated to obtain crude product 3C, which was directly used in the next step.

[0322] LCMS m / z=193.1[M+H] + ;

[0323] Step 3:

[0324] In a 50 mL single-necked flask, crude product 3C (2.95 g, 11.88 mmol) was dissolved in dichloromethane (30 mL). Trifluoroacetic acid (15 mL) was slowly added dropwise at 0-5°C. The mixture was allowed to react 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 = 1 / 1) to obtain 3D (800 mg, 45% yield).

[0325] 1 H NMR (400MHz, DMSO-d6) δ6.98(s,2H),5.03–5.02(m,2H),4.33-4.32(m,4H).

[0326] Step 4:

[0327] In a 25 mL single-necked flask, 3D (0.22 g, 1.48 mmol) and cesium carbonate (1.29 g, 3.96 mmol) were added to dry N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Intermediate 2 (0.36 g, 0.99 mmol) was then added at 50°C and stirred at 80°C overnight. After the reaction was complete, the reaction solution was filtered, the filter cake was treated with N,N-dimethylformamide (4 mL), and the filtrate was directly purified by HPLC to yield compound 3 (52 mg, 10%).

[0328] LCMS m / z=492.1[M+H] + ;

[0329] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.34(s,1H),7.90–7.86(m,1H),7.83-7.80(d,1H),7.74-7.71(dd,1H),7. 58-7.55(dd,1H),7.44-7.43(d,1H),6.51-6.22(m,1H),5.08–5.07(m,2H),4.53-4.51(m,4H),4.48–4.43(m,2H).

[0330] Example 4:

[0331] first step:

[0332] Compound 4A (300 mg, 1.52 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react at room temperature for 3 h. After the reaction, the mixture was concentrated to obtain crude product 4B, which was directly used in the next step.

[0333] LCMS m / z=98.20[M+H] + ;

[0334] Step 2:

[0335] Compound 4B (0.14 g, 1.44 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of triethylamine (0.44 g, 4.32 mmol) and intermediate 4 (0.65 g, 2.16 mmol). The mixture was allowed to react overnight at room temperature. After completion of the reaction, the product was concentrated and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to afford the target compound 4C (0.23 g, 58% yield).

[0336] LCMS m / z=221.10[M-56+H] + ;

[0337] Step 3:

[0338] Compound 4C (0.23 g, 1.44 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (4 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the crude product 4D was obtained by concentration and directly carried to the next step.

[0339] LCMS m / z=177.10[M+H] + ;

[0340] Step 4:

[0341] Compound 4D (0.11 g, 0.62 mmol) and cesium carbonate (0.22 g, 0.66 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Intermediate 2 (0.12 g, 0.33 mmol) was then added and stirred at 80°C overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 4 (80 mg, 47% yield).

[0342] LCMS m / z=520.20[M+H] + ;

[0343] 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.34(s,1H),7.91-7.84(m,1H),7.81(d,1H),7.74-7.6 9(m,1H),7.58-7.53(m,1H),7.43(d,1H),6.52-6.18(m,1H),4.52-4.44(m,6H),1.48(s,6H).

[0344] Example 5:

[0345] first step:

[0346] In a 25 mL single-necked flask, 3D (166.70 mg, 1.13 mmol) and cesium carbonate (977.46 mg, 3.00 mmol) were added to dry N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Intermediate 3 (260 mg, 0.75 mmol) was then added at 50°C and stirred at 80°C overnight. After the reaction was complete, the reaction solution was filtered, the filter cake was treated with N,N-dimethylformamide (4 mL), and the filtrate was directly purified by HPLC to obtain compound 5 (130 mg, 36% yield).

[0347] LCMS m / z=474.2[M+H] + ;

[0348] 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.80-7.77(d,1H),7.69-7.66(dd,2H),7.49-7.45(dd,1H),7.40-7.39(d,1 H),5.02–5.01(m,2H),4.78-4.75(t,1H),4.66-4.64(t,1H),4.40(s,4H),4.35-4.33(t,1H),4.29-4.26(t,1H).

[0349] Example 6:

[0350] first step:

[0351] Dissolve 6A (4.5 g, 24.56 mmol) in dichloromethane (60 mL) and slowly add trifluoroacetic acid (20 mL) dropwise at 0-5°C. Allow to react at room temperature for 2 hours. After completion of the reaction, concentrate the reaction mixture to obtain crude product 6B, which was directly used in the next step.

[0352] Step 2:

[0353] Crude product 6B and acetonitrile (40 mL) were added to a 100 mL single-necked flask. Triethylamine (12.42 g, 122.70 mmol) and intermediate 4 (8.87 g, 29.45 mmol) were slowly added at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to afford crude product 6C (2.7 g, 41% yield).

[0354] LCMS m / z=207.1[M-55] + ;

[0355] Step 3:

[0356] In a 100 mL single-necked flask, crude product 6C (2.70 g, 10.29 mmol) was dissolved in dichloromethane (60 mL). Trifluoroacetic acid (20 mL) was slowly added dropwise at 0-5°C. The mixture was allowed to react 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 = 1 / 1) to obtain 6D (1.2 g, 71% yield).

[0357] Step 4:

[0358] In a 25 mL single-necked flask, 6D (201.95 mg, 1.24 mmol) and cesium carbonate (1.08 g, 3.32 mmol) were added to dry N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Intermediate 2 (0.30 g, 0.83 mmol) was then added at 50°C and stirred at 80°C overnight. After the reaction was complete, the reaction solution was filtered, the filter cake was treated with N,N-dimethylformamide (4 mL), and the filtrate was directly purified by HPLC to afford compound 6 (130 mg, 31% yield).

[0359] LCMS m / z=506.2[M+H] + ;

[0360] 1 H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.34(s,1H),7.89–7.80(m,2H),7.73-7.70(dd,1H),7.56-7.52(dd,1H),7.41- 7.40(d,1H),6..51-6.22(m,1H),5.00(s,2H),4.52-4.43(td,2H),3.87(s,2H),3.39-3.35(t,2H),2.58-2.55(t,2H).

[0361] Example 7:

[0362] first step:

[0363] Compound 7A (1.5 g, 8.19 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react at room temperature for 3 h. After the reaction, the mixture was concentrated to obtain crude product 7B, which was directly used in the next step.

[0364] LCMS m / z=84.20[M+H] + ;

[0365] Step 2:

[0366] Compound 7B (0.68 g, 8.18 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of triethylamine (2.00 g, 19.76 mmol) and intermediate 4 (3.71 g, 12.27 mmol). The mixture was allowed to react overnight at room temperature. After completion of the reaction, the crude product was concentrated and purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to afford the target compound 7C (1.0 g, 47% yield).

[0367] LCMS m / z=207.00[M-56+H] + ;

[0368] Step 3:

[0369] Compound 7C (1.0 g, 3.81 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (4 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the crude product 7D was obtained by concentration and directly carried out to the next step.

[0370] LCMS m / z=163.10[M+H] + ;

[0371] Step 4:

[0372] Compound 7D (0.46 g, 1.65 mmol) and cesium carbonate (1.08 g, 3.30 mmol) were added to N,N-dimethylformamide (15 mL) and reacted at 50°C for 30 min. Intermediate 2 (0.4 g, 1.10 mmol) was then added and stirred at 80°C overnight. After the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 7 (100 mg, 20% yield).

[0373] LCMS m / z=506.20[M+H] + ;

[0374] 1H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.34(s,1H),7.91-7.84(m,1H),7.81(d,1H),7.74-7.69(m,1H),7. 58-7.53(m,1H),7.43(d,1H),6.52-6.18(m,1H),5.45-5.36(m,1H),4.53-4.42(m,6H),1.51-1.45(m,3H).

[0375] Example 8:

[0376] first step:

[0377] Dissolve 8A (1.00 g, 5.46 mmol, synthesis reference WO2021 / 108483,2021,A1) in dichloromethane (15 mL) and slowly add trifluoroacetic acid (5 mL) dropwise at 0-5°C. Allow to react overnight at room temperature. After completion of the reaction, concentrate the reaction mixture to obtain crude product 8B, which was directly used in the next step.

