Pharmaceutical composition comprising braf inhibitor and use of pharmaceutical composition in medicine
Patent Information
- Application Number
- AU2025210152
- Authority / Receiving Office
- AU · AU
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-01-17
- Filing Date
- 2025-01-17
- Publication Date
- 2026-08-13
AI Technical Summary
Existing BRAF inhibitors are difficult to penetrate the blood-brain barrier and cannot effectively treat brain tumors with BRAF mutations. Common kinase inhibitors such as verofibir and darafinib are restricted in the brain, resulting in brain metastasis ineffective.
A pharmaceutical composition containing a BRAF inhibitor is developed, combined with a pharmaceutical excipient, to optimize its oral performance and pharmacokinetics, improve bioavailability, reduce inhibitory effects on CYP enzymes, and enhance penetration to the brain.
The effective distribution of BRAF inhibitors in the brain is achieved, the efficacy of treating tumors with BRAF mutations is improved, and the toxic side effects is reduced, and it has good safety and selectivity.
Abstract
Description
A pharmaceutical composition containing a BRAF inhibitor and its medical application Technical Field
[0001] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition or pharmaceutical preparation, comprising a therapeutically effective amount of an active ingredient M and a pharmaceutical excipient, wherein the active ingredient M is selected from a compound of general formula (I) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and the pharmaceutical composition or pharmaceutical preparation comprises 1-1000 mg of the active ingredient M. The present invention also relates to the use of the pharmaceutical composition or pharmaceutical preparation in the preparation of a drug for treating cancer. Background Art
[0002] 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.
[0003] 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).
[0004] 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 cascade 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.
[0005] In addition, BRAF has been identified as a potential target for the treatment of primary brain tumors. The prevalence of the BRAF V600E mutation in primary brain tumors has been reported by Schindler et al. in their analysis of 1,320 central nervous system (CNS) tumors and Behling et al. in their analysis of 969 CNS tumors in pediatric and adult populations. These studies, combined with other studies, have reported the presence of the BRAF V600E mutation in various cancers, including papillary craniopharyngioma, pleomorphic xanthomatous astrocytoma (PXA), ganglioglioma, astroblastoma, and others.
[0006] 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 treatments using 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; whereas vemurafenib was reported to have an MDR1 efflux ratio of 83, a BCRP efflux ratio of 495, and a total brain to plasma ratio of 0.004.
[0007] 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
[0008] The present invention provides a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of an active ingredient M and a pharmaceutical excipient, wherein the active ingredient M is selected from a compound of formula (I) or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and wherein the pharmaceutical composition or pharmaceutical preparation has a dosage of 1-1000 mg. The present invention also relates to the use of the pharmaceutical composition or pharmaceutical preparation in the preparation of a drug for treating cancer.
[0009] The pharmaceutical composition or pharmaceutical preparation of the present invention has the advantages of good oral performance, good efficacy, low toxicity and side effects, good safety, high selectivity, good pharmacokinetics, high bioavailability, and no inhibition on CYP enzymes.
[0010] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, comprising a therapeutically effective amount of an active ingredient M and a pharmaceutical excipient. The pharmaceutical composition may be in the form of a unit preparation.
[0011] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises an active ingredient M and a pharmaceutical excipient, wherein the active ingredient M is selected from the compounds of general formula I and II or stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof.
[0012] wherein Cy is selected from P1, P2, P3, P4, P5, P6, P7 or P8;
[0013] Ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1-2 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, the alkyl group is substituted by a 5-membered heteroaryl group. In some embodiments, the heteroaryl group is selected from pyrazolyl, oxazolyl, imidazolyl, triazole, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyridinyl, pyrimidinyl, etc., and the heteroaryl group is optionally substituted by 1-2 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 Ring B is a 5-membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic ring is optionally substituted by 1-3 heteroatoms selected from =O, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, OH and halogenated C 1-4 Alkoxy group substitution;
[0014] # indicates that a point is selected to connect with Y;
[0015] n is selected from 0 or 1;
[0016] Each X1 is independently N or C; in some embodiments, each X1 is independently C;
[0017] X2 is N or CR3; in some embodiments, X2 is N; in some embodiments, X2 is CR3;
[0018] X3 is N or CR 31 ; In some embodiments, X3 is N or CH;
[0019] X4 is N or CR 32 ;; In some embodiments, X4 is N or CH;
[0020] X5 is N or CR 33 ; In some embodiments, X5 is N or CH;
[0021] X6 is C(O), S(O) or S(O)2; in some embodiments, X6 is C(O) or S(O)2; in some embodiments, X6 is S(O)2;
[0022] X7 is CR7 or N; in some embodiments, X7 is N; in some embodiments, X7 is CH;
[0023] R1, R2 and R4 are independently H, halogen, OH, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl; the -NHC 1-4 Alkyl includes -NH methyl, -NH ethyl, -NH isopropyl, -NH propyl, -NH butyl, the -N(C 1-4 Alkyl) 2 includes dimethylamino, diethylamino, etc.;
[0024] R3, R 31 、R 32 、R 33 are independently H, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, CN or C 3-6 Cycloalkyl, in some embodiments, R3, R 31 、R 32 、R 33 are independently H, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2 or CN; in some embodiments, R3 is C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2 or CN; in some embodiments, R3 is C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 In some embodiments, R3 is H, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1- 4 Alkoxy, halogenated C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2 or CN;
[0025] or R 31 With R 32 , or R 32 With R33 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 groups are substituted; in some embodiments, optionally substituted with 1-3 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy and CN; in some embodiments, R 31 With R 32 , or R 32 With R 33 and its connected atoms together form C 3-6 Cycloalkyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, or forming a 5-6 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, such as azetidinyl, oxetinyl, azocyclopentenyl, oxetinyl, azocyclohexenyl, oxetinyl, the cycloalkyl and heterocycloalkyl are optionally substituted by 1-3 halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy and CN group substitution;
[0026] R5 is C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyloxy, the cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the heterocycloalkyl includes but is not limited to aziridine, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, oxirane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, etc., and is optionally substituted by 1-3 halogen, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, CN, C 1-4 In some embodiments, R5 is C 1-4 Alkyl, halogenated C 1-4 Alkyl, C3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3-6 Cycloalkyloxy, and optionally 1-3 selected from halogen, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, CN and C 1-4 In some embodiments, R5 is C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 3- 6-cycloalkyloxy, and optionally 1-3 selected from halogen, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2, CN and C 1- 4-alkyl; in some embodiments, optionally substituted with 1-3 groups selected from halogen, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkyl, CN and C 1-4 In some embodiments, R5 is substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, substituted or unsubstituted C 3-6 Cycloalkyloxy, substituted or unsubstituted C 1-4 Alkoxy or substituted or unsubstituted halogenated C 1-4 Alkoxy, substituents are as described above; in some embodiments, R5 is C 1-2 Alkyl, CN substituted C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 3-4 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy or C 3-4 Cycloalkyloxy; in some embodiments, R5 is selected from C 1-2 Alkyl, CN substituted C 1-2Alkyl, halogenated C 1-2 Alkyl or C 1-2 Alkoxy; in some embodiments, R5 is selected from -CH2-CN, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2F, -CHF2, -CF3;
[0027] R6 is H, halogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; in some embodiments, R6 is H;
[0028] Or R5 and R6 and their connecting atoms together form a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O, and the heterocyclic ring is optionally substituted by 1-3 heteroatoms selected from halogen, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2, CN and C 1-4 The heterocyclic ring includes heteroaryl and heterocycloalkyl; in some embodiments, a 5-membered heterocyclic ring is formed; in some embodiments, a 5-membered heterocycloalkyl is formed, and is optionally substituted by 1-3 groups selected from halogen, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2, CN and C 1-4 Alkyl radical substitution;
[0029] R7, R8, and R9 are independently H, halogen, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, halo C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Alkoxy; in some embodiments, R7, R8, R9 are independently H, halogen, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-4 Alkyl, C 1- 4-Alkoxy or halogenated C 1-4 Alkoxy; in some embodiments, R7 is H or halogen; in some embodiments, R8 is halogen, OH, NH2, -NHC 1-4 Alkyl, -N(C 1-4 Alkyl)2, CN, C 1-4 Alkoxy or halogenated C 1-4 Alkoxy; in some embodiments, R8 is halogen, -NHC1-4 Alkyl, -N(C 1-4 Alkyl)2, CN, C 1-4 Alkoxy or halogenated C 1-4 Alkoxy; in some embodiments, R9 is H or halogen;
[0030] Y is C 1-2 Alkylene, O or NR y ; In some embodiments, Y is O; In some embodiments, Y is NH; In some embodiments, Y is methylene or ethylene;
[0031] R y H or C 1-4 Alkyl; in some embodiments, R y is H; in some embodiments, R y is methyl, ethyl, propyl or isopropyl, etc.;
[0032] M is C 1-2 Alkylene, O or NR m ; In some embodiments, M is NH; In some embodiments, M is methylimino, ethylimino, propylimino, or isopropylimino;
[0033] W is a bond, O or NR w ; In some embodiments, W is a bond, O, NH or NC 1-4 alkyl;
[0034] R m and R w are independently H or C 1-4 Alkyl; in some embodiments, R m and R w are independently H, methyl, ethyl, propyl or isopropyl;
[0035] R is selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O or -OC 3-6 Cycloalkyl, the alkyl, cycloalkyl and heterocycle are 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 In some embodiments, R is selected from C 1-4 Alkyl, C 3-8Cycloalkyl or 4-10 membered heterocycle containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl and heterocycle are 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 In some embodiments, R is selected from C 3-8 Cycloalkyl or a 4-10 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and optionally 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 In some embodiments, R is C 3-4 cycloalkyl or 4-membered monocyclic heterocycloalkyl, 6-8-membered monocyclic heterocycloalkyl, 5-6-membered monocyclic heteroaryl, 5-10-membered heterocycloalkyl, 5-10-membered bridged heterocycloalkyl or 6-10-membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and optionally substituted by 1-3 halogen, C 1-4 Alkyl, 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 C 1-4 Alkyl, C 3-8 Cycloalkyl or 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, wherein the alkyl, cycloalkyl and 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 In some embodiments, R is selected from C 1-4 Alkyl, C 3-8 Cycloalkyl or 4-7 membered monocyclic heterocycloalkyl, 5-10 membered heterocycloalkyl, 5-10 membered bridged heterocycloalkyl or 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and optionally substituted by 1-3 halogen, C 1-4 Alkyl, C 1-4Alkoxy, 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 a saturated 4-7 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, a saturated 5-10 membered heterocycloalkyl, a saturated 5-10 membered heterocycloalkyl bridged ring, or a saturated 6-10 membered spirocyclic heterocycloalkyl, and 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 C 3-8 Cycloalkyl, saturated 4-7 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, 5-10 membered heterocycloheterocycloalkyl, 5-10 membered bridged heterocycloalkyl or 6-10 membered spirocyclic heterocycloalkyl, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc., the monocyclic heterocycloalkyl is selected from aziridine, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, oxirane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, etc., and heterocycloheterocycloalkyl is selected from etc., the bridged heterocycloalkyl group is selected from etc., spirocyclic heterocycloalkyl is selected from:
[0036] The above groups are 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 Alkyl radical substitution;
[0037] When Cy is P2, R is a 4-10 membered saturated heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, and 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 radical substitution;
[0038] The pharmaceutical composition or pharmaceutical preparation contains 1-1000 mg of active ingredient M, and the excipients contain one or more of a filler, a binder, a glidant, a lubricant, and a disintegrant;
[0039] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 5-800 mg of active ingredient M;
[0040] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 5-600 mg of active ingredient M;
[0041] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 5-400 mg of active ingredient M;
[0042] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 20-800 mg of active ingredient M;
[0043] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 20-600 mg of active ingredient M;
[0044] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 20-400 mg of active ingredient M;
[0045] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 5 mg of active ingredient M;
[0046] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 10 mg of active ingredient M;
[0047] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 20 mg of active ingredient M;
[0048] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 50 mg of active ingredient M;
[0049] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 60 mg of active ingredient M;
[0050] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 70 mg of active ingredient M;
[0051] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 80 mg of active ingredient M;
[0052] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 90 mg of active ingredient M;
[0053] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 100 mg of active ingredient M;
[0054] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 150 mg of active ingredient M;
[0055] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 200 mg of active ingredient M;
[0056] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 400 mg of active ingredient M;
[0057] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 600 mg of active ingredient M;
[0058] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 800 mg of active ingredient M;
[0059] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present invention comprises 1000 mg of active ingredient M;
[0060] In some embodiments, R6 and R9 are H; Y is O, M is NH, X2 is CR3, X3 is CR3, and X4 is CR 32 , X5 is CH, X6 is SO2, X7 is CH,
[0061] R3 is C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -NHC 1- 2-alkyl, -N(C 1-2 alkyl)2 or CN,
[0062] R 31 、R 32 are independently H, F, Cl, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy, -NHC 1-2 Alkyl, -N(C 1-2 alkyl) 2、 CN or C 3-6 Cycloalkyl,
[0063] R5 is C 1-2Alkyl, CN or =O substituted C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 3-4 Cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, O, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy or C 3-4 Cycloalkyloxy,
[0064] R8 is selected from H, F, Cl, CN, C 1-2 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo C 1-2 Alkyl, C 1-2 Alkoxy or halogenated C 1-2 Alkoxy,
[0065] R is a 4-5 membered monocyclic heterocycloalkyl group, a 6-8 membered monocyclic heterocycloalkyl group, a 5-6 membered monocyclic heteroaryl group, a 5-10 membered cyclic heterocycloalkyl group, a 5-10 membered bridged heterocycloalkyl group, a 6-10 membered spirocyclic heterocycloalkyl group or -OC 3-6 Cycloalkyl, the 4-membered monocyclic heterocycloalkyl is 1-3 selected from F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy, OH, NH2, -NHC 1-2 Alkyl, -N(C 1-2 Alkyl)2 and halogenated C 1-2 The alkyl group is substituted, and the 6-8 membered monocyclic heterocycloalkyl, 5-6 membered monocyclic heteroaryl, 5-10 membered heterocyclic heterocycloalkyl, 5-10 membered bridged heterocycloalkyl, 6-10 membered spiro heterocycloalkyl or C 3-6 Cycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, C 1-2 Alkyl, C 1-2 Alkoxy, OH, NH2, -NHC 1-2 Alkyl, -N(C 1-2 Alkyl)2 and halogenated C 1-2 Alkyl radical substitution;
[0066] In some embodiments, R3 is CN,
[0067] R 31 、R 32 Each independently is H, F, Cl or C 3-6 Cycloalkyl,
[0068] R5 is selected from C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 1-2 Alkoxy, or C substituted by CN or =O 1-2 alkyl,
[0069] R8 is H,
[0070] R is a 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, a 4-5 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, or -OC 3-6 Cycloalkyl, the 6-10 membered spirocyclic heterocycloalkyl, 4-5 membered monocyclic heterocycloalkyl, C 3-6 Cycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, C 1-2 Alkyl or C 1-2 Alkoxy group substitution;
[0071] In some embodiments, R3 is CN,
[0072] R 31 、R 32 are each independently H, F, Cl, cyclopropane, cyclobutane, cyclopentane or cyclohexane,
[0073] R5 is selected from -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2Cl, -C H2CHCl2, -CH2CCl3, -CHClCH2Cl, -CHClCHCl2, -CHClCCl3, -CCl2CH2Cl, -CCl2CHCl2, -CCl2CCl3, -OCH3, -OCH2CH3, -CH2CN, -CH2CH2CN, -CH(CN)CH3, -COCH3, -COCH2CN, R8 is H,
[0074] R is a 6-10 membered spirocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, a 4-5 membered monocyclic heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, or -OC 3-6 Cycloalkyl, the 6-10 membered spirocyclic heterocycloalkyl, 4-5 membered monocyclic heterocycloalkyl, C 3-6 Cycloalkyl is optionally substituted by 1-3 groups selected from F, Cl, C 1-2 Alkyl or C 1-2 Alkoxy groups are substituted.