[0378] Step 2:

[0379] Crude product 8B and acetonitrile (10 mL) were added to a 50 mL single-necked flask. Triethylamine (2.74 g, 27.05 mmol) and intermediate 4 (1.96 g, 6.49 mmol) were slowly added at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to afford crude product 8C (0.50 g, 35% yield).

[0380] LCMS m / z=207.1[M-55] + ;

[0381] Step 3:

[0382] In a 50 mL single-necked flask, crude product 8C (0.50 g, 1.91 mmol) was dissolved in dichloromethane (12 mL). Trifluoroacetic acid (4 mL) was slowly added dropwise at 0-5°C. The mixture was allowed to react 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 = 1 / 1) to obtain 8D (300 mg, 97% yield).

[0383] LCMS m / z=163.1[M+H] + ;

[0384] Step 4:

[0385] In a 25 mL single-necked bottle, 8D (82.73 mg, 0.51 mmol) and cesium carbonate (0.55 g, 1.70 mmol) were added to dry N,N-dimethylformamide (10 mL) and reacted at 50°C for 10 min. Intermediate 2 (125 mg, 0.34 mmol) was then added at 50°C. After the addition, the mixture was stirred at 80°C overnight. After the reaction was complete, the reaction solution was filtered, the filter cake was treated with N,N-dimethylformamide (4 mL), and the filtrate was directly purified by HPLC to obtain compound 8.

[0386] LCMS m / z=506.1[M+H] + ;

[0387] Example 9:

[0388] first step:

[0389] 9A (1.00 g, 10.19 mmol) and dichloromethane (20 mL) were added to a 100 mL single-necked flask. Triethylamine (2.06 g, 20.38 mmol) and methanesulfonyl chloride (1.40 g, 12.23 mmol) were then added and reacted at room temperature for 30 min. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to afford 9B (1.80 g, 100% yield).

[0390] Step 2:

[0391] 9B (1.80 g, 10.22 mmol), 6-methoxy-4(1H)-quinazolinone (1.80 g, 10.22 mmol), potassium carbonate (2.83 g, 20.44 mmol), and acetonitrile (40 mL) were added to a 100 mL single-necked flask and reacted at 80°C overnight. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to obtain 9C (1.3 g, 49% yield).

[0392] LCMS m / z=257.1[M+H]+;

[0393] Step 3:

[0394] 9C (1.30 g, 5.07 mmol) and N,N-dimethylformamide (20 mL) were added to a 100 mL single-necked flask, followed by sodium ethanethiolate (1.49 g, 17.75 mmol). After the addition, the mixture was stirred at 135°C under nitrogen for 12 hours. After completion of the reaction, the reaction solution was concentrated, and the pH was adjusted to acidic by adding dilute hydrochloric acid and alkaline by using saturated sodium bicarbonate solution. The mixture was then concentrated to obtain a residue, which was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2, v / v) to afford 9D (1.20 g, 97% yield).

[0395] LCMS m / z=243.1[M+H] + ;

[0396] Step 4:

[0397] In a 100 mL single-necked flask, 9D (1.20 g, 4.95 mmol) was dissolved in dry N,N-dimethylformamide (30 mL). Cesium carbonate (3.23 g, 9.90 mmol) was slowly added at 0-5°C and stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (0.86 g, 5.45 mmol) was slowly added dropwise in an ice bath and stirred at room temperature overnight. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 9E (1.70 g, 90% yield).

[0398] LCMS m / z=380.2[M+H]+;

[0399] Step 5:

[0400] In a 25 mL single-necked flask, intermediate 1 (0.21 g, 1.19 mmol) and cesium carbonate (1.03 g, 3.16 mmol) were added to dry N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Then, 9E (0.30 g, 0.79 mmol) was added at 50°C and stirred at 80°C overnight. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by HPLC to obtain compound 9 (240 mg, 56% yield).

[0401] LCMS m / z=536.3[M+H] + ;

[0402] 1H NMR(400MHz, CDCl3)δ8.29(s,1H),7.80-7.77(d,1H),7.55–7.49(m,3H),7.39-7.35(t,1H),4.77(s,2H),4 .08-4.06(d,2H),3.90(s,4H),2.81–2.76(m,3H),2.46-2.43(d,2H),2.13-2.09(t,4H),1.81–1.73(m,2H).

[0403] Example 10:

[0404] first step:

[0405] Compound 10A (2.0 g, 11.82 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react at room temperature for 3 h. After the reaction, the crude product 10B was obtained by concentration and directly carried out in the next step.

[0406] Step 2:

[0407] Compounds 10B (1.41 g, 7.70 mmol) and 10C (1.00 g, 5.13 mmol) were dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (2.13 g, 15.39 mmol) was added. The mixture was stirred at 100°C overnight. After the reaction was complete, 40 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain compound 10D (1.0 g, yield: 85%).

[0408] LCMS m / z=228.10[M+H] + ;

[0409] Step 3:

[0410] Compound 10D (1.0 g, 4.40 mmol) was dissolved in N,N-dimethylformamide (20 mL), and sodium ethanethiolate (1.48 g, 17.60 mmol) was added. The reaction solution was purged with nitrogen three times, and then heated to 130°C for 12 hours. After the reaction was completed, the solution was filtered and the filtrate was concentrated to obtain crude product 10E, which was directly used for the next step.

[0411] LCMS m / z=214.10[M+H] + ;

[0412] Step 4:

[0413] Compound 10E (1.0 g, 4.69 mmol) was dissolved in N,N-dimethylformamide (20 mL). Cesium carbonate (3.0 g, 9.21 mmol) was slowly added under ice-water bath. After stirring at room temperature for 30 min, a solution of 2,3,6-trifluorobenzonitrile (1.11 g, 7.07 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise under ice-water bath. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (50 mL), washed sequentially with water (50 mL × 1) and saturated brine (50 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain 10F (0.70 g, 42% yield).

[0414] LCMS m / z=351.10[M+H] + ;

[0415] Step 5:

[0416] Intermediate 1 (0.23 g, 1.31 mmol) and cesium carbonate (0.56 g, 1.72 mmol) were added to N,N-dimethylformamide (15 mL) and reacted at 50°C for 30 min. Compound 10F (0.3 g, 0.86 mmol) was then added and stirred at 80°C overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 10 (100 mg, 23% yield).

[0417] LCMS m / z=507.10[M+H] + ;

[0418] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.31(s,1H),7.93-7.82(m,2H),7.60-7.48(m,1H),7.31-7.23(m,1 H),6.83(d,1H),5.16-5.10(m,2H),4.84-4.76(m,4H),3.84(s,4H),2.15-2.05(m,4H),1.80-1.69(m,2H).

[0419] Example 11:

[0420] first step:

[0421] Dissolve (fluoromethyl)triphenylphosphine tetrafluoroborate (19 g, 49.72 mmol) in dry tetrahydrofuran (380 mL). Slowly add sodium bis(trimethylsilyl)amide (25 mL, 49.72 mmol, 2 M in THF) dropwise at -78°C. After the addition is complete, react at -78°C for 1 h. Then, slowly add a solution of compound 11A (8.5 g, 49.72 mmol) in tetrahydrofuran (20 mL) dropwise at -78°C. After the addition is complete, react at room temperature overnight. The reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1 (v / v)). After completion of the reaction, saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and filtered. The residue was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to obtain compound 11B (4.5 g, yield: 48%).

[0422] LCMS m / z=132.2[M+1] +

[0423] 1 H NMR (400MHz, CDCl3) δ6.53–6.27(m,1H),4.48–4.39(m,2H),4.36(dt,2H),1.34(s,9H).

[0424] 19 F NMR(376MHz, CDCl3)δ-137.81(s).

[0425] Step 2:

[0426] Compound 11B (1.0 g, 5.34 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain crude product 11C, which was directly used in the next step.

[0427] LCMS m / z=88.2[M+1] +

[0428] Step 3:

[0429] Compound 11C (466 mg, 5.34 mmol) was dissolved in acetonitrile (20 mL). Triethylamine (3.7 mL, 26.7 mmol) was slowly added dropwise under an ice bath. Intermediate 4 (2.42 g, 8.01 mmol) was then added and allowed to react overnight at room temperature. TLC (petroleum ether:ethyl acetate = 1:1 (v / v)) confirmed the reaction was complete. After completion, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to afford compound 11D (530 mg, 37% yield).

[0430] LCMS m / z=265.2[M-1] -

[0431] Step 4:

[0432] Compound 11D (530 mg, 1.99 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain compound 11E (280 mg, 85% yield).

[0433] LCMS m / z=167.2[M+1] +

[0434] Step 5:

[0435] Intermediate 2 (580 mg, 1.60 mmol) was dissolved in dry N,N-dimethylformamide (20 mL), and cesium carbonate (1.04 g, 3.20 mmol) and compound 11E (280 mg, 1.68 mmol) were added in sequence. After the addition, the mixture was reacted at 80°C for 6 h. TLC monitoring (petroleum ether:ethyl acetate = 1:2 (v / v)) confirmed the completion of the reaction. After the reaction was completed, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol).

[0436] =50:1 (v / v)) to obtain compound 11 (148 mg, yield: 18%).

[0437] LCMS m / z=510.3[M+1] +

[0438] Example 12:

[0439] first step:

[0440] Compound 12A (450 mg, 2.05 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (120 mg, 3.07 mmol) was slowly added in an ice-water bath. After stirring for 30 min, iodomethane (440 mg, 3.07 mmol) was added and stirred at room temperature for 3 h. After completion of the reaction, 20 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 10:1) to obtain compound 12B (350 mg, yield: 73%).

[0441] Step 2:

[0442] Compound 12B (350 mg, 1.50 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, the crude product 12C was obtained by concentration and directly carried out in the next step.

[0443] LCMS m / z=134.10[M+H] + ;

[0444] Step 3:

[0445] Compound 12C (200 mg, 1.50 mmol) was dissolved in acetonitrile (10 mL). Triethylamine (460 mg, 4.50 mmol) and intermediate 4 (680 mg, 2.25 mmol) were slowly added at 0-5°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to afford compound 12D (150 mg, 32% yield).

[0446] LCMS m / z=257.20[M-56+H] + ;

[0447] Step 4:

[0448] Compound 12D (150 mg, 0.48 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react at room temperature for 3 h. After the reaction, the crude product 12E was obtained by concentration and directly carried out in the next step.

[0449] LCMS m / z=213.10[M+H] + ;

[0450] Step 5:

[0451] Compound 12E (100 mg, 0.47 mmol) and cesium carbonate (270 mg, 0.84 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Intermediate 2 (100 mg, 0.28 mmol) was then added and stirred at 80°C overnight. After the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 12 (30 mg, 20% yield).

[0452] LCMS m / z=556.50[M+H] + ;

[0453] Example 13:

[0454] first step:

[0455] Compound 12A (250 mg, 1.14 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, the crude product 13A was obtained by concentration and directly carried out in the next step.

[0456] LCMS m / z=120.10[M+H] + ;

[0457] Step 2:

[0458] Compound 13A (140 mg, 1.18 mmol) was dissolved in acetonitrile (10 mL). Triethylamine (360 mg, 3.54 mmol) and intermediate 4 (540 mg, 1.77 mmol) were slowly added at 0-5°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to afford compound 13B (200 mg, 35% yield).

[0459] LCMS m / z=243.40[M-56+H] + ;

[0460] Step 4:

[0461] Compound 13B (200 mg, 0.67 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) was slowly added dropwise in an ice-water bath. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, the crude product 13C was obtained by concentration and directly carried out in the next step.

[0462] LCMS m / z=199.00[M+H] + ;

[0463] Step 5:

[0464] Compound 13C (130 mg, 0.67 mmol) and cesium carbonate (300 mg, 0.92 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Intermediate 2 (100 mg, 0.28 mmol) was then added and stirred at 80°C overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 13 (25 mg, 17% yield).

[0465] LCMS m / z=542.00[M+H] + ;

[0466] Example 14:

[0467] first step:

[0468] Compound 7D (0.20 g, 1.23 mmol) and cesium carbonate (0.49 g, 1.51 mmol) were added to N,N-dimethylformamide (15 mL) and reacted at 50°C for 30 min. Intermediate 3 (0.25 g, 0.72 mmol) was then added and stirred at 80°C overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 14 (65 mg, 18% yield).

[0469] LCMS m / z=488.10[M+H] + ;

[0470] 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.33(s,1H),7.91-7.84(m,1H),7.81(d,1H),7.74-7.69(m,1H),7.58- 7.53(m,1H),7.41(d,1H),5.46-5.34(m,1H),4.79-4.63(m,2H),4.47(d,4H),4.35-4.32(m,2H),1.48(d,3H).

[0471] Example 15 and Example 16:

[0472] first step:

[0473] Dissolve (fluoromethyl)triphenylphosphine tetrafluoroborate (13 g, 34.02 mmol) in dry tetrahydrofuran (260 mL). Slowly add sodium bis(trimethylsilyl)amide (17 mL, 34.02 mmol, 2 M in THF) dropwise at -78°C. After the addition is complete, react at -78°C for 1 h. Then, slowly add a solution of compound 15A (6.30 g, 34.02 mmol) in tetrahydrofuran (15 mL) dropwise at -78°C. After the addition is complete, react at room temperature overnight. The reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1 (v / v)). After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to obtain compound 15B (3.06 g, yield: 45%).

[0474] LCMS m / z=146.2[M+1-56] +

[0475] Step 2:

[0476] Compound 15B (860 mg, 4.27 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain crude product 15C, which was directly used in the next step.

[0477] LCMS m / z=102.2[M+1] +

[0478] Step 3:

[0479] Compound 15C (432 mg, 4.27 mmol) was dissolved in acetonitrile (20 mL). Triethylamine (2.7 mL, 19.2 mmol) was slowly added dropwise under an ice bath. Intermediate 4 (1.94 g, 6.41 mmol) was then added and allowed to react overnight at room temperature. TLC (petroleum ether:ethyl acetate = 1:1 (v / v)) confirmed the reaction was complete. After completion, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product 15D, which was directly used in the next step.

[0480] LCMS m / z=281.2[M-1] -

[0481] Step 4:

[0482] Compound 15D (1.2 g, 4.27 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain compound 15E (420 mg, 55% yield).

[0483] LCMS m / z=181.2[M+1] +

[0484] Step 5:

[0485] Intermediate 2 (627 mg, 1.73 mmol) was dissolved in dry N,N-dimethylformamide (20 mL). Cesium carbonate (1.97 g, 6.04 mmol) and compound 15E (420 mg, 2.33 mmol) were added sequentially, and the mixture was allowed to react at 80°C for 6 h. TLC (petroleum ether:ethyl acetate = 1:2 (v / v)) confirmed the completion of the reaction. After completion, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (eluent: dichloromethane:methanol = 65:1 (v / v)) to obtain the title compound. Chiral SFC preparation gave P1 (125 mg, yield: 17%, retention time: 11.08 minutes, designated as compound 15) and P2 (145 mg, yield: 20%, retention time: 19.00 minutes, designated as compound 16).

[0486] SFC preparation method: 1. Instrument: SFC Prep 150AP; Chromatographic column: TORUS2-PIC (19 mm × 250 mm). 2. Dissolve the sample in methanol and filter through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: CO2; Mobile phase B: methanol. b. Isocratic elution, mobile phase B content: 40%. c. Flow rate: 46 ml / min. After separation, the fractions were dried on a rotary evaporator in a 45°C water bath to obtain the product. The solvent was then dried in a lyophilizer at -80°C to yield compounds 15 and 16.

[0487] Compound 15, LCMS m / z=524.2[M+H]+.