[0075] 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,
[0076] Table 1:
[0077] As a specific technical solution of the present invention, the compound of the present invention, its stereoisomer, deuterated substance or pharmaceutically acceptable salt, the compound is selected from one of the structures in Table 2,
[0078] Table 2:
[0079] In some embodiments, the active ingredient M is selected from the following structures:
[0080] The pharmaceutical composition or pharmaceutical preparation according to any one of the preceding embodiments comprises the active ingredient M and a pharmaceutically acceptable excipient, wherein the content of the active ingredient M is 0.5%-99%; in some embodiments, 1%-90%; in some embodiments, 1%-80%; in some embodiments, 1%-70%; in some embodiments, 1%-60%; in some embodiments, 1%-50%; in some embodiments, 1%-40%; in some embodiments, 1%-30%; in some embodiments, 1%-20%; in some embodiments, 1%-10%; in some embodiments, 5%-90%; in some embodiments, 5%-80%; in some embodiments, 5%-70%; in some embodiments, 5 %-60%; in some embodiments, 5%-45%; in some embodiments, 5%-40%; in some embodiments, 5%-30%; in some embodiments, 5%-20%; in some embodiments, 5%-10%; in some embodiments, 10%-90%; in some embodiments, 10%-80%; in some embodiments, 10%-70%; in some embodiments, 10%-60%; in some embodiments, 10%-50%; in some embodiments, 10%-45%; in some embodiments, 10%-40%; in some embodiments, 10%-30%; in some embodiments, 10%-25%; in some embodiments, 25%; in some embodiments, 10%.
[0081] Any pharmaceutical composition or pharmaceutical preparation according to the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises one or more of a filler, a binder, a glidant, a lubricant, and a disintegrant.
[0082] Any pharmaceutical composition or pharmaceutical preparation according to the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, and a disintegrant.
[0083] Any pharmaceutical composition or pharmaceutical preparation according to the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further contains one or more of a solubilizer, a pH regulator, and a surfactant.
[0084] Any pharmaceutical composition or pharmaceutical preparation according to the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and a solubilizer.
[0085] Any pharmaceutical composition or pharmaceutical preparation according to the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and a pH regulator.
[0086] Any pharmaceutical composition or pharmaceutical preparation according to the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and a surfactant.
[0087] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, silicified microcrystalline cellulose, sucrose, sorbitol, dextran, calcium dihydrogen phosphate or starch; in some embodiments, the filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose or sorbitol; in some embodiments, the filler is selected from microcrystalline cellulose.
[0088] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the binder is selected from one or more of povidone, hydroxypropyl cellulose, hypromellose, methylcellulose, sodium carboxymethyl cellulose or sodium carboxymethyl cellulose; in some embodiments, the binder is selected from one or more of hypromellose, methylcellulose or sodium carboxymethyl cellulose; in some embodiments, the binder is selected from hypromellose.
[0089] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the glidant is selected from one or more of talc, silicon dioxide, micropowder silica gel, polyethylene glycol or magnesium lauryl sulfate; in some embodiments, the glidant is selected from one or more of silicon dioxide or micropowder silica gel; in some embodiments, the glidant is selected from colloidal silicon dioxide.
[0090] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, and sodium stearyl fumarate; in some embodiments, the lubricant is selected from sodium stearyl fumarate.
[0091] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or calcium carboxymethyl cellulose; in some embodiments, the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose or calcium carboxymethyl cellulose; in some embodiments, the disintegrant is selected from cross-linked polyvinylpyrrolidone.
[0092] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the solubilizer is selected from one or more of oxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, polyethylene glycol 15-hydroxystearic acid, poloxamer, cyclodextrin, hydroxypropyl beta-cyclodextrin, docusate sodium or vitamin E polyethylene glycol succinate; in some embodiments, the solubilizer is selected from one or more of cyclodextrin or hydroxypropyl beta-cyclodextrin; in some embodiments, the solubilizer is selected from cyclodextrin; in some embodiments, the solubilizer is selected from hydroxypropyl beta-cyclodextrin.
[0093] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation. The surfactant is selected from sodium lauryl sulfate.
[0094] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation. The pH regulator is selected from magnesium oxide.
[0095] The pharmaceutical composition or pharmaceutical preparation according to any one of the preceding embodiments comprises the active ingredient M and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and optionally further comprises one or more of a solubilizer, a pH regulator, and a surfactant, wherein the content of the active ingredient M is 0.5%-99%; in some embodiments, 1%-90%; in some embodiments, 1%-80%; in some embodiments, 1%-70%; in some embodiments, 1%-60%; in some embodiments, 1%-50%; in some embodiments, 1%-40%; in some embodiments, 1%-30%; in some embodiments, 1%-20%; in some embodiments, 1%-10%; in some embodiments, 5%-90%; in some embodiments, 5%- 80%; in some embodiments, 5%-70%; in some embodiments, 5%-60%; in some embodiments, 5%-45%; in some embodiments, 5%-40%; in some embodiments, 5%-30%; in some embodiments, 5%-20%; in some embodiments, 5%-10%; in some embodiments, 10%-90%; in some embodiments, 10%-80%; in some embodiments, 10%-70%; in some embodiments, 10%-60%; in some embodiments, 10%-50%; in some embodiments, 10%-45%; in some embodiments, 10%-40%; in some embodiments, 10%-30%; in some embodiments, 10%-25%; in some embodiments, 25%; in some embodiments, 10%.
[0096] The pharmaceutical composition or pharmaceutical preparation according to any one of the embodiments of the present invention comprises the active ingredient M in any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the filler content is 10%-90%; in some embodiments, the content is 10%-80%; in some embodiments, the content is 10%-75%; in some embodiments, the content is 10%-70%; in some embodiments, the content is 10%-60%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 10%-30%; in some embodiments, the content is 10%-20%; in one embodiment, the content is 10%-20%. In some embodiments, the content is 20%-80%; in some embodiments, the content is 20%-75%; in some embodiments, the content is 20%-70%; in some embodiments, the content is 20%-60%; in some embodiments, the content is 20%-50%; in some embodiments, the content is 30%-80%; in some embodiments, the content is 30%-75%; in some embodiments, the content is 30%-70%; in some embodiments, the content is 40%-80%; in some embodiments, the content is 40%-75%; in some embodiments, the content is 40%-70%; in some embodiments, the content is 37%; in some embodiments, the content is 40%; in some embodiments, the content is 72.5%; in some embodiments, the content is 80%.
[0097] The pharmaceutical composition or pharmaceutical preparation according to any one of the preceding embodiments comprises the active ingredient M and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the binder content is 1%-50%; in some embodiments, the content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-10%; in some embodiments, in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-4%; in some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2.5%; in some embodiments, the content is 1.5%-2.5%; in some embodiments, the content is 2%-2.5%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%.
[0098] The pharmaceutical composition or pharmaceutical preparation according to any one of the embodiments of the present invention comprises the active ingredient M in any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the content of the glidant is 0.5%-10%; in some embodiments, the content is 0.5%-8%; in some embodiments, the content is 0.5%-6%; in some embodiments, the content is 0.5%-5%; in some embodiments, the content is 0.5%-4%; in some embodiments, the content is 0 .5%-3%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-4%; in some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 1%-2.5%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 3%.
[0099] The pharmaceutical composition or pharmaceutical preparation according to any one of the embodiments of the present invention comprises the active ingredient M of any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the lubricant content is 0.1%-10%; in some embodiments, the content is 0.1%-8%; in some embodiments, the content is 0.1%-6%; in some embodiments, the content is 0.1%-5%; in some embodiments, the content is 0.5%-8%; in some embodiments, the content is 0.5%-6%; in some embodiments, the content is 0.5%-5%; in some embodiments, the content is 0.5%-4%; in some embodiments, the content is 0 .5%-3%; in some embodiments, the content is 0.5%-2.0%; in some embodiments, the content is 0.5%-1%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 0.5%; in some embodiments, the content is 0.6%; in some embodiments, the content is 0.7%; in some embodiments, the content is 0.8%; in some embodiments, the content is 0.9%; in some embodiments, the content is 1.0%; in some embodiments, the content is 2%.
[0100] The pharmaceutical composition or pharmaceutical preparation according to any one of the embodiments of the present invention comprises the active ingredient M of any one of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further optionally contains one or more of a solubilizer, a pH regulator, and a surfactant, wherein the content of the disintegrant is 0.5%-10%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-9%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-7%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-4%; in one embodiment, the content is 1%-20%; in some embodiments, the content is 1%-10%; in some embodiments ... In some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 2%-10%; in some embodiments, the content is 2%-8%; in some embodiments, the content is 2%-7%; in some embodiments, the content is 2%-6%; in some embodiments, the content is 3%-7%; in some embodiments, the content is 4%-7%; in some embodiments, the content is 5%-7%; in some embodiments, the content is 2%; in some embodiments, the content is 3%; in some embodiments, the content is 5%; in some embodiments, the content is 6%; in some embodiments, the content is 7%; in some embodiments, the content is 10%.
[0101] The pharmaceutical composition or pharmaceutical preparation according to any one of the preceding embodiments comprises the active ingredient M and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further comprises a solubilizer, wherein the solubilizer content is 5%-50%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 30%-50%; in some embodiments, the content is 30%-45%; in some embodiments, the content is 10%; in some embodiments, the content is 20%; in some embodiments, the content is 30%; in some embodiments, the content is 32%; in some embodiments, the content is 40%; in some embodiments, the content is 42.5%; in some embodiments, the content is 45%.
[0102] The pharmaceutical composition or pharmaceutical preparation according to any one of the preceding embodiments comprises the active ingredient M and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further comprises a surfactant, wherein the surfactant content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-20%; in some embodiments, the content is 5%-20%; in some embodiments, the content is 10%-20%; in some embodiments, the content is 10%-15%; in some embodiments, the content is 5%; in some embodiments, the content is 10%; in some embodiments, the content is 15%; in some embodiments, the content is 20%.
[0103] The pharmaceutical composition or pharmaceutical preparation according to any one of the preceding embodiments comprises the active ingredient M and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and further comprises a pH adjuster, wherein the content of the pH adjuster is 1%-50%; in some embodiments, the content is 1%-9%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%; in some embodiments, the content is 4%; in some embodiments, the content is 5%;
[0104] The present invention relates to a pharmaceutical composition and a pharmaceutical preparation, comprising:
[0105] (i) active ingredient M, present in an amount of 0.5% to 99%; in some embodiments, 1% to 90%; in some embodiments, 1% to 80%; in some embodiments, 1% to 70%; in some embodiments, 1% to 60%; in some embodiments, 1% to 50%; in some embodiments, 1% to 40%; in some embodiments, 1% to 30%; in some embodiments, 1% to 20%; in some embodiments, 1% to 10%; in some embodiments, 5% to 90%; in some embodiments, 5% to 80%; in some embodiments, 5% to 70%; in some embodiments, 5% to 60%; in some embodiments, 5% to 45%; in some embodiments, 5% to 40%; %; in some embodiments, 5%-30%; in some embodiments, 5%-20%; in some embodiments, 5%-10%; in some embodiments, 10%-90%; in some embodiments, 10%-80%; in some embodiments, 10%-70%; in some embodiments, 10%-60%; in some embodiments, 10%-50%; in some embodiments, 10%-40%; in some embodiments, 10%-30%; in some embodiments, 10%-25%; in some embodiments, 25%-40%; in some embodiments, 25%-50%; in some embodiments, 42%; in some embodiments, 25%; in some embodiments, 10%;
[0106] (ii) a filler, which is one or more of microcrystalline cellulose, silicified microcrystalline cellulose, or sorbitol, and is present in an amount of 10% to 90%; in some embodiments, in an amount of 10% to 80%; in some embodiments, in an amount of 10% to 70%; in some embodiments, in an amount of 10% to 60%; in some embodiments, in an amount of 10% to 50%; in some embodiments, in an amount of 10% to 40%; in some embodiments, in an amount of 10% to 30%; in some embodiments, in an amount of 10% to 20%; in some embodiments, in an amount of 30% to 80%; in some embodiments, in an amount of 40% to 80%; in some embodiments, in an amount of 37%; in some embodiments, in an amount of 40%; in some embodiments, in an amount of 72.5%; in some embodiments, in an amount of 80%;
[0107] (iii) a binder, which is one or more of hypromellose, methylcellulose, or sodium carboxymethylcellulose, and is present in an amount of 1% to 50%; in some embodiments, in an amount of 1% to 40%; in some embodiments, in an amount of 1% to 30%; in some embodiments, in an amount of 1% to 20%; in some embodiments, in an amount of 1% to 15%; in some embodiments, in an amount of 1% to 10%; in some embodiments, in an amount of 1% to 6%; in some embodiments, in an amount of 1% to 5%; in some embodiments, in an amount of 1% to 4%; in some embodiments, in an amount of 1% to 3%; in some embodiments, in an amount of 1% to 2.5%; in some embodiments, in an amount of 1.5% to 2.5%; in some embodiments, in an amount of 2% to 2.5%; in some embodiments, in an amount of 2%; in some embodiments, in an amount of 2.5%; in some embodiments, in an amount of 3%;
[0108] (iv) a glidant, which is one or more of silicon dioxide or micronized silica, and has an amount of 0.5% to 10%; in some embodiments, 0.5% to 5%; in some embodiments, 0.5% to 4%; in some embodiments, 0.5% to 3%; in some embodiments, 0.5% to 2%; in some embodiments, 1% to 2%; in some embodiments, 0.5%; in some embodiments, 1%; in some embodiments, 2%; in some embodiments, 3%;
[0109] (v) a lubricant, wherein the lubricant is sodium stearyl fumarate, and the content is 0.1%-10%; in some embodiments, the content is 0.1%-8%; in some embodiments, the content is 0.1%-6%; in some embodiments, the content is 0.1%-5%; in some embodiments, the content is 0.5%-2.0%; in some embodiments, the content is 0.5%-1%; in some embodiments, the content is 0.5%; in some embodiments, the content is 0.6%; in some embodiments, the content is 0.7%; in some embodiments, the content is 0.8%; in some embodiments, the content is 0.9%; in some embodiments, the content is 1.0%.