[0488] 1H NMR(400MHZ,DMSO-d6)δ10.41(s,1H),8.34(s,1H),7.87(t,1H),7.83–7.78(m,1H),7.72(m,1H),7.54(dd,1 H),7.42(d,1H),7.04–6.79(m,1H),6.51–6.21(m,1H),4.47(m,2H),3.88(s,2H),3.40(t,2H),2.63(t,2H).

[0489] Compound 16, LCMS m / z=524.2[M+H]+.

[0490] 1 H NMR(400MHZ,DMSO-d6)δ10.39(s,1H),8.34(s,1H),7.90–7.83(m,1H),7.81(d,1H),7.71(m,1H),7.54(m ,1H),7.42(d,1H),6.84(m,1H),6.36(m,1H),4.47(m,2H),4.00(s,2H),3.37(m,2H),2.55–2.51(m,2H).

[0491] Example 17:

[0492] first step:

[0493] Intermediate 3 (400 mg, 1.10 mmol) was dissolved in dry N,N-dimethylformamide (20 mL), and cesium carbonate (1.26 g, 3.85 mmol) and compound 11E (247 mg, 1.49 mmol) were added in sequence. After the addition, the mixture was reacted at 80°C for 6 h. TLC monitoring (petroleum ether:ethyl acetate = 1:2 (v / v)) showed that the reaction was complete. After the reaction was completed, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol).

[0494] =55:1 (v / v)) to obtain compound 17 (142 mg, yield: 26%).

[0495] LCMS m / z=492.0[M+1] +

[0496] 1H NMR(400MHZ,DMSO-d6)δ8.33(s,1H),7.88(dd,1H),7.80(d,1H),7.71(dd,1H),7.57(dd,1H),7.43(d,1H),7.03–6.99(m ,0.5H),6.83–6.78(m,0.5H),4.77(t,1H),4.64(t,1H),4.62–4.57(m,2H),4.56–4.49(m,2H),4.34(t,1H),4.28(t,1H).

[0497] Example 18:

[0498] first step:

[0499] 2-Difluoromethanesulfonylpyridine (5.08 g, 26.29 mmol) and 18A (5.0 g, 29.21 mmol) were dissolved in dry DMF (50 mL). Potassium tert-butoxide (4.92 g, 43.81 mmol, dissolved in 15 mL DMF) was slowly added dropwise at -45°C. After the addition, the mixture was reacted at room temperature overnight. The reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1 (v / v)). After completion of the reaction, saturated aqueous ammonium chloride solution (100 mL) was added to quench the reaction, 3 M HCl (14 mL) was added and stirring was continued for 3 h, followed by the addition of ethyl acetate (200 mL) and stirring for one hour. The reaction system was then allowed to stand for 48 h, the layers were separated, and the organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to obtain compound 18B (0.9 g, yield: 15%).

[0500] 1 H NMR (400MHz, CDCl3) δ4.48 (t, 4H), 1.45 (s, 9H).

[0501] Step 2:

[0502] Compound 18B (0.9 g, 4.39 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain crude product 18C, which was directly used in the next step.

[0503] LCMS m / z=106.1[M+1] +

[0504] Step 3:

[0505] Compound 18C (1.1 g, 5.02 mmol) was dissolved in acetonitrile (20 mL). Triethylamine (1.52 g, 26.7 mmol) was slowly added dropwise under an ice bath. Intermediate 4 (1.67 g, 5.52 mmol) was then added and allowed to react overnight at room temperature. TLC (petroleum ether:ethyl acetate = 1:1 (v / v)) confirmed the reaction was complete. After completion, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to afford compound 18D (350 mg, 24.5% yield).

[0506] Step 4:

[0507] Compound 18D (350 mg, 1.23 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain compound 18E (200 mg, yield: 88%).

[0508] Step 5:

[0509] Intermediate 2 (300 mg, 0.83 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), and cesium carbonate (0.81 g, 2.49 mmol) and compound 18E (200 mg, 1.08 mmol) were added sequentially. The mixture was reacted at 80°C for 16 h. TLC (petroleum ether:ethyl acetate = 1:2 (v / v)) confirmed the completion of the reaction. After completion, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1 (v / v)) to obtain compound 18 (130 mg, 30% yield).

[0510] LCMS m / z=528.0[M+1] +

[0511] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),7.79(d,1H),7.68(d,1H),7.53(d,1H),7.40(s,2H),6.37(t,1H),4.47(t,2H),4.35(s,4H).

[0512] Example 19-P1 and Example 19-P2:

[0513] first step:

[0514] Compound 8 (140 mg, synthetic reference compound 8) was prepared by chiral SFC to give compound 19-P1 (17 mg, yield: 12%, retention time: 1.634 minutes) and compound 19-P2 (14 mg, yield: 10%, retention time: 1.865 minutes).

[0515] SFC preparation method: 1. Instrument: Waters 150Prep SFC. Column: Chiral OX column. Mobile phase: A represents CO2; B represents 0.1% NH3·H2O in methanol. Slope: B represents 30%. Flow rate: 100 mL / min. Back pressure: 100 bar. Column temperature: Room temperature. Wavelength: 220 nm. Cycle time: 3.5 minutes. 2. Sample preparation: Dissolve the compound in acetonitrile and methanol at a concentration of 1.0 mg / mL. Injection: 1.0 mL per injection. After separation, the fractions were dried on a rotary evaporator in a 45°C water bath to obtain the product. The solvent was then dried in a lyophilizer at -80°C to yield compounds 19-P1 and 19-P2.

[0516] Compound 19-P1, LCMS m / z=506.2[M+H]+.

[0517] 1 H NMR(400MHZ,DMSO-d6)δ8.34(s,1H),7.95(dd,1H),7.83(d,1H),7.72(dd,1H),7.68(dd,1H),7.4 4(d,1H),6.36(tt,1H),5.23(d,2H),4.48(dt,3H),4.29(d,1H),4.26–4.19(m,1H),1.39(d,3H).

[0518] Compound 19-P2, LCMS m / z=506.2[M+H]+.

[0519] 1 H NMR(400MHZ,DMSO-d6)δ8.34(s,1H),7.95(dd,1H),7.83(d,1H),7.72(dd,1H),7.68(dd,1H),7.4 4(d,1H),6.36(tt,1H),5.23(d,2H),4.48(dt,3H),4.29(d,1H),4.27–4.18(m,1H),1.39(d,3H).

[0520] Example 20:

[0521] first step:

[0522] 2-Difluoromethanesulfonylpyridine (4.69 g, 24.29 mmol) and 15A (5.0 g, 26.99 mmol) were dissolved in dry DMF (50 mL). Potassium tert-butoxide (4.54 g, 40.48 mmol, dissolved in 15 mL DMF) was slowly added dropwise at -45°C. The mixture was allowed to react overnight at room temperature. TLC (petroleum ether:ethyl acetate = 5:1 (v / v)) confirmed the completion of the reaction. After completion, the reaction was quenched with saturated aqueous ammonium chloride (100 mL). 3M HCl (14 mL) was added and stirring was continued for 3 h. Ethyl acetate (200 mL) was then added and stirring continued for another hour. The mixture was separated, and the organic phase was washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to obtain compound 20B (1.5 g, 15% yield).

[0523] Step 2:

[0524] Compound 20B (0.35 g, 1.60 mmol) was dissolved in dichloromethane (12 mL) and trifluoroacetic acid (4 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain crude product 20C, which was directly used in the next step.

[0525] LCMS m / z=120.1[M+1] +

[0526] Step 3:

[0527] Compound 20C (0.2 g, 1.68 mmol) was dissolved in acetonitrile (5 mL). Triethylamine (0.51 g, 5.04 mmol) was slowly added dropwise under an ice bath. Intermediate 4 (0.61 g, 2.02 mmol) was then added and allowed to react overnight at room temperature. TLC (petroleum ether:ethyl acetate = 1:1 (v / v)) confirmed the completion of the reaction. After completion, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to afford compound 20D (260 mg, 52% yield).

[0528] Step 4:

[0529] Compound 20D (260 mg, 0.87 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain compound 20E (170 mg, yield: 98%).

[0530] Step 5:

[0531] Intermediate 2 (230 mg, 0.63 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), and cesium carbonate (0.62 g, 1.89 mmol) and compound 20E (160 mg, 0.82 mmol) were added sequentially. The mixture was reacted at 80°C for 16 h. TLC (petroleum ether:ethyl acetate = 1:2 (v / v)) confirmed the completion of the reaction. After completion, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1 (v / v)) to obtain compound 20 (120 mg, 35% yield).

[0532] LCMS m / z=542.1[M+1] +

[0533] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.91–7.84(m,1H),7.81(d,1H),7.72(dd,1H),7.55(dd,1 H),7.42(d,1H),6.52–6.20(m,1H),4.47(td,2H),3.96(s,2H),3.42(t,2H),2.62–2.54(m,2H).

[0534] Example 21

[0535] first step:

[0536] Methyltriphenylphosphine iodide (3.00 g, 7.39 mmol) and toluene (30 mL) were added to a single-necked flask and stirred at 0°C. A 1M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (7.4 mL, 7.39 mmol) was then slowly added dropwise. After the addition was complete, the mixture was stirred for 0.5 hours. Finally, 21A (1.00 g, 4.92 mmol) was added. After completion of the reaction, as monitored by LCMS, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to afford compound 21B (0.45 g, 45.0%).

[0537] LC-MS (ESI): m / z = 146.1 [M-55] + .

[0538] Step 2:

[0539] Dissolve 21B (0.45 g, 2.24 mmol) in dichloromethane (15 mL) and slowly add trifluoroacetic acid (5 mL) dropwise at 0°C. Allow to react at room temperature for 2 hours. After completion of the reaction, concentrate the reaction mixture to obtain crude product 21C, which was directly used in the next step.

[0540] LC-MS (ESI): m / z = 102.2 [M+H] + .

[0541] Step 3:

[0542] Crude product 21C and acetonitrile (15 mL) were added to a single-necked flask. Triethylamine (0.90 g, 8.96 mmol) was slowly added at 0°C, followed by intermediate 4 (0.81 g, 2.67 mmol). The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to afford crude product 21D (0.42 g, 67.0%).

[0543] LC-MS (ESI): m / z = 225.1 [M-55] + .

[0544] Step 4:

[0545] Dissolve 21D (0.42 g, 1.50 mmol) in dichloromethane (15 mL) and slowly add trifluoroacetic acid (5 mL) dropwise at 0°C. After addition, allow to react at room temperature for 2 hours. After completion of the reaction, concentrate the reaction mixture to obtain crude product 21E, which was directly used in the next step.

[0546] LC-MS (ESI): m / z = 181.2 [M+H] + .

[0547] Step 5:

[0548] The crude compound 21E from the previous step and cesium carbonate (1.46 g, 4.5 mmol) were added to N,N-dimethylformamide (15 mL), followed by intermediate 2 (0.65 g, 1.80 mmol). The mixture was stirred at 80°C overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 21 (30 mg, 3.8%).

[0549] 1H NMR((400MHz,DMSO-d6)δ10.45(s,1H),8.34(s,1H),7.90-7.85(m,1H),7.81(d,1H),7.70(dd,1H),7.53(dd,1H),7.42(d,1H),6.51-6. 22(m,1H),5.55-5.38(m,2H),4.52-4.43(m,2H),4.11-4.07(m,1H),3.95-3.92(m,1H),3.63-3.50(m,3H),LC-MS(ESI):m / z=524.1[M+H] + .

[0550] Example 22:

[0551] first step:

[0552] Compound 22A (1.50 g, 8.01 mmol) (synthesis reference patent WO2019 / 060611, A1 for compound 22A) was dissolved in N,N-dimethylformamide (30 mL). Cesium carbonate (5.22 g, 16.02 mmol) was slowly added in an ice-water bath. After stirring at room temperature for 30 min, a solution of 2,3,6-trifluorobenzonitrile (2.52 g, 16.02 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise in an ice-water bath. The mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL) and washed sequentially with water (50 mL × 1) and saturated brine (50 mL × 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain 22B (1.20 g, 46% yield).

[0553] LCMS m / z=325.00[M+H] + ;

[0554] Step 2:

[0555] Compound 7D (0.20 g, 1.23 mmol) and cesium carbonate (0.53 g, 1.62 mmol) were added to N,N-dimethylformamide (15 mL) and reacted at 50°C for 30 min. Compound 22B (0.25 g, 0.77 mmol) was then added and stirred at 80°C overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 22 (110 mg, 30% yield).

[0556] LCMS m / z=467.10[M+H] + ;

[0557] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.69(s,1H),8.02(d,1H),7.99-7.96(m,1H),7.94-7.88(m,1H),7.78( d,1H),7.64-7.57(m,1H),5.46-5.34(m,1H),4.74-4.63(m,2H),4.21(d,4H),4.20-4.10(m,2H),1.49(d,3H).

[0558] Example 23:

[0559] first step:

[0560] Compound 3D (0.15 g, 1.02 mmol) and cesium carbonate (0.44 g, 1.36 mmol) were added to N,N-dimethylformamide (15 mL) and reacted at 50°C for 30 min. Compound 2C (0.25 g, 0.68 mmol) was then added and stirred at 80°C overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 23 (90 mg, 27% yield).

[0561] LCMS m / z=497.30[M+H] + ;

[0562] 1 H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.74(s,1H),7.94-7.80(m,2H),7.60-7.51(m,1 H),7.31-7.21(m,1H),6.83(d,1H),5.09-5.04(m,2H),4.57-4.47(m,4H),3.72(s,8H).

[0563] Example 24:

[0564] first step:

[0565] 1-Fluoroethyltriphenylphosphonium tetrafluoroborate (10 g, 25.24 mmol) was dissolved in dry tetrahydrofuran (200 mL). Sodium bis(trimethylsilyl)amide (23 mL, 25.24 mmol, 2 M in THF) was slowly added dropwise at -78°C. After the addition, the mixture was allowed to react at -78°C for 1 h. A solution of compound 11A (4.32 g, 25.24 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise at -78°C. After the addition, the mixture was allowed to react at room temperature overnight. The reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 5:1 (v / v)). After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (800 mL × 2). The combined organic phases were washed with saturated brine (250 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 (v / v)) to obtain compound 24B (1.2 g, yield: 24%).

[0566] LCMS m / z=146.2[M+1-56] +

[0567] Step 2:

[0568] Compound 24B (1.2 g, 5.96 mmol) was dissolved in dichloromethane (25 mL) and trifluoroacetic acid (5 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain the trifluoroacetic acid salt of crude product 24C, which was directly used for the next reaction.

[0569] LCMS m / z=102.2[M+1] +

[0570] Step 3:

[0571] The trifluoroacetic acid salt of compound 24C (1283 mg, 5.96 mmol) was dissolved in acetonitrile (40 mL). Triethylamine (3.7 mL, 26.7 mmol) was slowly added dropwise under an ice bath. Intermediate 4 (2.42 g, 8.01 mmol) was then added and allowed to react overnight at room temperature. TLC (petroleum ether:ethyl acetate = 1:1 (v / v)) confirmed the reaction was complete. After completion, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product 24D, which was directly used in the next step.

[0572] LCMS m / z=225.2[M+1-56] +

[0573] Step 4:

[0574] Compound 24D (1.67 g, 5.96 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 (v / v)) to obtain compound 24E (800 mg, 74% yield).

[0575] LCMS m / z=181.2[M+1] +

[0576] Step 5:

[0577] Intermediate 2 (580 mg, 1.60 mmol) was dissolved in dry N,N-dimethylformamide (30 mL), and cesium carbonate (2.17 g, 6.66 mmol) and compound 24E (600 mg, 3.33 mmol) were added sequentially. The mixture was reacted at 80°C for 6 h. TLC (petroleum ether:ethyl acetate = 1:2 (v / v)) confirmed the completion of the reaction. After completion, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1 (v / v)) to obtain compound 24 (524 mg, 63% yield).