[0110] (vi) a disintegrant, which is one or more of crospovidone, croscarmellose sodium, or carboxymethylcellulose calcium, and is present in an amount of 0.5% to 10%; in some embodiments, in an amount of 1% to 10%; in some embodiments, in an amount of 1% to 9%; in some embodiments, in an amount of 1% to 8%; in some embodiments, in an amount of 1% to 7%; in some embodiments, in an amount of 1% to 6%; in some embodiments, in an amount of 1% to 5%; in some embodiments, in an amount of 1% to 4%; in some embodiments, in an amount of 1% to 3%; in some embodiments, in an amount of 1% to 2%; in some embodiments, in an amount of In some embodiments, the content is 1.5%-10%; in some embodiments, the content is 2%-10%; in some embodiments, the content is 2%-8%; in some embodiments, the content is 2%-7%; in some embodiments, the content is 2%-6%; in some embodiments, the content is 3%-7%; in some embodiments, the content is 4%-7%; in some embodiments, the content is 5%-7%; in some embodiments, the content is 2%; in some embodiments, the content is 3%; in some embodiments, the content is 4%; in some embodiments, the content is 6%; in some embodiments, the content is 8%; in some embodiments, the content is 10%;
[0111] (vii) In some embodiments, the composition may further comprise one or more of a solubilizer, a surfactant, and a pH adjuster, preferably one of a solubilizer, a surfactant, and a pH adjuster;
[0112] The solubilizer is one or more of cyclodextrin or hydroxypropyl beta-cyclodextrin, and the content is 5%-50%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-45%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 30%-50%; in some embodiments, the content is 30%-45%; in some embodiments, the content is 10%; in some embodiments, the content is 20%; in some embodiments, the content is 30%; in some embodiments, the content is 32%; in some embodiments, the content is 40%; in some embodiments, the content is 42.5%; in some embodiments, the content is 45%;
[0113] The surfactant is sodium lauryl sulfate, and the content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-20%; in some embodiments, the content is 5%-20%; in some embodiments, the content is 10%-20%; in some embodiments, the content is 10%-15%; in some embodiments, the content is 5%; in some embodiments, the content is 10%; in some embodiments, the content is 15%; in some embodiments, the content is 20%;
[0114] The pH adjuster is magnesium oxide, and the content is 1%-50%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-9%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%; in some embodiments, the content is 4%; in some embodiments, the content is 5%.
[0115] Optionally, the pharmaceutical preparation as described above is characterized in that the binder can be added in a solution state or in a powder state; the disintegrant can be added internally, externally, or both internally and externally.
[0116] The present invention also provides a use of a pharmaceutical composition or a pharmaceutical preparation in preparing drugs for treating cancer.
[0117] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein, preferably 1-1000 mg. The disease is preferably cancer, such as BRAF-mediated cancer, such as a solid tumor.
[0118] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1000 mg, 2-1000 mg, 3-1000 mg, 4-1000 mg, 5-1000 mg, 6-1000 mg, 10-1000 mg, 20-1000 mg, 25-1000 mg, 30-1000 mg, 40-1000 mg, 50-1000 mg, 60-1000 mg, 70-1000 mg, 75-1000 mg, 80-1000 mg, 90-1000 mg, 100-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg, 500-1000 mg, 600-1000 mg, 700-1000 mg, 750-1000 mg, 800-1000 mg, 900-1000 mg, 1000-1000 mg, 2000-1000 mg, 3000-1000 mg, 4000-1000 mg, 5000-1000 mg, 6000-1000 mg, 7000-1000 mg, 7500-1000 mg, 8000-1000 mg, 9000-1000 mg, 10000-1000 mg, 20000-1000 mg, 30000-1000 mg, 40000-1000 mg, 1000mg, 400-1000mg, 1-900mg, 2-900mg, 3-900mg, 4-900mg, 5-900mg, 6-900mg, 10-900mg, 20-900mg, 25-900mg, 30-900mg, 40-900mg, 50-900mg, 60-900mg, 70-900mg, 75-900mg, 80-900mg, 90-900mg, 100-900mg, 200-900mg, 300-900mg, 400-900mg 1-800mg, 2-800mg, 3-800mg, 4-800mg, 5-800mg, 6-800mg, 10-800mg, 20-800mg, 25-800mg, 30-800mg, 40-800mg, 50-800mg, 60-800mg, 70-800mg, 75-800mg, 80-800mg, 90-800mg, 100-800mg, 200-800mg, 300-800mg, 400-800mg 1-700mg, 2-700mg, 3-700mg, 4-700mg, 5-700mg, 6-700mg, 10-700mg, 20-700mg, 25-700mg, 30-700mg, 40-700mg, 50-700mg, 60-700mg, 70-700 mg, 75-700mg, 80-700mg, 90-700mg, 100-700mg, 200-700mg, 300-700mg, 400-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-500mg,10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-50 0mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 7 5-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300 mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 2 50-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90 -200mg, 100-200mg, 125-200mg, 150-200mg, 1-100mg, 2-100mg, 5-100mg, 10-100mg, 15-100mg, 20-100mg, 25-100mg, 30-100mg, 40-100mg, 50-100mg, 6 0-100 mg, 70-100 mg, 75-100 mg, 80-100 mg, 90-100 mg; in some embodiments, examples of therapeutically effective amounts include, but are not limited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg,240mg、250mg、300mg、350mg、400mg、600mg、800mg。、
[0119] In some embodiments, the formulation specifications of the pharmaceutical composition or pharmaceutical preparation of the present invention include but are not limited to 1-1000 mg, 2-1000 mg, 3-1000 mg, 4-1000 mg, 5-1000 mg, 6-1000 mg, 10-1000 mg, 20-1000 mg, 25-1000 mg, 30-1000 mg, 40-1000 mg, 50-1000 mg, 60-1000 mg, 70-1000 mg, 75-1000 mg, 80-1000 mg, 90-1000 mg, 100-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg, 1-900 mg , 2-900mg, 3-900mg, 4-900mg, 5-900mg, 6-900mg, 10-900mg, 20-900mg, 25-900mg, 30-900mg, 40-900mg, 50-900mg, 60-900mg, 70-900mg, 75-900mg, 80- 900mg, 90-900mg, 100-900mg, 200-900mg, 300-900mg, 400-900mg, 1-800mg, 2-800mg, 3-800mg, 4-800mg, 5-800mg, 6-800mg, 10-800mg, 20-800mg, 25-8 00mg, 30-800mg, 40-800mg, 50-800mg, 60-800mg, 70-800mg, 75-800mg, 80-800mg, 90-800mg, 100-800mg, 200-800mg, 300-800mg, 400-800mg, 1-700mg, 2-700mg, 3-700mg, 4-700mg, 5-700mg, 6-700mg, 10-700mg, 20-700mg, 25-700mg, 30-700mg, 40-700mg, 50-700mg, 60-700mg, 70-700mg, 75-700mg, 80-7 00mg, 90-700mg, 100-700mg, 200-700mg, 300-700mg, 400-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-500mg, 10-500mg, 20-500mg, 25-50 0mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg,300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80 -400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20- 300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150- 300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg , 70-200 mg, 75-200 mg, 80-200 mg, 90-200 mg, 100-200 mg, 125-200 mg, 150-200 mg, 1-100 mg, 2-100 mg, 5-100 mg, 10-100 mg, 15-100 mg, 20-100 mg, 25-100 mg, 30-100 mg, 40-100 mg, 50-100 mg, 60-100 mg, 70-100 mg, 75-100 mg, 80-100 mg, 90-100 mg; in some embodiments, examples of therapeutically effective amounts include, but are not limited to, 1 mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 12 5mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg, 350mg, 400mg, 600mg, 800mg. ,
[0120] In some embodiments, the amount of the active ingredient M in a unit preparation of the pharmaceutical composition or pharmaceutical preparation of the present invention includes but is not limited to 1-1000 mg, 2-1000 mg, 3-1000 mg, 4-1000 mg, 5-1000 mg, 6-1000 mg, 10-1000 mg, 20-1000 mg, 25-1000 mg, 30-1000 mg, 40-1000 mg, 50-1000 mg, 60-1000 mg, 70-1000 mg, 75-1000 mg, 80-1000 mg, 90-1000 mg, 100-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg. g, 1-900mg, 2-900mg, 3-900mg, 4-900mg, 5-900mg, 6-900mg, 10-900mg, 20-900mg, 25-900mg, 30-900mg, 40-900mg, 50-900mg, 60-900mg, 70-900mg, 75- 900mg, 80-900mg, 90-900mg, 100-900mg, 200-900mg, 300-900mg, 400-900m, 1-800mg, 2-800mg, 3-800mg, 4-800mg, 5-800mg, 6-800mg, 10-800mg, 20-80 0mg, 25-800mg, 30-800mg, 40-800mg, 50-800mg, 60-800mg, 70-800mg, 75-800mg, 80-800mg, 90-800mg, 100-800mg, 200-800mg, 300-800mg, 400-800mg , 1-700mg, 2-700mg, 3-700mg, 4-700mg, 5-700mg, 6-700mg, 10-700mg, 20-700mg, 25-700mg, 30-700mg, 40-700mg, 50-700mg, 60-700mg, 70-700mg, 75-7 00mg, 80-700mg, 90-700mg, 100-700mg, 200-700mg, 300-700mg, 400-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-600mg, 10-600mg, 20-60 0mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 300-600mg, 400-600mg,1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-50 0mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400m g, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 3 00-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90 -300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg , 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 1-100mg, 2-100mg, 5-100mg, 10-100mg, 15-100m g, 20-100 mg, 25-100 mg, 30-100 mg, 40-100 mg, 50-100 mg, 60-100 mg, 70-100 mg, 75-100 mg, 80-100 mg, 90-100 mg; in some embodiments, examples of therapeutically effective amounts include, but are not limited to, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg,160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg, 350mg, 400mg, 600mg, 800mg. ,
[0121] A method for treating a disease in a mammal, the method comprising administering an active ingredient M to a subject at a daily dose of 1-1200 mg / day, the daily dose being a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-3600 mg / day, 25-3600 mg / day, 50-3600 mg / day, 100-3600 mg / day, 200-3600 mg / day, 10-2400 mg / day, 25-2400 mg / day, 50-2400 mg / day, 100-2400 mg / day, 200-2400 mg / day, 10-1200 mg / day, 25-1200 mg / day, 50-1200 In some embodiments, the daily dose includes but is not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 120 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 300 mg / day, 240 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 2400 mg / day, and 3600 mg / day.
[0122] The present invention relates to a kit, which may include a pharmaceutical composition or pharmaceutical preparation in a single-dose or multi-dose form, wherein the kit contains an amount of the active ingredient M in the pharmaceutical composition of the present invention including but not limited to 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 350 mg, 400 mg, 600 mg, 800 mg, and 1200 mg.
[0123] Unless otherwise stated, the terms used in this specification and claims have the following meanings.
[0124] "Preparation specifications" refers to the weight of the main drug (active ingredient M) contained in each vial, tablet or other unit preparation.
[0125] Synthesis route
[0126] The compounds used in the reactions described herein were prepared using organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" were obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.
[0127] the term
[0128] Unless otherwise specified in the present invention, the terms of the present invention have the following meanings:
[0129] 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.
[0130] "Halogen" herein refers to F, Cl, Br, I, or isotopes thereof.
[0131] "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.
[0132] "Deuterium" refers to the isotope deuterium of hydrogen (H).
[0133] "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.
[0134] “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.
[0135] "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.
[0136] "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.
[0137] "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.
[0138] "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.
[0139] "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.
[0140] "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.
[0141] "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.
[0142] "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.
[0143] "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.
[0144] "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.
[0145] "Cycloalkylene" refers to a divalent radical of a cycloalkyl group.
[0146] "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.
[0147] "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.
[0148] "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, azolinyl, oxolanyl, oxekinyl, and the like. Heterocycloalkyl groups may be optionally substituted with substituents.
[0149] "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, which may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic rings may be bridged, parallel, spirocyclic or combinations thereof; when bicyclic or polycyclic, it may be a fusion of a heteroaryl and an aryl, or a fusion of a heteroaryl and a heteroaryl, wherein either the heteroaryl or the aryl may be a connection site. Non-limiting examples include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl, The heteroaryl group may be optionally substituted by a substituent.
[0150] "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.
[0151] "Heterocyclylene" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include wait.
[0152] "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.
[0153] "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.
[0154] "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,
[0155] "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(C 1-6 alkyl)2,-OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C1- 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.
[0156] "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.
[0157] "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.
[0158] 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.
[0159] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
[0160] "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.
[0161] An "excipient" is a substance that is not itself a therapeutic agent but is used as a diluent, adjuvant, binder, and / or vehicle and is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration. As known to those skilled in the art, pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, 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.
[0162] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, and conformational isomers.
[0163] "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.
[0164] 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
[0165] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.
[0166] Detection method
[0167] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 - 6 The unit of (ppm) is given. 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).
[0168] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));
[0169] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);
[0170] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm;
[0171] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;
[0172] RuPhos-Pd-G3: a catalyst having a CAS No. of 1445085-77-7.
[0173] Example 1
[0174] Step 1: 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 afford 1B (180 mg, 17% yield).
[0175] Step 2: In a 50 mL reaction bottle, 1C (250 mg, 0.8 mmol, preparation method reference WO2021116050A1), 1B (160 mg, 0.9 mmol), cesium carbonate (310 mg, 0.96 mmol) and N, N-dimethylformamide (10 mL) were added in sequence. After the addition, the mixture was stirred at 80 ° C for 18 hours. Ethyl acetate (50 mL) was added to the reaction solution, and then washed with water (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) was used to separate and purify compound 1 (86 mg, yield 23%).
[0176] LCMS m / z=470.5[M+H] + ;
[0177] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.36(s,1H),7.90–7.84(m,1H),7.78(d,1H),7.68(dd ,1H),7.53(dd,1H),7.39(d,1H),3.84(s,4H),3.48(s,3H),2.10(t,4H),1.78–1.69(m,2H).
[0178] Example 2
[0179] Step 1: To a 50 mL reaction flask, 2A (520 mg, 4.34 mmol), triethylamine (2.19 g, 21.64 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 (500 mg, 4.34 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 (50 mL × 1) and saturated brine (50 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 afford 2B (450 mg, 32% yield).
[0180] Step 2: Referring to the reaction operation of step 2 of Example 1, compound 2 (60 mg, yield 16%) was obtained by separation and purification.
[0181] LCMS m / z=456.2[M+H] + ;
[0182] 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.35(s,1H),7.89-7.84(m,1H),7.78(d,1H),7.67(dd,1H),7.50(dd, 1H),7.39(d,1H),3.47(s,3H),3.37-3.34(m,4H),1.59-1.56(m,2H),0.65-0.59(m,1H),0.19-0.16(m,1H).
[0183] Example 3
[0184] Step 1: To a 50 mL reaction flask, add aminosulfonyl chloride (1.0 g, 8.68 mmol), triethylamine (2.63 g, 26.04), and dichloromethane (10 mL). Stir at 0°C for 20 minutes. Slowly add cyclopropanol (1.11 g, 17.36 mmol) dropwise and stir at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure to yield 3B, which is used in the next step without purification.
[0185] Step 2: Referring to the second step of the synthetic reaction in Example 1, compound 3 was obtained by separation and purification (100 mg, yield 14.5%).
[0186] LCMS m / z=431.1[M+H] + ;
[0187] 1 H NMR(400MHz,CD3OD)δ8.26(s,1H),7.77(d,1H),7.67–7.54(m,3H),7.48(dd ,1H),4.24–4.13(m,1H),3.58(s,3H),0.94–0.83(m,2H),0.79–0.68(m,2H).
[0188] Example 4
[0189] Step 1: In a 250 mL nitrogen-protected three-necked flask, 4A (4.0 g, 26.08 mmol) was dissolved in dry tetrahydrofuran (80 mL). Triphosgene (2.94 g, 9.91 mmol) was slowly added under ice bath. After the addition, the mixture was stirred at 70°C for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by slurrying with petroleum ether. The solid was filtered and dried to obtain 4B (3.86 g, yield
[0190] 83%).
[0191] 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),9.84(s,1H),7.24–7.18(m,2H),7.03(dd,1H).
[0192] Step 2: In a 250 mL single-necked flask, 4B (3.85 g, 21.51 mmol) was dissolved in a 60 mL solution of sodium hydroxide (1.03 g, 25.75 mmol). Methoxyamine hydrochloride (2.69 g, 32.27 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was dissolved in a mixture of dichloromethane (200 mL) and methanol (10 mL), dried over anhydrous sodium sulfate, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20 / 1) to afford 4C (2.8 g, 71% yield).
[0193] LCMS m / z=183.1[M+H] + ;
[0194] Step 3: In a 50 mL single-necked flask, 4C (2.6 g, 14.27 mmol) was dissolved in trimethyl orthoformate (54 mL). After addition, the mixture was stirred at 105°C for 4 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by slurrying with petroleum ether. The solid was filtered and dried to afford 4D (2.4 g, 88% yield).
[0195] LCMS m / z=193.1[M+H] + ;
[0196] Step 4: In a 100 mL single-necked flask, 4D (2.4 g, 12.49 mmol) was dissolved in dry N,N-dimethylformamide (40 mL). Cesium carbonate (4.88 g, 14.99 mmol) was slowly added under ice-cooling and stirred at room temperature for 0.5 h. A solution of 2,3,6-trifluorobenzonitrile (2.32 g, 14.99 mmol) in N,N-dimethylformamide (10 mL) was slowly added dropwise under ice-cooling and stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into ice water (250 mL), stirred for 30 min, and filtered. The resulting solid was dried and purified by slurrying with a mixture of petroleum ether (100 mL) and ethyl acetate (10 mL). The solid was filtered and dried to afford 4E (3.6 g, 88% yield).
[0197] LCMS m / z=330.1[M+H] + ;
[0198] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.98(m,1H),7.83(d,1H),7.75(dd,1H),7.64–7.53(m,2H),4.06(s,3H).
[0199] 19 F NMR(377MHz, DMSO-d6)δ-107.70(s),-128.37(s).
[0200] Step 5: Compound 4 (32 mg, 7% yield) was obtained by synthesis, separation and purification according to the second step of Example 1.
[0201] LCMS m / z=478.1[M+H] + ;
[0202] 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.63(s,1H),7.91–7.81(m,2H),7.71(dd,1H),7.56(d, 1H),7.41(d,1H),5.40(m,0.5H),5.27(m,0.5H),4.05(s,3H),3.58–3.32(m,4H),2.17(m,2H).
[0203] 19 F NMR(377MHz, DMSO-d6)δ-127.22(s),-172.76(s).
[0204] Example 5
[0205] Step 1: To a 50 mL reaction flask, 5A (720 mg, 6.04 mmol), triethylamine (1.83 g, 18.12 mmol), and dichloromethane (10 mL) were added sequentially. After complete addition, the mixture was stirred at 0°C for 20 minutes. A solution of aminosulfonyl chloride (700 mg, 6.04 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 1-2 hours. The reaction solution was diluted with dichloromethane (100 mL), washed sequentially with water (40 mL × 1) and saturated brine (40 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 = 12 / 1) to afford 5B (600 mg, 61% yield).
[0206] Step 2: Compound 5 (12 mg, yield 1%) was obtained by synthesis, separation and purification according to the second step of Example 1.
[0207] LCMS m / z=456.30[M+H] + ;
[0208] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.76(d,1H),7.63(dd,2H),7.48(dd,1H),7.38(d,1H),7.08(s,1H),3.83(s,4H),3.47(s,3H),0.56(s,4H).
[0209] 19 F NMR(377MHz,DMSO-d6)δ-134.36(s).
[0210] Example 6
[0211] Step 1: To a 50 mL reaction flask, 6A (synthesis method reference: WO2017 / 1660,2017,A1) (620 mg, 5.38 mmol), triethylamine (1633.21 mg, 16.14 mmol), and dichloromethane (20 mL) were added sequentially. After complete addition, the mixture was stirred at 0°C for 20 minutes. A solution of aminosulfonyl chloride (622 mg, 5.38 mmol) in dichloromethane (10 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 1-2 hours. The reaction solution was diluted with dichloromethane (100 mL), washed sequentially with water (40 mL × 1) and saturated brine (40 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 = 20 / 1) to obtain 6B (500 mg, 48% yield).
[0212] Step 2: Compound 6 (8 mg, yield 1%) was obtained by synthesis, separation and purification according to the second step of Example 1.
[0213] LCMS m / z=488.20[M+H] + ;
[0214] 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.34(s,1H),7.77(d,2H),7.66(dd,1H),7.47(dd,1H),7.38 (d,1H),5.01(s,0.5H),4.87(s,0.5H),3.81(d,4H),3.47(s,3H),2.56(m,2H),2.37–2.18(m,2H).
[0215] Example 7
[0216] Step 1: Synthesize, separate and purify the compound 7 (58 mg, yield: 8%) by referring to the second step of Example 1.
[0217] LCMS m / z=486.1[M+H] + ;
[0218] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.63(s,1H),7.93–7.85(t,1H),7.84(d,1H),7.72(dd ,1H),7.54(dd,1H),7.41(d,1H),4.04(s,3H),3.84(s,4H),2.10(t,4H),1.81–1.66(m,2H).
[0219] 19 F NMR(377MHz,DMSO-d6)δ-127.26(s).
[0220] Example 8
[0221] Step 1: Synthesize, separate and purify the compound 8 (0.3 g, yield: 42%) by referring to the second step of Example 1.
[0222] LCMS m / z=472.1[M+H] + ;
[0223] 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.63(s,1H),7.93–7.86(t,1H),7.84(d,1H) ,7.72(dd,1H),7.60(dd,1H),7.43(d,1H),4.05(s,3H),3.98(s,4H),0.62(s,4H).
[0224] 19 F NMR(377MHz,DMSO-d6)δ-127.15(s).
[0225] Example 9
[0226] Step 1: Add 9A (25 g, 184.46 mmol) and sodium formate (15.55 g, 21.51 mmol) to a 250 mL single-necked flask and react at 130°C for 2 hr. After the reaction is complete, cool to room temperature and filter the filtrate to yield 9B (22.0 g, 94% yield).
[0227] LCMS m / z=128.2[M+H] + ;
[0228] Step 2: In a 250 mL single-necked flask, 2-amino-5-hydroxybenzoic acid (1.0 g, 6.52 mmol) was added to 9B (6 mL, 36.2 mmol) and reacted at 150°C for 21 hr. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed twice with ethyl acetate (1 mL) and then concentrated to afford 9C (1.3 g, 82% yield).
[0229] LCMS m / z=245.2[M+H] + ;
[0230] Step 3: In a 25 mL single-necked flask, 9C (0.60 g, 2.46 mmol) was dissolved in dry N,N-dimethylformamide (6 mL). Cesium carbonate (1.6 g, 4.91 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (0.41 g, 2.61 mmol) was slowly added dropwise under ice-cooling. The reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (10 mL) was added to dilute the reaction system. Water (20 mL) was then added to quench the reaction. 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 afford 9E (0.75 g, 80% yield).
[0231] LCMS m / z=382.0[M+H] + ;
[0232] Step 4: Referring to the second step of synthesis in Example 1, separation and purification were performed to obtain 100 mg of solid, which was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 9 (22 mg, yield 3%).
[0233] LCMS m / z=538.1[M+H] + ;
[0234] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.39(s,1H),7.89-7.82(dd,2H),7.75-7.72(dd,1H),7.55-7. 52(dd,1H),7.44-7.43(d,1H),4.98-4.91(q,2H),3.83(s,4H),2.11-2.07(t,4H),1.77–1.70(m,2H).
[0235] 19 F NMR(377MHz, DMSO-d6)δ-127.30(s),-67.08(s).
[0236] Example 10
[0237] Step 1: 10A (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 10B (3.1 g, 12% yield).
[0238] LCMS m / z=100.2[M+H] + ;
[0239] 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).
[0240] Step 2: In a 25 mL single-necked flask, 2-amino-5-hydroxybenzoic acid (0.5 g, 3.31 mmol) was added to 10B (3.1 mL, 28.4 mmol) and reacted at 150°C for 21 hours. After the reaction was complete, 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 10C (0.70 g, 94% yield).
[0241] LCMS m / z=227.2[M+H] + ;
[0242] Step 3: In a 25 mL single-necked flask, 10C (0.70 g, 3.09 mmol) was dissolved in dry N,N-dimethylformamide (6 mL). Cesium carbonate (2.01 g, 6.17 mmol) was slowly added under ice-cooling. 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. The reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (5 mL) was added to dilute the reaction system. Water (20 mL) was then added to quench the reaction. 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 (v / v) = 4 / 1) to afford 10E (1.1 g, 98% yield).
[0243] LCMS m / z=364.2[M+H] + ;
[0244] Step 4: In a 25 mL single-necked vial, 10E (0.50 g, 1.38 mmol) was dissolved in dry N,N-dimethylformamide (5 mL). Cesium carbonate (0.90 g, 2.76 mmol) and 1B (0.24 g, 1.38 mmol) were slowly added under ice. The mixture was stirred at 100°C for 4 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative liquid chromatography (Waters 2767 preparative liquid chromatography; SunFire@Prep C18 column (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to afford compound 10 (150 mg, 21% yield).
[0245] LCMS m / z=520.0[M+H] + ;
[0246] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.34(s,1H),7.87-7.80(m,2H),7.74-7.71(dd,1H),7.54-7.50(dd,1H) ,7.41-7.40(d,1H),6.51–6.22(m,1H),4.51-4.43(m,2H),3.82(s,4H),2.11-2.07(t,4H),1.78–1.70(m,2H).
[0247] 19 F NMR(377MHz, DMSO-d6)δ-127.22(s),-120.46(s).
[0248] Example 11
[0249] Step 1: In a 100 mL reaction flask, 11A (5.0 g, 87.62 mmol) and ethyl formate (40 mL) were added sequentially. After addition, the mixture was stirred at 55°C for 12 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain 11B (7.0 g, 93% yield).
[0250] LCMS m / z=86.20[M+H] + ;
[0251] Step 2: In a 100 mL reaction flask, 11B (7.0 g, 82.26 mmol) and 4A (1.5 g, 9.83 mmol) were added in sequence. After the addition, the mixture was stirred at 145°C for 10 hours. After the reaction was completed, the mixture was filtered and the obtained solid was purified by slurrying with ethyl acetate. The solid was filtered and dried to obtain 11C (1.5 g, yield 75%).
[0252] LCMS m / z=203.10[M+H] + ;
[0253] Step 3: In a 100 mL reaction flask, 11C (1.5 g, 7.42 mmol) was dissolved in dry N,N-dimethylformamide (20 mL). Cesium carbonate (3.63 g, 11.13 mmol) was added under ice-cooling. The mixture was allowed to react at room temperature for 0.5 h. A solution of 2,3,6-trifluorobenzonitrile (1.28 g, 8.16 mmol) in N,N-dimethylformamide (15 mL) was slowly added dropwise under ice-cooling. The mixture was allowed to react at room temperature for 2 h. The reaction solution 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 (PE / EA = 2 / 1) to afford 11D (1.4 g, 56% yield).
[0254] LCMS m / z=340.10[M+H] + ;
[0255] Step 4: In a 100 mL reaction flask, 11D (0.2 g, 0.59 mmol), 1B (0.2 g, 1.12 mmol), cesium carbonate (0.38 g, 1.18 mmol) and N,N-dimethylformamide (10 mL) were added in sequence. After the addition, the mixture was stirred at 100 ° C for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution, and then washed with water (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 11 (150 mg, yield 52%).
[0256] LCMS m / z=496.20[M+H] + ;
[0257] 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.27(s,1H),7.91-7.85(m,1H),7.76(d,1H),7.67(dd,1H),7.53(dd, 1H),7.37(d,1H),3.84(s,4H),3.28-3.14(m,1H),2.13-2.06(m,4H),1.79-1.70(m,2H),1.06-0.90(m,4H).
[0258] Example 12
[0259] Step 1: To a 50 mL reaction flask, 12A (100 mg, 0.75 mmol), triethylamine (150 mg, 1.50 mmol), and dichloromethane (10 mL) were added sequentially. After complete addition, the mixture was stirred at 0°C for 20 minutes. A solution of aminosulfonyl chloride (92 mg, 0.80 mmol) in dichloromethane (5 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (40 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 afford 12B (80 mg, 55% yield).
[0260] Step 2: In a 50 mL reaction flask, 1C (100 mg, 0.32 mmol), 12B (80 mg, 0.45 mmol), cesium carbonate (200 mg, 0.61 mmol) and N,N-dimethylformamide (10 mL) were added in sequence. After the addition, the mixture was stirred at 100°C for 12 hours. Ethyl acetate (40 mL) was added to the reaction solution, which was then washed with water (40 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 12 (35 mg, yield 23%).
[0261] LCMS m / z=470.50[M+H] + ;
[0262] 1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.35(s,1H),7.92–7.84(m,1H),7.78(d,1H),7.68(dd,1H),7.54(dd,1H),7.36 (d,1H),3.56-3.50(m,2H),3.47(s,3H),1.94-1.84(m,2H),1.80–1.72(m,2H),1.08-0.98(m,2H),0.57-0.51(m,2H).
[0263] Example 13
[0264] Step 1: To a 50 mL reaction flask, 13A (500 mg, 3.21 mmol), triethylamine (0.97 g, 9.59 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 (740 mg, 6.40 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to yield 13B (500 mg, crude product).
[0265] Step 2: In a 50 mL reaction flask, 1C (1.58 g, 5.04 mmol), 13B (500 mg, 2.52 mmol), cesium carbonate (2.46 g, 7.62 mmol) and N,N-dimethylformamide (15 mL) were added in sequence. After the addition, the mixture was stirred at 100°C for 12 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 13 (46.76 mg, yield 3.78%).
[0266] LCMS m / z=492.4[M+H] + ;
[0267] 1 H NMR (400MHz, CDCl3) δ8.30(s,1H),7.83(dd,1H),7.63-7.58(m,3H),7.47(t,1H),6.86(s,1H),4.20-4.14(m,4H),3.63(s,3H),1.52(t,2H).
[0268] Example 14
[0269] Step 1: To a 50 mL reaction flask, add aminosulfonyl chloride (0.18 g, 1.59 mmol), triethylamine (0.48 g, 4.74 mmol), and dichloromethane (5 mL) in sequence. Stir at 0°C for 20 minutes. Slowly add 14A (0.20 g, 1.59 mmol) dropwise, and stir at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, and the crude product is used directly in the next step without purification.
[0270] Step 2: In a 50 mL reaction flask, 1C (490 mg, 1.56 mmol), 14B (0.30 g crude product), cesium carbonate (1.52 mg, 4.67 mmol) and N,N-dimethylformamide (5 mL) were added in sequence. After the addition, the mixture was stirred at 100°C for 18 hours. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (40 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by medium pressure preparative chromatography (instrument: Biotage Isolera One; column: C18 spherical 20-35 μm 100A80 g (Agela Technologies); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water; gradient: 5%-90% acetonitrile isocratic elution; cycle time: 20 min; retention time: 7 min) to obtain compound 14 (28 mg, yield 3.89%).
[0271] LCMS m / z=462.1[M+H] + ;
[0272] 1 H NMR(400MHz,CD3OD)δ8.22(s,1H),7.75–7.70(m,1H),7.57(dd,2H),7.47(dd,1H),7.33–7.25 (m,1H),4.59(d,1H),4.47(d,1H),3.88(t,2H),3.64(dd,2H),3.57(s,3H),2.88–2.76(m,1H).
[0273] 19 F NMR(377MHz, DMSO-d6)δ-146.12(s),-220.65(s).