[0578] LCMS m / z=524.1[M+1] +

[0579] 1H NMR(400MHZ,DMSO-d6)δ10.57(s,1H),8.34(s,1H),7.91–7.83(m,1H),7.81(d,1H),7.72 (dd,1H),7.56(dd,1H),7.44(d,1H),6.36(tt,1H),4.55–4.41(m,6H),1.85–1.77(m,3H).

[0580] Example 25:

[0581] first step:

[0582] 25A (0.8 g, 2.71 mmol, synthesis reference WO2020185593A1) and methanol (10 mL) were added to a 50 mL single-necked flask. 1-(Trifluoromethyl)-1,2-benzidoxyl-3(1H)-one (1.03 g, 3.25 mmol) and ferrous chloride (68.70 mg, 0.54 mmol) were then added and allowed to react overnight at room temperature. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1, v / v) to afford 25B (420 mg, 65% yield).

[0583] LCMS m / z=182.1[M-55] + ;

[0584] 1 H NMR (400MHz, CDCl3) δ5.52(m,1H),4.62-4.59(m,2H),4.52-4.48(m,2H),1.39(s,9H).

[0585] Step 2:

[0586] Dissolve 25B (0.42 g, 1.77 mmol) in dichloromethane (9 mL) and slowly add trifluoroacetic acid (3 mL) dropwise at 0-5°C. Allow to react at room temperature for 2 hours. After completion of the reaction, concentrate the reaction mixture to obtain crude product 25C, which was directly used in the next step.

[0587] LCMS m / z=138.2[M+H] + ;

[0588] Step 3:

[0589] Crude product 25C and acetonitrile (10 mL) were added to a 50 mL single-necked flask. Triethylamine (716.43 mg, 7.08 mmol) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)yl)sulfonyl)amide (803 mg, 2.65 mmol) were slowly added at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 7 / 3, v / v) to afford 25D (400 mg, 71% yield).

[0590] LCMS m / z=261.0[M-55] + ;

[0591] Step 4:

[0592] In a 50 mL single-necked flask, 25D (400 mg, 1.26 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was slowly added dropwise at 0-5°C. The mixture was allowed to react 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 = 3 / 2) to afford 25E (170 mg, 62% yield).

[0593] LCMS m / z=217.1[M+H] + ;

[0594] Step 5:

[0595] In a 25 mL single-necked flask, 25E ​​(169 mg, 0.78 mmol) and cesium carbonate (678 mg, 2.08 mmol) were added to dry N,N-dimethylformamide (5 mL) and reacted at 50°C for 30 min. Intermediate 2 (190 mg, 0.52 mmol) was then added at 50°C and stirred at 80°C overnight. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with N,N-dimethylformamide (2 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to afford compound 25 (15 mg, 5%).

[0596] LCMS m / z=560.2[M+H] + ;

[0597] 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.34(s,1H),7.91–7.86(m,1H),7.82-7.81(d,1H),7.74-7.71(dd,1H),7.60- 7.56(dd,1H),7.45-7.44(d,1H),6.51-6.22(m,1H),6.12–6.06(m,1H),4.78(s,2H),4.68(s,2H),4.52-4.43(m,2H).

[0598] Example 26:

[0599] first step:

[0600] 26A (4.6 g, 26.87 mmol, synthesis method referenced in WO2013 / 59587A1) was dissolved in dry dichloromethane (200 mL). DAST (25.99 g, 161.22 mmol) was slowly added dropwise at 0°C. The reaction was allowed to react overnight at room temperature. TLC (petroleum ether:ethyl acetate = 5:1 (v / v)) confirmed the completion of the reaction. After completion, the reaction was quenched with saturated aqueous sodium bicarbonate (150 mL). The mixture was then separated, and the aqueous phase was extracted with dichloromethane (150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 (v / v)) to afford compound 26B (2.8 g, 52.8% yield).

[0601] LCMS m / z=164.1[M-56+1] +

[0602] Step 2:

[0603] Compound 26B (0.8 g, 4.39 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain crude product 26C, which was directly used in the next step.

[0604] LCMS m / z=120.1[M+1] +

[0605] Step 3:

[0606] Crude product 26C was dissolved in acetonitrile (20 mL) and triethylamine (1.52 g, 26.7 mmol) was slowly added dropwise under an ice bath. Intermediate 4 (1.67 g, 5.52 mmol) was then added and allowed to react overnight at room temperature. TLC (petroleum ether:ethyl acetate = 1:1 (v / v)) confirmed the reaction was complete. After completion, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to afford compound 26D (300 mg, 27.2% yield).

[0607] Step 4:

[0608] Compound 26D (300 mg, 1.23 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated to obtain compound 26E (200 mg, yield: 100%).

[0609] Step 5:

[0610] Intermediate 2 (290 mg, 0.81 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), and cesium carbonate (0.66 g, 2.02 mmol) and compound 26E (200 mg, 1.01 mmol) were added sequentially. The mixture was reacted at 80°C for 16 h. TLC (petroleum ether:ethyl acetate = 1:2 (v / v)) confirmed the completion of the reaction. After completion, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1 (v / v)) to obtain compound 26 (85 mg, 15.6% yield).

[0611] LCMS m / z=542.0[M+1] +

[0612] 1 H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.35(s,1H),7.93–7.77(m,2H),7.73(dd,1H),7 .57(dd,1H),7.45(d,1H),6.63–6.20(m,2H),5.78(d,1H),4.67(d,4H),4.48(td,2H).

[0613] Example 27:

[0614] first step:

[0615] Compound 7D (0.30 g, 1.85 mmol) and cesium carbonate (0.78 g, 2.41 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Compound 27A (0.3 g, 0.96 mmol) (synthesis reference patent WO2021116050A1) was then added and stirred at 80°C overnight. After completion of the reaction, the mixture was filtered and the filtrate was concentrated. The resulting residue was purified by preparative liquid phase separation to afford compound 27 (280 mg, 64% yield).

[0616] LCMS m / z=456.10[M+H] + ;

[0617] 1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.36(s,1H),7.89-7.84(m,1H),7.77(d,1H),7.68-7.65(m,1H), 7.58-7.53(m,1H),7.41(d,1H),5.46-5.35(m,1H),4.53-4.42(m,4H),3.48(s,3H),1.51-1.45(m,3H).

[0618] Example 28:

[0619] first step:

[0620] In a 50 mL single-necked flask, 28A (10.0 g, 54.91 mmol) was added to 2B (30 g, 274 mmol) and reacted at 155°C for 12 hr. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (5 mL x 2) and then concentrated to afford 28B (4.0 g, 29% yield).

[0621] LCMS m / z=256.0[M+H] + ;

[0622] Step 2:

[0623] In a single-necked flask, compound 28B (4.0 g, 15.68 mmol), palladium on carbon (0.4 g), and methanol (200 mL) were added sequentially. The atmosphere was replaced with hydrogen three times, and the reaction was stirred at room temperature for 2 hours. Filtered through a pad of Celite, the solid was washed with methanol, and the filtrate was concentrated under reduced pressure to provide compound 28C (3.5 g, 99% yield), which was used directly in the next reaction without further purification.

[0624] LC-MS (ESI): m / z = 226.1 [M+H] + .

[0625] Step 3:

[0626] 28C (3.5 g, 15.5 mmol) was dissolved in acetonitrile (50 mL), and NCS (2.49 g, 18.7 mmol) was added at room temperature. The mixture was allowed to react overnight at 85°C. TLC (petroleum ether:ethyl acetate = 1:1 (v / v)) confirmed the completion of the reaction. After completion, the reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 2:1 (v / v)) to afford compound 28D (3.8 g, 94.2.2% yield).

[0627] LC-MS (ESI): m / z = 260.1 [M+H]+ .

[0628] Step 4:

[0629] A flask was charged with 28D (2.5 g, 9.63 mmol), 28E (3.58 g, 9.63 mmol), cesium carbonate (9.41 g, 28.89 mmol), and 1,4-dioxane (40 ml), followed by 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.11 g, 1.93 mmol) and tris(dibenzylideneindeneacetone)dipalladium (0.88 g, 0.96 mmol). The mixture was then reacted at 100°C under nitrogen for 16 hours. The mixture was cooled, added with water, extracted with ethyl acetate, washed, dried, concentrated, and purified by column chromatography to afford compound 28F (1.3 g, 26.8%).