[0274] Example 15
[0275] Step 1: In a 100 mL single-necked flask, 15A (0.25 g, 1.74 mmol) was dissolved in dry acetonitrile (15 mL). 15B (0.53 g, 1.74 mmol) was added and stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, crude compound 15C, which was directly carried to the next step without purification.
[0276] Step 2: Compound 15C (crude product) and dichloromethane (12 ml) were added to a single-necked flask, followed by trifluoroacetic acid (3 ml) and reacted at room temperature for 2 hours. After concentration, compound 15D was obtained and directly used for the next step without purification.
[0277] Step 3: In a 100 mL single-necked flask, 15D (crude product) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (2.27 g, 6.97 mmol) and 1C (300 mg, 0.96 mmol) were slowly added under ice, and the mixture was stirred at 100°C for 6 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain an oily liquid. The residue was isolated and purified by medium-pressure preparative chromatography (instrument: Biotage Isolera One; column: C18 spherical 20-35 μm 100A 80 g (Agela Technologies); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water; gradient: 5%-90% acetonitrile isocratic elution; cycle time: 20 min; retention time: 7 min) to afford compound 15 (120 mg, 14.4% total yield over three steps).
[0278] LCMS m / z=480.4[M+H] + ;
[0279] 1 H NMR(400MHz,CD3OD)δ8.25(s,1H),7.77–7.72(m,1H),7.59(dd,2H),7.46(dd,1H),7.30 (t,1H),6.11(td,1H),3.91(t,2H),3.82–3.75(m,2H),3.59(s,3H),2.98–2.84(m,1H).
[0280] 19 F NMR(377MHz, DMSO-d6)δ-121.73(s),-145.77(s).
[0281] Example 16
[0282] Step 1: In a 100 mL single-necked flask, 3-(trifluoromethyl)azetidine hydrochloride (16A) (0.25 g, 1.55 mmol) was dissolved in dry acetonitrile (15 mL). 15B (0.47 g, 1.55 mmol) was added and stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, crude compound 16C, which was directly carried to the next step without purification.
[0283] Step 2: Compound 16C (crude product) and dichloromethane (12 ml) were added to a single-necked flask, followed by trifluoroacetic acid (3 ml) and reacted at room temperature for 2 hours. After concentration, compound 16D was obtained and directly used for the next step without purification.
[0284] Step 3: In a 100 mL single-necked flask, 16D (crude product) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (2.02 g, 6.20 mmol) and 1C (300 mg, 0.96 mmol) were slowly added under ice, and the mixture was stirred at 100°C for 6 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain an oily liquid. The residue was isolated and purified by medium-pressure preparative chromatography (instrument: Biotage Isolera One; column: C18 spherical 20-35 μm 100A 80 g (Agela Technologies); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water; gradient: 5%-90% acetonitrile isocratic elution; cycle time: 20 min; retention time: 8 min) to afford compound 16 (100 mg, 12.9% total yield over three steps).
[0285] LCMS m / z=498.5[M+H] + ;
[0286] 1 H NMR(400MHz,CD3OD)δ8.23(s,1H),7.75–7.70(m,1H),7.57(dd,2H),7.45(dd,1H), 7.34–7.26(m,1H),3.96(t,2H),3.89–3.82(m,2H),3.57(s,3H),3.33–3.24(m,1H).
[0287] 19 F NMR(377MHz, DMSO-d6)δ-70.81(s),-145.19(s).
[0288] Example 17
[0289] Step 1: In a 100 mL single-necked flask, dissolve 2-azabicyclo[3.1.0]hexane hydrochloride (17A) (0.47 g, 3.97 mmol) in dry acetonitrile (25 mL). Add 15B (1.2 g, 3.97 mmol) and stir at 70°C for 4 h. After the reaction is complete, concentrate the reaction solution to obtain a solid, crude compound 17B, which is carried on to the next step without purification.
[0290] Step 2: Compound 17B (680 mg, 2.59 mmol) and dichloromethane (12 ml) were added to a single-necked flask, followed by trifluoroacetic acid (3 ml). The mixture was allowed to react at room temperature for 2 hours. After concentration, the residue was separated by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 0:1) to afford compound 17C (420 mg, 99% yield).
[0291] Step 3: In a 100 mL single-necked flask, 17C (217 mg, 1.34 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (655 mg, 2.01 mmol) was slowly added under ice-cooling. The reaction was stirred at 50°C for 0.5 h. A solution of 1C (420 mg, 1.34 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise under ice-cooling. The reaction was stirred at 100°C for 2 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid, which was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-80% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 17 (56 mg, yield: 9%).
[0292] LCMS m / z=456.5[M+H] + ;
[0293] 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.36(s,1H),7.86(t,1H),7.78(d,1H),7.68(dd,1H),7.63(dd,1H),7.38(d,1H) ,3.48(s,3H),3.39(t,1H),3.18(m,1H),2.93(m,1H),2.05(m,1H),1.98(m,1H),1.61(m,1H),0.78(m,1H),0.52(m,1H).
[0294] 19F NMR(377MHz,DMSO-d6)δ-128.22(s).
[0295] Example 18
[0296] Step 1: To a 50 mL reaction flask, 18A (500 mg, 5.08 mmol), triethylamine (1.54 g, 15.24 mmol), and dichloromethane (10 mL) were added sequentially. After complete addition, the mixture was stirred at 0°C for 20 minutes. A solution of aminosulfonyl chloride (1.17 g, 10.16 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to yield 18B (500 mg, crude product).
[0297] Step 2: In a 50 mL reaction flask, 1C (1.76 g, 5.62 mmol), 18B (500 mg, 2.81 mmol), cesium carbonate (2.75 g, 8.37 mmol) and N,N-dimethylformamide (15 mL) were added in sequence. After the addition, the mixture was stirred at 100°C for 12 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 18 (22.34 mg, yield 1.7%).
[0298] LCMS m / z=472.5[M+H] + ;
[0299] 1 H NMR(400MHz, CDCl3)δ8.31(s,1H),7.84(d,1H),7.62(dd,1H),7.57(d,1H),7. 54(dd,1H),7.45(t,1H),6.95(s,1H),4.78(s,4H),4.18(s,4H),3.63(s,3H).
[0300] Example 19
[0301] Step 1: To a 50 mL reaction flask, 19A (500 mg, 4.49 mmol), triethylamine (1.36 g, 13.47 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 (520 mg, 4.49 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 1-2 hours. The reaction solution was diluted with dichloromethane (100 mL), washed sequentially with water (40 mL × 1) and saturated brine (40 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 = 12 / 1) to afford 19B (600 mg, 70% yield).
[0302] Step 2: In a 100 mL reaction flask, 1C (0.9 g, 2.87 mmol), 19B (0.6 g, 3.16 mmol), cesium carbonate (1.12 g, 3.44 mmol) and N,N-dimethylformamide (20 mL) were added in sequence. After the addition, the mixture was stirred at 80°C for 18 hours. Ethyl acetate (100 mL) was added to the reaction solution, which was then washed with water (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 19 (12 mg, yield 1%).
[0303] LCMS m / z=484.60[M+H] + ;
[0304] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.36(s,1H),7.88(t,1H),7.78(d,1H),7.68(dd ,1H),7.56(dd,1H),7.39(d,1H),3.72(s,4H),3.48(s,3H),1.71(m,4H),1.50(m,4H).
[0305] 19 F NMR(377MHz,DMSO-d6)δ-127.31(s).
[0306] Example 20 and Example 21
[0307] Step 1: Dissolve trimethylsulfoxide iodide (100.45 g, 456.62 mmol) in tert-butanol (350 mL) in a 500 mL reaction bottle at room temperature. Add potassium tert-butoxide (45.0 g, 401.83 mmol) and react at 50°C for 1 h. Then cool to room temperature and slowly add 20A (40.0 g, 182.65 mmol). After the addition is complete, react at 50°C for 48 h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and water (50 mL) was added, followed by extraction with ethyl acetate (150 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain 10.0 g of the racemate. The racemate was separated by chiral preparative HPLC to obtain peak 1 (3.0 g, retention time 8.45 min, set as 20B) and peak 2 (3.0 g, retention time 11.62 min, set as 21B), respectively. Preparative chromatography separation conditions: instrument SFC Prep 150AP; chromatographic column: Daicel AD-H (19 mm × 250 mm); mobile phase system: A for CO2 and B for MeOH; gradient: B 10%; flow rate: 45 mL / min.
[0308] Step 2: In a 100 mL reaction flask, compound 20B (3.0 g, 12.13 mmol) was dissolved in methanol (30 mL) at room temperature. Pd / C (0.3 g, 10% Pd content) was added and the reaction was allowed to proceed under a hydrogen atmosphere for 3 hours. After the reaction was complete, the filtrate was filtered and concentrated to obtain the crude title compound 20C (1.1 g, 80%), which was used directly in the next step without purification.
[0309] LCMS m / z=114.2[M+H] + .
[0310] Step 3: In a 50 mL reaction flask, compound 20C (1.1 g, 9.72 mmol) was dissolved in 1,4-dioxane (15 mL) at room temperature. Sulfonamide (0.78 g, 8.11 mmol) was added and the mixture was reacted at 100°C for 12 hours. After the reaction was complete, water (10 mL) was added and extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain the title compound 20D (1.3 g, 70%).
[0311] LCMS m / z=193.1[M+H] + .
[0312] Step 4: To a 50 mL reaction flask, 1C (407.4 mg, 1.30 mmol), 20D (500 mg, 2.60 mmol), cesium carbonate (813.8 mg, 2.60 mmol), and N,N-dimethylformamide (10 mL) were added sequentially at room temperature. The mixture was stirred at 100°C for 12 hours. After the reaction was complete, water (10 mL) was added and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue was separated by preparative HPLC. Method: 1. Instrument: Waters 2767 Preparative HPLC; Column: SunFire@Prep C18 (19 mm x 250 mm). 2. The sample was filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: acetonitrile; Mobile phase B: water (containing 0.1% ammonium acetate); b. Gradient elution, mobile phase A content from 10% to 55%; c. Flow rate: 12 mL / min; d. Elution time: 20 min. Compound 20 (230 mg, 18%) was obtained with a retention time of 7.0 min.
[0313] LCMS m / z=486.1[M+H] + .
[0314] 1 H NMR(400MHz, CDCl3)δ8.00(s,1H),7.73(d,1H),7.68(s,1H),7.61(d,1H),7.58(dd,1H),7.52(dd,1H),7.41–7.34(m,1H),4.57–4.4 5(m,2H),3.93–3.87(m,1H),3.56(s,3H),3.56–3.51(m,2H),3.40(d,1H),2.73–2.63(m,2H),2.49–2.40(m,1H),2.07–1.98(m,1H).
[0315] Compound 21 (200 mg) was obtained by the same synthesis method as compound 20 using 21B (3 g) as the starting material.
[0316] LCMS m / z=486.1[M+H] + .
[0317] 1H NMR(400MHz, CDCl3)δ8.01(s,1H),7.75(s,1H),7.73(d,1H),7.61(d,1H),7.57(dd,1H),7.51(dd,1H),7.40–7.34(m,1H),4.56–4.4 5(m,2H),3.92–3.86(m,1H),3.56(s,3H),3.55–3.51(m,2H),3.40(d,1H),2.71–2.63(m,2H),2.47–2.40(m,1H),2.06–1.98(m,1H).
[0318] Example 22
[0319] Step 1: In a 100 mL reaction bottle, 22A (0.8 g, 3.98 mmol) (synthesis reference patent WO2019 / 60611,2019,A1 for compound 22A) was dissolved in acetonitrile (20 mL), and potassium permanganate (1.20 g, 7.61 mmol) and basic alumina (1.0 g, 9.79 mmol) were added sequentially. After the addition, the mixture was reacted at room temperature for 5 hours. After the reaction was completed, the filtrate was filtered and concentrated. The residue was separated and purified by column chromatography (PE / EA = 1 / 1) to obtain 22B (0.65 g, yield 82%).
[0320] LCMS m / z=200.10[M+H] + ;
[0321] Step 2: In a 100 mL reaction flask, 22B (0.6 g, 3.01 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium ethanethiolate (0.50 g, 5.94 mmol) was added. The reaction solution was purged with nitrogen three times, heated to 130°C, and reacted for 10 h. After the reaction was completed, the reaction was filtered and the filtrate was concentrated to obtain 22C (0.45 g, 80% yield).
[0322] LCMS m / z=186.10[M+H] + ;
[0323] Step 3: In a 100 mL reaction flask, 22C (0.45 g, 2.43 mmol) was dissolved in N,N-dimethylformamide (10 mL). Cesium carbonate (1.20 g, 3.75 mmol) was slowly added under ice-water bath. After stirring at room temperature for 0.5 hour, a solution of 2,3,6-trifluorobenzonitrile (0.38 g, 2.43 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise under ice-water bath. The mixture was reacted at room temperature for 1 hour. The reaction solution 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 (PE / EA = 2 / 1) to afford 22D (0.55 g, 70% yield).
[0324] LCMS m / z=323.30[M+H] + ;
[0325] Step 4: In a 100 mL reaction flask, 22D (0.25 g, 0.78 mmol), 1B (0.21 g, 1.17 mmol), cesium carbonate (0.51 g, 1.56 mmol) and N,N-dimethylformamide (15 mL) were added in sequence. After the addition, the mixture was stirred at 100°C for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution, which was then washed with water (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 10 minutes) to obtain compound 22 (150 mg, 40% yield).
[0326] LCMS m / z=479.10[M+H] + ;
[0327] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),9.27(s,1H),8.09(d,1H),8.01(d,1H),7.87(t,1H), 7.62(d,1H),7.59(d,1H),7.58-7.53(m,2H),3.83(s,4H),2.08(t,4H),1.75-1.66(m,2H).
[0328] Example 23
[0329] Step 1: 23A (1.00 g, 9.11 mmol) and acetic acid (15 mL) were added to a single-necked flask, followed by the addition of ethyl 3-ethoxy-2-methyl-2-propenoate (2.88 g, 18.22 mmol). The reaction was heated under reflux for 16 hours. After completion of the reaction, as monitored by LCMS, the acetic acid was removed by vortexing, and the remaining solid was slurried with ethyl acetate (20 mL). The solid was filtered and dried to yield product 23B (1.2 g, 74.7%).
[0330] LC-MS (ESI): m / z = 177.1 [M+H] + .
[0331] Step 2: 23B (0.20 g, 1.14 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of cesium carbonate (0.74 g, 2.27 mmol). 2,3,6-trifluorobenzonitrile (0.23 g, 1.48 mmol) was added with stirring at 0°C. After addition, the mixture was slowly warmed to room temperature and reacted for 2 h. After completion of the reaction, monitored by LCMS, the reaction solution was poured into water (15 mL), whereupon a large amount of solid precipitated. The solid was filtered and dried to yield product 23C (0.12 g, 33.6%).
[0332] LC-MS (ESI): m / z = 314.1 [M+H] + .
[0333] Step 3: 23C (120.0 mg, 0.38 mmol), 1B (87.0 mg, 0.49 mmol), cesium carbonate (250.0 mg, 0.76 mmol), and N,N-dimethylformamide (5 mL) were added sequentially to a single-necked flask. The mixture was stirred at 80°C for 18 hours. After completion of the reaction, monitored by LCMS, ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (40 mL x 2). 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 = 10 / 1) to afford compound 23 (50.0 mg, 28.0%).
[0334] 1 H NMR((400MHz,DMSO-d6)δ10.41(s,1H),8.38(d,1H),8.30(d,1H),8.00(dd,1H),7.86(t,1 H),7.78(d,1H),7.53(dd,1H),3.82(s,4H),2.12(s,3H),2.09(t,4H),1.77-1.69(m,2H).
[0335] LC-MS (ESI): m / z = 470.1 [M+H] + .
[0336] Example 24
[0337] Step 1: To a 50 mL reaction flask, 24A (1.2 g, 10.95 mmol), triethylamine (3.32 g, 32.85 mmol), and acetonitrile (20 mL) were added sequentially. After complete addition, the mixture was stirred for 30 minutes. 15B (4.97 g, 16.43 mmol) was slowly added dropwise and stirred at 40°C for 3 hours. The reaction solution was concentrated under reduced pressure to yield 24B (1 g, crude product).
[0338] Step 2: To a 50 mL reaction flask, 24B (0.8 g, 3.17 mmol) and dichloromethane (6 mL) were added sequentially. Trifluoroacetic acid (2 mL) was slowly added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 24C (0.8 g, crude product).
[0339] Step 3: To a 50 mL reaction flask, 24C (0.8 g, 5.26 mmol), cesium carbonate (2.57 g, 7.89 mmol), and N,N-dimethylformamide (15 mL) were added sequentially. The mixture was stirred at 50°C for 2 hours. Then, 4E (2.08 g, 6.31 mmol) was added and the mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated and purified by preparative liquid chromatography (Waters 2767 preparative liquid chromatography; SunFire@Prep C18 column (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to afford compound 24 (91.8 mg, 3.79% yield).
[0340] LCMS m / z=462.1[M+H] + ;
[0341] 1 H NMR(400MHz, CDCl3)δ8.26(s,1H),7.80(d,1H),7.65-7.61(m,2H),7.58(dd, 1H),7.44(t,1H),4.24(t,2H),4.15(s,3H),3.73(t,2H),2.47-2.40(m,2H).
[0342] Example 25
[0343] Step 1: In a 25 mL reaction flask, compound 1 (180 mg, 0.38 mmol), Lawesson's reagent (768 mg, 1.90 mmol) and dry tetrahydrofuran (9 mL) were added in sequence. After the addition, the reaction was stirred at 80 ° C for 4 hours. The reaction solution was directly concentrated under reduced pressure. The residue was separated and purified by column chromatography (DCM / MeOH = 15 / 1) to obtain a crude product, which was separated and purified by preparative liquid phase to obtain compound 25 (35 mg, yield 19%).
[0344] LCMS m / z=486.1[M+H] + ;
[0345] 1 H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.70(s,1H),7.99(d,1H),7.89(dd,2H),7.7 7(dd,1H),7.56(dd,1H),3.87(s,3H),3.83(s,4H),2.09(t,4H),1.78–1.65(m,2H).
[0346] 19 F NMR(377MHz,DMSO-d6)δ-127.24(s).
[0347] Example 26
[0348] Step 1: 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 an ice-water bath. After stirring for 30 minutes, 4B (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 26A (3.8 g, 86% yield).
[0349] LCMS m / z=199.10[M+H] + ;
[0350] Step 2: In a 20 mL microwave tube, 26A (1.5 g, 8.58 mmol) was dissolved in triethyl orthoformate (10 mL). The reaction solution was heated to 185°C for 2 h. After the reaction was completed, the mixture was filtered and the filter cake was dried to obtain 26B (1.6 g, yield 89%).
[0351] LCMS m / z=209.10[M+H] +;
[0352] Step 3: In a 100 mL reaction flask, 26B (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. 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 afford 26C (1.35 g, 54% yield).
[0353] LCMS m / z=346.10[M+H] + ;
[0354] Step 4: In a 100 mL reaction flask, 26C (0.4 g, 1.16 mmol), 1B (0.31 g, 1.74 mmol), cesium carbonate (0.76 g, 2.32 mmol) and N,N-dimethylformamide (15 mL) were added in sequence, and the mixture was reacted at 100 ° C for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution, and then washed with water (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 10 minutes) to obtain compound 26 (320 mg, yield 55%).
[0355] LCMS m / z=502.10[M+H] + ;
[0356] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.33(s,1H),7.88(t,1H),7.80(d,1H),7.76-7.68(m,1H),7.56-7.5 1(m,1H),7.39(d,1H),4.79-4.62(m,2H),4.36-4.25(m,2H),3.83(s,4H),2.09(t,4H),1.78-1.69(m,2H).
[0357] Example 27
[0358] Step 1: In a 100 mL single-necked flask, 27A (1.0 g, 8.96 mmol) was dissolved in dry acetonitrile (15 mL). 15B (2.71 g, 8.96 mmol) and triethylamine (1.81 g, 17.96 mmol) were added and stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, compound 27C, which was carried on to the next step without purification.
[0359] Step 2: Compound 27C and dichloromethane (12 ml) were added to a single-necked flask, followed by trifluoroacetic acid (6 ml). The mixture was allowed to react at room temperature for 2 hours. After concentration, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 27D (800 mg, 57.9% total yield over two steps).
[0360] Step 3: In a 100 mL single-necked flask, 27D (0.45 g, 2.92 mmol) was dissolved in dry N,N-dimethylformamide (6 mL). Cesium carbonate (0.95 g, 2.92 mmol) and 4E (800 mg, 2.43 mmol) were slowly added, and the mixture was stirred at 80°C for 6 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain an oily liquid. The residue was isolated and purified by medium-pressure preparative chromatography (instrument: Biotage Isolera One; column: C18 spherical 20-35 μm 100A 80 g (Agela Technologies); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water; gradient: 5%-90% acetonitrile isocratic elution; cycle time: 20 min; retention time: 7.5 min) to afford compound 27 (85 mg, 7.5% yield).
[0361] LCMS m / z=464.1[M+H] + ;
[0362] 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),7.96–7.78(m,2H),7.73(dd,1H),7.56(dd,1H) ,7.44(d,1H),5.47-5.28(m,1H),4.25-4.16(m,2H),4.05(s,3H),4.04–3.95(m,2H).
[0363] 19 F NMR(377MHz, DMSO-d6)δ-126.63(s),-177.31(s).
[0364] Example 28
[0365] Step 1: In a 100 mL single-necked flask, 28A (1.0 g, 7.72 mmol) was dissolved in dry acetonitrile (15 mL). 15B (2.33 g, 7.72 mmol) and triethylamine (1.56 g, 15.44 mmol) were added and stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, crude compound 28C, which was directly carried to the next step without purification.
[0366] Step 2: Compound 28C (crude) and dichloromethane (12 ml) were added to a single-necked flask, followed by trifluoroacetic acid (6 ml). The mixture was allowed to react at room temperature for 2 hours. After concentration, the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to afford compound 28D (670 mg, 56.30% total yield over two steps).
[0367] Step 3: In a 100 mL single-necked flask, 28D (0.47 g, 2.74 mmol) was dissolved in dry N,N-dimethylformamide (6 mL). Cesium carbonate (0.89 g, 2.74 mmol) and 4E (750 mg, 2.28 mmol) were slowly added and the mixture was stirred at 80°C for 6 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated to obtain an oily liquid. The residue was isolated and purified by medium-pressure preparative chromatography (instrument: Biotage Isolera One; column: C18 spherical 20-35 μm 100A 80 g (Agela Technologies); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water; gradient: 5%-90% acetonitrile isocratic elution; cycle time: 20 min; retention time: 8 min) to afford compound 28 (180 mg, 16.4% yield).
[0368] LCMS m / z=482.1[M+H] + ;
[0369] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.91(dd,1H),7.84(d,1H),7.73(dd,1H),7.58(dd,1H),7.45(d,1H),4.41(t,4H),4.05(s,3H).
[0370] 19 F NMR(377MHz, DMSO-d6)δ-90.00(s),-126.12.(s).
[0371] Example 29
[0372] Step 1: In a 100 mL single-necked vial, compound 29A (0.4 g, 2.64 mmol) was dissolved in acetonitrile (25 mL). Compound 15B (1.10 g, 3.64 mmol) was then added and the mixture was allowed to react at 40°C for 3 hours. After the reaction was complete, the reaction solution was concentrated to afford compound 29B (1.5 g, crude product), which was directly carried to the next step.
[0373] Step 2: In a 100 mL single-necked vial, compound 29B (1.5 g, 5.10 mmol) was dissolved in dichloromethane (30 mL). Trifluoroacetic acid (10 mL) was added and the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the residue was concentrated and purified by column chromatography (PE / EA = 1 / 1) to afford compound 29C (420 mg, 43% yield).
[0374] LCMS m / z=502.10[M+H] + ;
[0375] Step 3: In a 100 mL single-necked flask, compound 4E (0.5 g, 1.52 mmol) was dissolved in dry N,N-dimethylformamide (20 mL). Cesium carbonate (1.0 g, 3.07 mmol) was added and stirred at 50°C for 0.5 h. A solution of 29C (0.42 g, 2.16 mmol) in N,N-dimethylformamide (5 mL) was then added dropwise. After complete addition, the reaction mixture was stirred at 100°C for 12 h. After the reaction, the product was filtered and the filtrate was concentrated. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 10 minutes) to obtain compound 29 (80 mg, 10% yield).
[0376] LCMS m / z=504.10[M+H] + ;
[0377] 1H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.63(s,1H),7.89(t,1H),7.83(d,1H),7.75-7.68(m,1H),7.57-7.53(m,1H),7.42(d,1H),5. 04-4.84(m,1H),4.18(d,1H),4.04(s,3H),3.94(d,1H),3.86-3.79(m,2H),2.19-2.10(m,1H),2.02-1.78(m,2H),1.70-1.62(m,1H).
[0378] Example 30
[0379] Step 1: In a 250 mL single-necked flask, 4B (4 g, 22.29 mmol) was dissolved in a 40 mL solution of sodium hydroxide (2.85 g, 71.33 mmol). 1-Methylcyclopropylamine hydrochloride (8.39 g, 78.02 mmol) was added and the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was dissolved in a mixture of dichloromethane (200 mL) and methanol (10 mL), dried over anhydrous sodium sulfate, and filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20 / 1) to afford 30A (4.0 g, 87% yield).
[0380] Step 2: In a 50 mL single-necked flask, 30A (4.0 g, 19.39 mmol) was dissolved in trimethyl orthoformate (32 mL). The reaction was stirred at 105°C for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by slurrying with petroleum ether. The solid was filtered and dried to obtain 30B (2.4 g, 57% yield).
[0381] LCMS m / z=217.1[M+H] + ;
[0382] Step 3: In a 100 mL single-necked flask, 30B (2.0 g, 9.25 mmol) was dissolved in dry N,N-dimethylformamide (40 mL). Cesium carbonate (3.62 g, 11.1 mmol) was slowly added under ice-cooling and stirred at room temperature for 0.5 h. A solution of 2,3,6-trifluorobenzonitrile (1.45 g, 9.25 mmol) in N,N-dimethylformamide (10 mL) was slowly added dropwise under ice-cooling and stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was poured into ice water (250 mL), stirred for 30 min, and filtered. The resulting solid was dried and purified by slurrying with a mixture of petroleum ether (100 mL) and ethyl acetate (10 mL). The solid was filtered and dried to afford 30C (2.5 g, 76% yield).
[0383] LCMS m / z=354.1[M+H] + ;
[0384] Step 4: In a 100 mL single-necked flask, compound 1B (240 mg, 1.36 mmol) was dissolved in dry N,N-dimethylformamide (8 mL). Cesium carbonate (552 mg, 1.69 mmol) was slowly added under ice-cooling. The mixture was stirred at 50°C for 0.5 h. A solution of compound 30C (400 mg, 1.13 mmol) in N,N-dimethylformamide (2 mL) was slowly added dropwise under ice-cooling. The mixture was stirred at 100°C for 6 h. After the reaction was complete, the reaction solution was poured into ice water (50 mL), stirred for 30 min, and filtered. The resulting solid was dried and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 30 (240 mg, yield 42%).
[0385] LCMS m / z=510.2[M+H] + ;
[0386] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.36(s,1H),7.93–7.84(m,1H),7.77(d,1H),7.68(dd,1H),7.54 (dd,1H),7.35(d,1H),3.84(s,4H),2.10(t,4H),1.75(dd,2H),1.45(s,3H),1.06(t,2H),0.94(t,2H).
[0387] 19 F NMR(377MHz,DMSO-d6)δ-127.33(s).
[0388] Example 31
[0389] Step 1: To a 250 mL reaction flask, 31A (10 g, 39.61 mmol), aqueous ammonia (20 mL), and 1,4-dioxane (100 mL) were added sequentially and stirred at 100°C for 24 h. The reaction mixture was extracted with ethyl acetate, washed, and concentrated to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) afforded 31B (8.5 g, 86.02% yield).
[0390] Step 2: To a 50 mL reaction flask, 31B (2 g, 8.02 mmol), 6-hydroxy-3-methylquinazolin-4(3H)-one (CAS: 19181-69-2, 2.31 g, 12.03 mmol), 18-crown 6 (2.12 g, 8.02 mmol), potassium carbonate (3.33 g, 24.06 mmol), and N-methylpyrrolidone (20 mL) were added sequentially. After complete addition, the mixture was stirred at 110°C for 12 hours. The reaction solution was extracted (ethyl acetate), washed, and concentrated to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) afforded 31C (500 mg, 17.28% yield).
[0391] Step 3: To a 50 mL reaction flask, 31C (0.25 g, 0.73 mmol), copper bromide (0.49 g, 2.19 mmol), tert-butyl nitrite (0.23 g, 2.19 mmol), and acetonitrile (3 mL) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was extracted (ethyl acetate), washed, and concentrated to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) afforded 31D (250 mg, 83.81% yield).
[0392] Step 4: To a 50 mL reaction vial were added 31D (250 mg, 0.61 mmol), 1B (0.22 g, 1.22 mmol), potassium carbonate (100 mg, 0.73 mmol), Xantphos (71 mg, 0.12 mmol), Pd2(dba)3 (56 mg, 0.06 mmol), and 1,4-dioxane (5 mL), followed by stirring at 120°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation to afford compound 31 (88.1 mg, 28.6% yield).
[0393] LCMS m / z=504.8[M+H] + ;
[0394] 1 H NMR (400MHz, CDCl3) δ8.09(s,1H),7.79(d,1H),7.64-7.56(m,3H),3.99(s,4H),3.60(s,3H),2.20(t,4H),1.89-1.81(m,2H).
[0395] Example 32
[0396] Step 1: To a 50 mL reaction flask, 31B (2 g, 8.02 mmol), 4D (2.31 g, 12.03 mmol), 18-crown 6 (2.12 g, 8.02 mmol), potassium carbonate (3.33 g, 24.06 mmol), and N-methylpyrrolidone (20 mL) were added sequentially. The mixture was stirred at 110°C for 12 hours. The reaction mixture was extracted with ethyl acetate, washed, and concentrated to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) afforded 32A (500 mg, 17.28% yield).
[0397] Step 2: To a 50 mL reaction flask, 32A (0.13 g, 0.36 mmol), copper bromide (0.24 g, 1.08 mmol), tert-butyl nitrite (0.11 g, 1.08 mmol), and acetonitrile (3 mL) were added sequentially and stirred at room temperature for 2 hours. The reaction solution was extracted (ethyl acetate), washed, and concentrated to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) afforded 32B (90 mg, 58.88% yield).