[0630] LC-MS (ESI): m / z=503.0[M+H]+.

[0631] Step 5:

[0632] 28F (1.3 g, 2.58 mmol) was dissolved in a 1,4-dioxane solution of hydrochloric acid (20 mL, 4 mmol / L) and reacted at room temperature for 5 hours. After the reaction, the reaction solution was dried to obtain the product 28G (1.0 g, 81.3%), which was directly used for the next step.

[0633] LCMS m / z=403.0[M+H]+.

[0634] Step 6:

[0635] 28G (0.4 g, 0.99 mmol) was dissolved in DCM (15 mL), and triethylamine (0.3 g, 2.97 mmol) and 28H (0.18 g, 0.99 mmol) were added sequentially. The mixture was reacted at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated to obtain crude 28I, which was used in the next step.

[0636] Step 7:

[0637] The crude product 28I was dissolved in acetonitrile (15 mL), and 3-methyleneazetidine hydrochloride (0.19 g, 1.82 mmol) and triethylamine (280 mg, 2.73 mmol) were added sequentially. The mixture was reacted at 80°C for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 50:1 (v / v)) to obtain compound 28 (28 mg, two-step yield: 5.9%).

[0638] LCMS m / z=534.1[M+1] +

[0639] 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.82(s,1H),7.55-7.35(m,3H),6.79(d,1H),6.38(t,1H),5.04(s,2H),4.46(d,6H).

[0640] Biological testing

[0641] 1.BRAF V600E Enzyme activity test

[0642] BRAF V600E (ABCAM, ab204154), MEK1 K97R The protein (USBio, M2865-06J) was diluted to an appropriate multiple using 1×Assay buffer (pH=7.4 Tris-HCl buffer, supplemented with 10 mM MgCl2) to make BRAF V600E The final concentration was 10 ng / μL, substrate MEK1 K97R The final concentration is 1 μM. 1 μL BRAF V600E , 1 μL of compound serial dilution solution (final concentration 2 μM, 5-fold dilution, 8 concentrations), 6 μL of Assay buffer to a 20 μL volume 384-well reaction plate, pre-incubated in a constant temperature incubator at 37°C for 30 minutes. Then add 1 μL of 200 μM ATP and 1 μM MEK1 K97R Add the sample to the reaction well corresponding to the compound incubation, shake and mix, and pre-incubate in a constant temperature incubator at 37°C for 60 minutes for enzymatic reaction. After the reaction is completed, pipette 5 μL of the above reaction product into another 384-well plate and add 5 μL of the prepared ADP-Glo TM Reagent (Promega, V9101) was pipetted and mixed, and the mixture was placed at room temperature for 40 minutes. 10 μL Kinase Detection Reagent was added to the 384-well plate and incubated at room temperature for 40 minutes. Finally, the Luminescence module was selected to detect the fluorescence of each well using a microplate reader (BMG LRBTECH) (Gain value was fixed at 3600). The LUM fluorescence value was calculated by the formula Calculate the effect of compounds on BRAF V600E The inhibition rate of the sample was calculated using the Graphpad software log (inhibitor) vs. response--Variable slope (four parameters) equation for fitting analysis. 50 Numeric value.

[0643] The compounds of the present invention, such as the compounds in the examples, have very good enzyme activity, IC 50 ≤100nM. Some compounds have an inhibitory effect on BRAF V600E The inhibitory activities are shown in Table 1.

[0644] Table 1 Compounds for BRAF V600E Inhibitory activity

[0645] A stands for IC 50 ≤10nM, B means 10nM<IC 50 ≤30nM, C means 30nM<IC 50 ≤100nM.

[0646] 2.A375 cell proliferation inhibition test

[0647] A375 cells (ATCC, CRL-1619) were cultured in DMEM complete medium (+10% FBS) in a CO2 incubator at 37°C for 48 h. The cells were trypsinized and counted, and then the density was adjusted to 1.67 × 10 4 Cells / mL. 90 μL (1500 cells) 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 (final concentration 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 well, the plate was placed in a CO2 incubator at 37°C for 72 hours. After the incubation, the cells were removed. The kit detection solution (Vazyme, DD1101-03) was returned to room temperature, 100 μL of CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a film, and the plate was placed on an oscillator for 15 minutes (the whole process should be kept away from light). The fluorescence signal value LUM of each well was detected using the Luminescence module of the microplate reader (BMG LRBTECH). Calculate the inhibition rate of the compound. Use Graphpad software to fit the log (inhibitor) vs. response--Variable slope (four parameters) equation to calculate the IC of the sample. 50 The vertical axis is the percentage of inhibition rate, and the horizontal axis is the logarithm of the sample concentration (Log 10 ).

[0648] The compounds of the present invention, such as the compounds in the examples, have very good cell activity, IC 50 ≤100nM. The inhibitory activities of some compounds on A357 cells are shown in Table 2.

[0649] Table 2 Inhibitory activity of compounds on A375 cells

[0650] A stands for IC 50 ≤10nM, B means 10nM<IC 50 ≤50nM, C means 50nM<IC 50 ≤100nM.

[0651] Conclusion: The compounds of the present invention, such as the compounds in the examples, showed high inhibitory activity at the cellular level. For example, the IC50 of compound 3 was 0.14 nM, the IC50 of compound 7 was 0.66 nM, the IC50 of compound 14 was 1.44 nM, and the IC50 of compound 24 was 2.16 nM.

[0652] 3: Pharmacokinetic test in mice

[0653] 3.1 Experimental Animals: Male ICR mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0654] 3.2 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 before administration and fed 4 hours after administration.

[0655] Table 3.1 Dosage Information Note: Reference compound 1 is compound Example 1 in document WO2021116055A1;

[0656] Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0657] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 7, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0658] Table 3.2 Pharmacokinetic parameters of test compounds in mouse plasma Note: Reference compound 1 is compound Example 1 in document WO2021116055A1; -: not applicable.

[0659] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in mice.

[0660] 4: Beagle dog pharmacokinetic test

[0661] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0662] Experimental Methods: On the day of the experiment, beagle dogs were randomly divided into groups based on body weight. Food and water were withheld for 12-14 hours prior to dosing. Food was allowed 4 hours after dosing. Dosing was performed according to Table 4.

[0663] Test compounds: Example compounds and control compounds.

[0664] Table 4. Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0665] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose solution;)

[0666] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. For both the intravenous and oral administration groups, blood was collected at the following time points: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0667] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.

[0668] 5: Rat pharmacokinetic test

[0669] 5.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0670] 5.2 Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0671] 5.3 Test compounds: Example compounds and control compounds.

[0672] Table 5.1 Dosage Information

[0673] Dosing vehicle: 0.5% MC

[0674] Before and after drug administration, 0.1 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from the venous group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24 hours, and 48 hours; from the gavage group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24 hours, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0675] Table 5.2 Pharmacokinetic parameters of test compounds in rat plasma Note: Reference compound 1 is compound Example 1 in document WO2021116055A1; -: not applicable.

[0676] Conclusion: The compounds of the present invention, such as the compounds in the Examples, have good pharmacokinetic characteristics in rats.

[0677] 6. Liver microsome stability test

[0678] In this study, liver microsomes from five species, including humans, monkeys, dogs, rats and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0679] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and hepatic intrinsic clearance CL int(Liver) .

[0680] Table 6 Results of test compounds in monkey liver microsome model

[0681] Conclusion: The compounds of the present invention, such as the example compounds, have good stability characteristics in monkey liver microsomes.

[0682] 7. Monkey Pharmacokinetic Test

[0683] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0684] Experimental method: On the day of the experiment, monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0685] Table 7. Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC; *Dosage is based on free base.

[0686] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0687] Conclusion: The compounds of the present invention, such as the compounds in the Examples, have good pharmacokinetic characteristics in cynomolgus monkeys.