[0398] Step 3: To a 50 mL reaction vial, 32B (90 mg, 0.21 mmol), 1B (74 g, 0.42 mmol), potassium carbonate (35 mg, 0.25 mmol), Xantphos (24 mg, 0.04 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), and 1,4-dioxane (3 mL) were added sequentially and stirred at 120°C for 5 hours. The reaction mixture was filtered, the filtrate concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Waters 2767 preparative liquid chromatography; SunFire@Prep C18 column (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to afford compound 32 (18.28 mg, 16.74% yield).
[0399] LCMS m / z=520.9[M+H] + ;
[0400] 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),7.84(d,1H),7.66-7.59(m,3H),4.17(s,3H),3.99(s,4H),2.20(t,4H),1.89-1.81(m,2H).
[0401] Example 33
[0402] Step 1: 33A (2.92 g, 39.98 mmol) and water (40 mL) were added to a 250 mL single-necked flask. 4B (2.10 g, 11.76 mmol) was added at 0-5°C and allowed to react at room temperature for 4 hr. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford 33B (2.2 g, 89% yield).
[0403] LCMS m / z=209.1[M+H] + ;
[0404] Step 2: In a 100 mL single-necked flask, 33B (2.0 g, 9.61 mmol) was added to trimethyl orthoformate (20 mL) and reacted at 105°C overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to afford 33C (870 mg, 41% yield).
[0405] LCMS m / z=219.1[M+H] + ;
[0406] Step 3: In a 25 mL single-necked flask, 33C (0.87 g, 3.99 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (1.56 g, 4.79 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (0.66 g, 4.19 mmol) was slowly added dropwise under ice-cooling. The reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (15 mL) was added to dilute the reaction system. Water (20 mL) was then added to quench the reaction. 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 = 1 / 1) to afford 33D (0.71 g, 50% yield).
[0407] LCMS m / z=356.2[M+H] + ;
[0408] 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.00–7.94(m,1H),7.82-7.80(d,1H),7.76-7.73 (dd,1H),7.61-7.55(m,2H),5.55-4.47(p,1H),4.97-4.93(t,2H),4.89-4.85(t,2H).
[0409] Step 4: In a 25 mL single-necked flask, 1B (0.22 g, 1.24 mmol) and cesium carbonate (0.44 g, 1.36 mmol) were added to dry N,N-dimethylformamide (10 mL). The mixture was reacted at 50°C for 30 min. Then, a solution of 33D (0.40 g, 1.13 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50°C. After the addition, the mixture was stirred at 80°C for 4 hrs. After the reaction was complete, the reaction was filtered and the filtrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain 220 mg of a solid. The solid was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 33 (160 mg, 27% yield).
[0410] LCMS m / z=512.6[M+H] + ;
[0411] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.38(s,1H),7.89–7.80(m,2H),7.72-7.69(dd,1H),7.55-7.52(dd,1H),7.37-7. 36(d,1H),5.53-5.45(p,1H),4.96-4.92(t,2H),4.88-4.84(t,2H),3.83(s,4H),2.12-2.08(t,4H),1.78–1.70(m,2H).
[0412] 19 F NMR(377MHz,DMSO-d6)δ-127.30(s).
[0413] Example 34
[0414] Step 1: 34A (2.00 g, 17.57 mmol) and water (20 mL) were added to a 250 mL single-necked flask. A solution of sodium hydroxide (0.62 g, 15.62 mmol) in water (20 mL) was slowly added dropwise at 0-5°C. The mixture was reacted at 0-5°C for 10 min. 4B (0.87 g, 4.88 mmol) was then added at 0-5°C and allowed to react at room temperature for 4 hr. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford 34B (0.83 g, 80% yield).
[0415] LCMS m / z=213.1[M+H] + ;
[0416] Step 2: In a 100 mL single-necked flask, 34B (0.72 g, 3.39 mmol) was added to trimethyl orthoformate (10 mL) and reacted at 105°C overnight. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to afford 34C (280 mg, 37% yield).
[0417] LCMS m / z=223.2[M+H] + ;
[0418] Step 3: In a 25 mL single-necked flask, 34C (0.28 g, 1.26 mmol) was dissolved in dry N,N-dimethylformamide (4 mL). Cesium carbonate (0.49 g, 1.51 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (0.22 g, 1.39 mmol) was slowly added dropwise under ice-cooling. The reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (10 mL) was added to dilute the reaction system. Water (10 mL) was then added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was washed with water (10 mL x 2). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford 34D (0.25 g, 55% yield).
[0419] LCMS m / z=360.1[M+H] + ;
[0420] 1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.01–7.95(m,1H),7.81-7.73(m,2H),7.62–7.56(m,2H),5.17 –5.04(m,1H),4.91-4.86(dd,0.5H),4.79–4.75(m,1H),4.67-4.63(dd,0.5H),1.48-1.45(dd,3H).
[0421] Step 4: In a 25 mL single-necked flask, 1B (0.13 g, 0.73 mmol) and cesium carbonate (0.27 g, 0.84 mmol) were added to dry N,N-dimethylformamide (6 mL). The mixture was reacted at 50°C for 30 min. Then, a solution of 34D (0.25 g, 0.70 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50°C. After the addition, the mixture was stirred at 80°C for 4 hrs. After the reaction was complete, the reaction was filtered and the filtrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 34 (110 mg, 30% yield).
[0422] LCMS m / z=516.2[M+H] + ;
[0423] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.42(s,1H),7.90-7.85(dd,1H),7.8 2-7.79(d,1H),7.73-7.70(dd,1H),7.56-7.52(dd,1H),7.38-7.37(d,1H),5 .13-5.04(m,1H),4.90-4.85(dd,0.5H),4.78–4.73(m,1H),4.65-4.62(dd,0 .5H),3.84(s,4H),2.11-2.07(t,4H),1.77–1.70(m,2H),1.45–1.44(m,3H).
[0424] 19 F NMR(377MHz, DMSO-d6)δ-72.80(s),-127.34(s).
[0425] Example 35
[0426] Step 1: 35A (2.50 g, 22.01 mmol) and water (25 mL) were added to a 250 mL single-necked flask. A solution of sodium hydroxide (0.79 g, 19.78 mmol) in water (25 mL) was slowly added dropwise at 0-5°C. The mixture was reacted at 0-5°C for 10 min. 4B (1.10 g, 6.18 mmol) was then added at 0-5°C and allowed to react at room temperature for 4 hr. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford 35B (0.65 g, 49% yield).
[0427] LCMS m / z=213.1[M+H] + ;
[0428] Step 2: In a 100 mL single-necked vial, 35B (0.72 g, 3.39 mmol) was added to triethyl orthoformate (10 mL) and reacted at 180°C under microwave conditions for 2.5 hr. After completion of the reaction, the mixture was cooled to room temperature and concentrated to afford crude product 35C, which was directly used in the next step.
[0429] LCMS m / z=223.2[M+H] + ;
[0430] Step 3: In a 25 mL single-necked flask, crude 35C was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (1.1 g, 3.41 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (0.49 g, 3.12 mmol) was slowly added dropwise under ice-cooling. The reaction was stirred at room temperature overnight. After completion of the reaction, ethyl acetate (20 mL) was added to dilute the reaction system. Water (20 mL) was then added to quench the reaction. 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 = 3 / 1) to afford 35D (0.16 g, 15% yield).
[0431] LCMS m / z=360.1[M+H] + ;
[0432] Step 4: In a 25 mL single-necked flask, 1B (83.27 mg, 0.47 mmol) and cesium carbonate (0.17 g, 0.54 mmol) were added to dry N,N-dimethylformamide (4 mL). The mixture was reacted at 50°C for 30 min. Then, a solution of 35D (0.16 g, 0.45 mmol) in N,N-dimethylformamide (1 mL) was added dropwise at 50°C. After the addition, the mixture was stirred at 80°C for 3 hrs. After the reaction was complete, the reaction was filtered and the filtrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 35 (105 mg, 45% yield).
[0433] LCMS m / z=516.6[M+H] + ;
[0434] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.42(s,1H),7.90–7.79(m,2H),7.73-7.70(dd,1H),7.56-7.52(dd,1H),7.38-7.37(d,1H),5.13–5.04( m,1H),4.89-4.85(dd,0.5H),4.78–4.73(m,1H),4.65-4.62(dd,0.5H) ,3.83(s,4H),2.11-2.07(t,4H),1.77–1.70(m,2H),1.46-1.44(d,3H).
[0435] 19 F NMR(377MHz, DMSO-d6)δ-74.66(s),-129.42(s).
[0436] Example 36 and Example 37
[0437] Compound 17 (300 mg) was separated by chiral SFC to afford P1 (retention time: 0.588 min, identified as compound 36) and P2 (retention time: 0.694 min, identified as compound 37). Separation method: Instrument: Waters 150Prep-SFC F; Column: Chiralcel AD-Column; Mobile phases: A for CO2 and B for 0.1% NH3·H2O in MEOH and ACN; Gradient: Isocratic elution with 35% mobile phase B; Flow rate: 120 mL / min. Sample preparation: The compound was dissolved in acetonitrile at a concentration of 10 mg / mL; Injection: 2.0 mL per injection; Workup: After separation, the product was concentrated by rotary evaporation at 35°C and then dried in a lyophilizer at -80°C to afford compound 36 (86 mg, 29%) and compound 37 (74 mg, 25%).
[0438] Compound 36:
[0439] LCMS m / z=456.1[M+H] + ;
[0440] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.35(s,1H),7.84(t,1H),7.78(d,1H),7.68(dd,1H),7.62(dd,1H),7.37(d,1H),3.47(s,3H ),3.40–3.34(m,1H),3.17(dd,1H),2.93(dd,1H),2.10–2.01(m,1H),1.96(dd,1H),1.60(dt,1H),0.81–0.75(m,1H),0.50(dd,1H).
[0441] 19 F NMR(377MHz,DMSO-d6)δ-128.22(s).
[0442] Compound 37:
[0443] LCMS m / z=456.1[M+H] + ;
[0444] 1H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.36(s,1H),7.85(t,1H),7.78(d,1H),7.68(dd,1H),7.62(dd,1H),7.38(d,1H),3. 47(s,3H),3.37(s,1H),3.17(s,1H),2.93(dd,1H),2.09–2.00(m,1H),1.98(d,1H),1.60(s,1H),0.78(s,1H),0.50(d,1H).
[0445] 19 F NMR(377MHz,DMSO-d6)δ-128.22(s).
[0446] Example 38
[0447] Step 1: 38A (16.66 g, 119.37 mmol) and water (120 mL) were added to a 1000 mL single-necked flask. A solution of sodium hydroxide (4.29 g, 107.30 mmol) in water (120 mL) was slowly added dropwise at 0-5°C. The mixture was reacted at 0-5°C for 10 min. 6-Hydroxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (6.00 g, 33.53 mmol) was then added at 0-5°C and allowed to react at room temperature for 4 hr. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford 38B (3.0 g, 37.56% yield).
[0448] LCMS m / z=239.1[M+H] + ;
[0449] Step 2: In a 100 mL single-necked flask, 38B (2.7 g, 11.33 mmol) was added to dry N,N-dimethylformamide (30 mL). Triethyl orthoformate (30 mL) was added at room temperature and the mixture was reacted at 150°C for 4 hr. After the reaction was complete, the mixture was cooled to room temperature and concentrated to afford crude product 38C, which was directly used in the next step.
[0450] LCMS m / z=249.1[M+H] + ;
[0451] Step 3: In a 25 mL single-necked flask, 38C was dissolved in dry N,N-dimethylformamide (30 mL). Cesium carbonate (4.11 g, 13.54 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (1.95 g, 12.41 mmol) was slowly added dropwise under ice-cooling. The reaction was stirred at room temperature overnight. After the reaction was complete, ethyl acetate (100 mL) was added to dilute the reaction system. Water (100 mL) was then added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was washed with water (100 mL x 2). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford 38D (2.4 g, 55% yield).
[0452] LCMS m / z=386.2[M+H] + ;
[0453] Step 4: In a 25 mL single-necked flask, 1B (1.32 g, 7.48 mmol) and cesium carbonate (3.04 g, 9.37 mmol) were added to dry N,N-dimethylformamide (20 mL) and reacted at 50°C for 30 min. Then, a solution of 38D (2.40 g, 6.23 mmol) in N,N-dimethylformamide (10 mL) was added dropwise at 50°C. After the addition, the mixture was stirred at 80°C overnight. After completion of the reaction, the reaction mixture was filtered, and the organic phase of the filtrate was concentrated and purified by column chromatography (dichloromethane / petroleum ether = 10 / 1) to afford compound 38E (2.1 g, 62% yield).
[0454] LCMS m / z=542.4[M+H] + ;
[0455] Step 5: In a 25 mL single-necked flask, 38E (2.00 g, 3.69 mmol) was added to methanol (5 mL). Ammonia methanol solution (7.0 M, 40 mL) was added dropwise at 0-5°C. After the addition, the mixture was stirred at room temperature overnight. After the reaction was complete, the reaction solution was concentrated to obtain compound 38F (crude product), which was directly used in the next step.
[0456] LCMS m / z=513.1[M+H] + ;
[0457] Step 6: In a 25 mL single-necked vial, 38F (0.21 g, 0.41 mmol) was added to dry dichloromethane (6 mL). Burgess reagent (195.41 g, 0.82 mmol) was then added at 0-5°C. The reaction mixture was stirred and allowed to react overnight at room temperature. The reaction mixture was filtered, and the filtrate was purified by preparative liquid chromatography (Waters 2767 preparative liquid chromatography; SunFire@Prep C18 column (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to afford compound 38 (35 mg, 17% yield).
[0458] LCMS m / z=495.1[M+H] + ;
[0459] 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.40(s,1H),7.90–7.82(m,2H),7.75-7.73(dd,1H),7.56-7.52 (dd,1H),7.44-7.43(d,J=2.9Hz,1H),5.08(s,2H),3.84(s,4H),2.11-2.08(t,4H),1.78–1.70(m,2H).
[0460] 19 F NMR(377MHz,DMSO-d6)δ-127.33(s).
[0461] Example 39
[0462] Step 1: In a 100 mL single-necked flask, 26B (627 mg, 3.01 mmol), 39A (701 mg, 3.01 mmol), and cesium carbonate (1.47 g, 4.51 mmol) were dissolved in dry N,N-dimethylformamide (25 mL). The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was diluted with ethyl acetate (200 mL). The organic phase was washed twice with water (60 mL) and twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 1:1) to afford compound 39C (800 mg, 74% yield).
[0463] Step 2: Compound 39C (800 mg, 2.22 mmol), copper bromide (992 mg, 4.44 mmol), and acetonitrile (40 ml) were added to a single-necked flask. Tert-butyl nitrite (458 mg, 4.44 mmol) was slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was padded with celite and filtered. The filtrate was concentrated and the residue was separated by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 0:1) to afford compound 39D (814 mg, 86% yield).
[0464] Step 3: In a 100 mL single-necked bottle, 39D (550 mg, 1.30 mmol), 39E (275 mg, 1.56 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (110 mg, 0.26 mmol), allylpalladium chloride (71 mg, 0.20 mmol), and potassium carbonate (629 mg, 4.55 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70°C for 5 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated. The resulting oily liquid was purified by column chromatography (DCM:EA=1:2) to obtain a crude compound. The crude product was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 30%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 39 (210 mg, yield: 31%).
[0465] LCMS m / z=520.50[M+H] + ;
[0466] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.80(d,1H),7.75(dd,1H),7.59(d,1H),7.53 (dd,1H),4.72(dt,2H),4.32(dt,2H),3.85(s,4H),2.10(t,4H),1.79–1.68(m,2H).