Claims

1. A compound of formula I, a stereoisomer, a deuterated substance or a pharmaceutically acceptable salt thereof, in, Cy is selected from 8-15 membered heterocyclic groups, wherein the heterocyclic groups are optionally substituted by 1-5 groups selected from halogen, CN, OH, =O, NH2, -SF5, -COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-4 Alkyl-C 3-6 substituted by a cycloalkyl, a 4-12 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, a 6-9 membered aryl, or a 5-9 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted by 1-3 halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl radical substitution; Y is C 1-2 Alkyl, O, C=O or NR y ; R y H or C 1-4 alkyl; M is C 1-2 Alkyl, O or NR m ; W is a bond, O or NR w ; R m and R w are independently H or C 1-4 alkyl; X4 is selected from C(O), S(O) or S(O)2; X5 is selected from N or CR x5 ; X6 is selected from N or CR x6 ; X7 is selected from N or CR x7 ; X8 is selected from N or CR x8 ; R x5 , R x6 , R x7 , R x8 are independently selected from H, halogen, CN, 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, C 3-6 Cycloalkyl, 5-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and 6-9 membered aryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic ring or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2 and CN radical substitution; R is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O, the cycloalkyl, heterocyclic group is optionally substituted by 1-3 halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 Alkyl radicals are substituted.

2. The compound according to claim 1, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, wherein: Cy is selected from P1, P2, P3 or P4; Ring A is a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocycloalkyl or heteroaryl is optionally substituted by 1-3 heteroatoms 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 radical substitution; Ring B 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 1-3 heteroatoms selected from =O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, O or -C 1-4 Alkyl-C 3-6 The cycloalkyl group is substituted, wherein the heterocyclic group, cycloalkyl group is optionally further substituted The group substitution; Ring D is a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic group is optionally substituted by 1-3 heteroatoms 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 radical substitution; Each n is independently selected from 0, 1, 2, 3, 4 or 5; Each X1 is independently selected from N, NR 11 , CR 11 or CR 11 R 12 ; Each X2 is independently selected from N, C or CR 21 ; X3 Selected from NR 31 , O or CR 31 R 32 ; R1, R2, R3 and R4 are each independently selected from H, halogen, OH, =O, -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, C 2-4 Alkynyl, 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, the alkyl, heterocycloalkyl, aryl are optionally substituted by 1-3 halogen, OH, NH2, CN and C 1-4 Alkyl radical substitution; R 11 , R 12 , R 21 , R 31 , R 32 are independently selected from H, halogen, CN, 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, C 3-6 Cycloalkyl, 5-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and 6-9 membered aryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic ring or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2 and CN radical substitution; Alternatively, R 11 With R 31 Together with the atoms to which it is connected, it forms C 3-6 A 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 by 1-3 heteroatoms selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH, NH2 and CN radical substitution; R is selected from C 5-10 Bicyclic cycloalkyl, C 3-6 monocyclic cycloalkyl, 5-10 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-6 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, the bicyclic cycloalkyl, bicyclic heterocycloalkyl are optionally substituted by 1-3 halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl and monocyclic heterocycloalkyl groups are optionally further substituted by 1-3 groups selected from halogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl radical substitution; The condition is that the monocyclic cycloalkyl and monocyclic heterocycloalkyl are at least one selected from The group is substituted.

3. The compound according to claim 1 or 2, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, in, Ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl or heteroaryl group is optionally substituted by 1-2 heteroatoms 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 radical substitution; Ring B is a 6-membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1-2 heteroatoms selected from =O, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-2 Alkyl-C 3-6 Cycloalkyl or a 5-6 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, wherein the heterocyclic group or cycloalkyl group is optionally further substituted by The group substitution; Ring D is a 5-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic group is optionally substituted by 1-2 heteroatoms selected from halogen, CN, C 1-4 Alkyl and halogenated C 1-4 Alkyl radical substitution; R1, R2, R3 and R4 are each independently selected from H, halogen, =O, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 alkyl, 5-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 6-9 membered aryl, wherein the alkyl, heterocycloalkyl, aryl are optionally substituted by 1-3 halogen, CN and C 1-4 Alkyl radicals are substituted.

4. The compound according to claim 1 or 2, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, in, Each n is independently selected from 0, 1, 2 or 3; Each X1 is independently selected from N or CR 11 ; Each X2 is independently selected from N, C or CR 21 ; X3 Selected from NR 31 or O; X4 is selected from S(O)2; X5 Selected from CR x5 ; X6 from CR x6 ; X7 from CR x7 ; X8 from CR x8 ; R 11 , R 21 , R 31 , R x5 , R x6 , R x7 , R x8 are independently selected from H, halogen, CN, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O and 6 membered aryl, wherein the alkyl, alkoxy, heterocyclic ring or aryl is optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl radicals are substituted.

5. The compound according to claim 1, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, in, Y is O, C=O or NH; M is NR m ; W is a key; R m is H; R is selected from 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 4-5 membered monocyclic heterocycloalkyl containing 1-2 heteroatoms selected from N, S, O, C 6-10 Spirocyclic cycloalkyl, C 4-5 The monocyclic cycloalkyl, the spirocyclic heterocycloalkyl, the spirocyclic cycloalkyl is optionally substituted by 1-3 selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic heterocyclic alkyl and monocyclic cycloalkyl groups are optionally further substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 group substitution; The condition is that the monocyclic heterocycloalkyl and monocyclic cycloalkyl are at least one selected from The group is substituted.

6. The compound according to claim 1, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, in, Y is O or C=O; M is NR m ; W is NR w ; R m is H; R w is H or CH3; R is selected from C 6-10 Spirocyclic cycloalkyl, C 4-5 The spirocyclic cycloalkyl is optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl, C 1- 4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 and halogenated C 1-4 The monocyclic cycloalkyl group is optionally further substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 group substitution; Provided that: the monocyclic cycloalkyl group is at least one selected from The group is substituted.

7. The compound according to claim 1, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, in, R is selected from the following groups optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: Alternatively, R is selected from the group consisting of 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 substituted with the following groups: and at least one selected The group substitution; Alternatively, R is selected from the group consisting of 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 substituted with the following groups: and at least one selected The group is substituted.

8. The compound according to claim 2, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, wherein P1 is selected from the following groups optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: P2 is selected from a 6-membered heterocycloalkyl group optionally substituted by 1-3 groups selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH3, cyclopropyl, a 6-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, O, Substituted with the following groups: P3 is selected from the following groups optionally substituted by 1-3 groups selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3: P4 is selected from the group consisting of 1-3 selected from F, Cl, Br, =O, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, Substituted with the following groups:

9. The compound according to 1, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, wherein Y is O or NH; M is NH; W is a key; X4 is selected from S(O)2; X5 Selected from CR x5 ; X6 from CR x6 ; X7 from CR x7 ; X8 from CR x8 ; R x5 , R x6 , R x7 , R x8 Each is independently selected from H, F, Cl, CN, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3; Cy is selected from the group consisting of 1-3 groups selected from F, Cl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -OCH3, cyclopropyl, Substituted with the following groups: R is selected from or optionally 1-2 selected from F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 substituted with the following groups: and At least one selected The group is substituted.

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

11. A pharmaceutical composition or pharmaceutical preparation comprising the compound according to any one of claims 1 to 10, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

12. The pharmaceutical composition or pharmaceutical preparation according to claim 11, comprising 1-1500 mg of the compound according to any one of claims 1-10, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

13. Use of the compound according to any one of claims 1 to 10, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, or the pharmaceutical composition or pharmaceutical preparation according to claim 11 in the preparation of a medicament for treating / preventing BRAF-mediated diseases.

14. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 10, a stereoisomer, a deuterated substance or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is preferably 1 to 1500 mg, and the disease is preferably a tumor, more preferably brain tumor, melanoma, colorectal cancer, non-small cell lung cancer, glioma, papillary thyroid carcinoma, skin cancer.

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