[0467] 19 F NMR(376MHz, DMSO-d6)δ-121.46(s),-150.87(s),-222.31(s).
[0468] Example 40 and Example 41:
[0469] Step 1: In a 25 mL single-necked flask, 29C (0.400 g, 2.06 mmol) and cesium carbonate (1.01 g, 3.09 mmol) were added to dry N,N-dimethylformamide (10 mL) and reacted at 50°C for 30 min. Then, a solution of 10E (0.748 g, 2.06 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50°C. The mixture was stirred at 100°C overnight. After completion of the reaction, the reaction mixture was filtered, and the filter cake was added to N,N-dimethylformamide (4 mL). The filtrate was concentrated and then dissolved in water (15 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous phase was extracted once with ethyl acetate (10 mL). The pH was adjusted to approximately 7 with saturated ammonium chloride solution, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to afford crude product 40A, which was directly used in the next step.
[0470] LCMS m / z=538.5[M+H] + ;
[0471] Step 2: Crude product 40A was separated by chiral SFC to yield P1 (retention time: 14.73 min, assumed to be compound 40) and P2 (retention time: 24.02 min, assumed to be compound 41). Separation method: Instrument: Waters 150SFC; Column: AD; Mobile phases: A for CO2 and B for IPA + MeOH (0.05% NH3·H2O); Flow rate: 42 mL / min; Column pressure: 100 bar; Column temperature: 25°C; Absorption wavelength: 220 nm; Cycle time: 40 min. Sample preparation: The compound was dissolved in methanol at a concentration of 40 mg / mL; Injection: 5 mL per injection; Workup: After separation, the sample was concentrated by rotary evaporation at 35°C, and the solvent was then dried in a lyophilizer at -80°C to yield P1 and P2.
[0472] Compound 40: (P1: 120 mg, 11%), 1 H NMR(400MHz, DMSO-d6)δ10.45(s,1H),8.33(s,1H),7.83–7.80(m,2H),7.72-7.69(dd,1H),7.54-7.50(dd,1H),7.43-7.42(d,1H),6.51–6.22( m,1H),5.02-4.99(dt,1H),4.51-4.43(td,2H),4.16-4.14(d,1H),3.92 –3.77(m,3H),2.18-2.07(m,1H),2.00–1.79(m,2H),1.69-1.62(m,1H).
[0473] 19 F NMR(376MHz, DMSO-d6)δ-120.44(s),-171.59(s),-216.41(s).
[0474] Compound 41: (P2: 140 mg, 13%), 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.34(s,1H),7.88-7.80(m,2H),7.73-7.70(dd,1H),7.54-7.51(dd,1H),7.43-7.42(d,1H),6.51–6.22( m,1H),5.03-4.99(dt,1H),4.51-4.43(td,2H),4.17-4.15(d,1H),3.93 –3.78(m,3H),2.18–2.10(m,1H),2.00–1.79(m,2H),1.69-1.62(m,1H).
[0475] 19 F NMR(376MHz, DMSO-d6)δ-120.44(s),-127.17(s),-171.59(s).
[0476] Example 42
[0477] Step 1: 42A (420 mg, 1.70 mmol) and acetonitrile (5 mL) were added to a 25 mL single-necked flask. Triethylamine (0.430 g, 4.25 mmol) and (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)yl)sulfonyl)amide (0.615 g, 2.04 mmol) were slowly added dropwise at 0-5°C. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated to afford crude product 42B, which was directly used in the next step.
[0478] LCMS m / z=257.1[M+H] + ;
[0479] Step 2: In a 25 mL single-necked flask, crude product 42B was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5 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 = 2 / 1) to afford 42C (0.250 g, 70% yield).
[0480] LCMS m / z=213.2[M+H] + ;
[0481] Step 3: In a 25 mL single-necked flask, 42C (0.250 g, 1.18 mmol) and cesium carbonate (0.577 g, 1.77 mmol) were added to dry N,N-dimethylformamide (5 mL) and reacted at 50°C for 30 min. Then, a solution of 10E (0.429 g, 1.18 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50°C. After the addition, the reaction was stirred at 80°C overnight. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 42 (110 mg, yield 17%).
[0482] LCMS m / z=556.0[M+H] + .
[0483] 1 H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.34(s,1H),7.92–7.87(m,1H),7.83-7.80(d,1H),7.73-7.70(dd,1H),7.55-7.52(dd,1H) ,7.44(d,1H),6.51-6.22(m,1H),4.52-4.43(m,2H),4.08-4.06(d,2H),3.91-3.88(d,2H),2.47–2.42(m,2H),2.04-2.00(m,2H).
[0484] 19 F NMR(376MHz, DMSO-d6)δ-98.98(s),-120.45(s),-126.75(s).
[0485] Example 43
[0486] Step 1: In a 100 mL single-necked flask, 10C (700 mg, 3.09 mmol), 39A (720 mg, 3.09 mmol), and cesium carbonate (1.53 g, 4.63 mmol) were dissolved in dry N,N-dimethylformamide (25 mL). The mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was diluted with ethyl acetate (200 mL). The organic phase was washed twice with water (60 mL) and twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 1:1) to afford compound 43C (830 mg, 71% yield).
[0487] Step 2: Compound 43C (830 mg, 2.22 mmol), copper bromide (992 mg, 4.44 mmol), and acetonitrile (40 ml) were added to a single-necked flask. tert-Butyl nitrite (458 mg, 4.44 mmol) was slowly added dropwise under an ice bath. The mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was padded with Celite and filtered. The filtrate was concentrated and the residue was separated by column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 to 0:1) to afford compound 43D (800 mg, 82% yield).
[0488] Step 3: In a 100 mL single-necked bottle, 43D (800 mg, 1.81 mmol), 1B (400 mg, 2.26 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (154 mg, 0.36 mmol), allylpalladium chloride (99 mg, 0.27 mmol), and potassium carbonate (625 mg, 4.25 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70°C for 5 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated. The resulting oily liquid was purified by column chromatography (DCM:EA=1:2) to obtain a crude compound. The crude product was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 30%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 43 (56 mg, yield: 6%).
[0489] LCMS m / z=538.1[M+H] + ;
[0490] 1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.81(d,1H),7.77(dd,1H),7.59(d,1H),7.52(dd,1 H),6.52-6.23(m,1H),4.49(td,2H),3.83(s,4H),2.08-2.11(m,4H),1.77-1.70(m,2H).
[0491] Example 44
[0492] Step 1: 44A (4.5 g, 23.13 mmol) and isopropanol (50 mL) were added to a 250 mL single-necked flask. Triethylamine (4.68 g, 46.26 mmol) and isopropanolamine (2.08 g, 27.76 mmol) were then added and reacted at 80°C for 1 hr. After the reaction was complete, the reaction mixture was concentrated, slurried with ethyl acetate (50 mL), filtered, and the filter cake washed with petroleum ether (50 mL) to afford 44B (5.30 g, 98% yield).
[0493] LCMS m / z=234.3[M+H] + ;
[0494] Step 2: Phosphorus oxychloride (60 mL) was added to a 250 mL single-necked flask. 44B (5.3 g, 22.72 mmol) was slowly added portionwise at 0-5°C. The reaction was incubated at 110°C for 5 hr. After completion of the reaction, the reaction solution was concentrated and quenched by the slow addition of water (100 mL) at 0-5°C. The mixture was then extracted with ethyl acetate (100 mL x 2). The organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 44C (3.6 g, 73% yield).
[0495] LCMS m / z=216.2[M+H] + ;
[0496] Step 3: 4C (2.80 g, 13.01 mmol) and acetonitrile (30 mL) were added to a 100 mL single-necked flask. Alumina (2.65 g, 25.99 mmol) and potassium permanganate (3.08 g, 19.49 mmol) were then added. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 2) to afford 44D (0.88 g, 31% yield).
[0497] LCMS m / z=214.1[M+H] + ;
[0498] 1H NMR (400MHz, DMSO-d6) δ9.01(s,1H),7.86-7.84(d,1H),7.74-7.73(d,1H),7.35(s,1H),7.32-7.29(dd,1H),3.94(s,3H),2.58(s,3H).
[0499] Step 4: 4D (0.88 g, 4.13 mmol) and N,N-dimethylformamide (10 mL) were added to a 50 mL single-necked flask, followed by sodium ethanethiolate (1.04 g, 12.35 mmol). After the addition, the mixture was stirred at 130°C under nitrogen atmosphere overnight. After completion of the reaction, the reaction solution was concentrated, and the pH was adjusted to acidic by adding dilute hydrochloric acid. The residue was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to afford 44E (0.68 g, 82% yield).
[0500] LCMS m / z=200.1[M+H] + ;
[0501] Step 5: In a 25 mL single-necked flask, 44E (0.30 g, 1.51 mmol) was dissolved in dry N,N-dimethylformamide (8 mL). Cesium carbonate (0.74 g, 2.26 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 0.5 h. 2,3,6-Trifluorobenzonitrile (0.28 g, 1.81 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 = 1 / 1) to afford 44F (0.45 g, 88% yield).
[0502] LCMS m / z=337.0[M+H] + ;
[0503] Step 6: In a 25 mL single-necked flask, 1B (0.21 g, 1.16 mmol) and cesium carbonate (0.47 g, 1.46 mmol) were added to dry N,N-dimethylformamide (5 mL) and reacted at 50°C for 30 min. Then, a solution of 44F (0.36 g, 0.97 mmol) in N,N-dimethylformamide (1 mL) was added dropwise at 50°C. After the addition, the mixture was stirred at 80°C for 4 hrs. After the reaction was complete, the reaction solution was filtered and the filter cake was washed with N,N-dimethylformamide (2 mL). The filtrate was concentrated and dissolved with ethyl acetate (15 mL) and water (15 mL). The aqueous phase was separated and the pH value was adjusted to neutral with saturated ammonium chloride. The product was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 44 (61 mg, yield 12%).
[0504] LCMS m / z=493.5[M+H] + ;
[0505] 1 H NMR(400MHz,DMSO-d6)δ10.44(s,1H),9.19(s,1H),8.00-7.98(d,1H),7.93-7.88(t,1H),7.81(s,1H), 7.59-7.55(m,2H),7.52-7.51(d,1H),3.84(s,4H),2.36(s,3H),2.10-2.06(t,4H),1.73–1.65(m,2H).
[0506] 19 F NMR(376MHz,DMSO-d6)δ-127.37(s).
[0507] Example 45
[0508] Step 1: 45A (10 g, 61.33 mmol) and N,N-dimethylformamide (100 mL) were added to a 250 mL single-necked flask. N,N-diisopropylethylamine (15.85 g, 122.64 mmol) and 1-fluoro-2-iodoethane (12.80 g, 73.63 mmol) were slowly added dropwise at 0-5°C. The mixture was allowed to react overnight at 80°C. After completion of the reaction, the reaction solution was added dropwise to water (500 mL), whereupon a large amount of solid precipitated. After stirring for 30 minutes, the mixture was filtered, and the filter cake was washed with water (100 mL) and petroleum ether (50 mL). The filter cake was concentrated to afford 45B (10.0 g, 78% yield).
[0509] LCMS m / z=210.2[M+H]+ ;
[0510] Step 2: In a 500 mL single-necked flask, 45B (10 g, 47.81 mmol) was dissolved in dichloromethane (260 mL) and methanol (26 mL). Hydrazine hydrate (5.98 g, 95.62 mmol) was slowly added dropwise at room temperature and allowed to react for 2.5 hr. After completion of the reaction, the reaction solution was filtered, the filtrate was washed with 5N aqueous ammonia (200 mL), and extracted with dichloromethane (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ethanol (50 mL), concentrated hydrochloric acid (8 mL) was added, stirred for 30 min, and concentrated. The resulting residue was slurried with ethyl acetate (30 mL) and filtered to afford 45C (1.90 g, 34% yield).
[0511] 1 H NMR (400MHz, DMSO-d6) δ11.25(s,3H),4.74–4.72(m,1H),4.62–4.60(m,1H),4.36–4.34(m,1H),4.29–4.27(m,1H).
[0512] Step 3: 45C (0.49 g, 3.23 mmol) and water (10 mL) were added to a 250 mL single-necked flask. A solution of sodium hydroxide (0.12 g, 3.04 mmol) in water (10 mL) was slowly added dropwise at 0-5°C. The mixture was reacted at 0-5°C for 10 min. Then, 6-hydroxy-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (0.17 g, 0.95 mmol) was added at 0-5°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to afford 45D (0.20 g, 98% yield).
[0513] LCMS m / z=215.1[M+H] + ;
[0514] Step 4: In a 100 mL single-necked flask, 45D (0.2 g, 0.93 mmol) was added to triethyl orthoformate (3 mL) and N,N-dimethylformamide (3 mL) and reacted at 150°C for 4 hr. After the reaction was complete, the mixture was cooled to room temperature and concentrated to afford crude product 45E, which was used directly in the next step.
[0515] LCMS m / z=225.1[M+H] + ;
[0516] Step 5: In a 25 mL single-necked vial, 45E (0.31 g, 1.38 mmol) was dissolved in dry N,N-dimethylformamide (5 mL). Cesium carbonate (0.54 g, 1.66 mmol) was added dropwise under ice-cooling, followed by the slow addition of 2,3,6-trifluorobenzonitrile (0.24 g, 1.52 mmol). The mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3) to afford 45F (0.36 g, 72% yield).
[0517] LCMS m / z=362.4[M+H] + ;
[0518] Step 6: In a 25 mL single-necked flask, 1B (0.21 g, 1.20 mmol) and cesium carbonate (0.49 g, 1.5 mmol) were added to dry N,N-dimethylformamide (8 mL). The mixture was reacted at 50°C for 30 min. Then, a solution of 45F (0.36 g, 1.00 mmol) in N,N-dimethylformamide (2 mL) was added dropwise at 50°C. After the addition, the mixture was stirred at 80°C overnight. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 45 (83.0 mg, yield 16%).
[0519] LCMS m / z=518.2[M+H] + ;
[0520] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.58(s,1H),7.91–7.83(m,2H),7.74-7.71(dd,1H),7.56-7.53(dd,1H) ,7.42-7.41(d,1H),4.83–4.69(m,2H),4.59–4.49(m,2H),3.84(s,4H),2.12-2.08(t,4H),1.78–1.70(m,2H).
[0521] 19 F NMR(376MHz, DMSO-d6)δ-127.24(s),-220.60(s).
[0522] Example 46
[0523] Step 1: In a 25 mL single-necked flask, 22C (1.35 g, 7.29 mmol) was dissolved in dry N,N-dimethylformamide (30 mL). Cesium carbonate (4.75 g, 14.58 mmol) was slowly added under ice-cooling. The reaction was stirred at room temperature for 0.5 h. 39A (1.51 g, 8.75 mmol) was slowly added dropwise under ice-cooling. The reaction was stirred at 30°C overnight. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 7) to afford 46A (2.3 g, 93% yield).
[0524] LCMS m / z=338.3[M+H] + ;
[0525] Step 2: In a 25 mL single-necked flask, 46A (2.30 g, 6.82 mmol) was dissolved in dry acetonitrile (50 mL). Tert-butyl nitrite (0.71 g, 6.89 mmol) and copper bromide (1.54 g, 6.90 mmol) were slowly added sequentially at 0-5°C. The reaction was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated and quenched with saturated sodium bicarbonate (100 mL). The solution was then dissolved in ethyl acetate (100 mL) and filtered. The filtrate was extracted with ethyl acetate (100 mL x 2). The organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 3) to afford 46B (1.00 g, 36% yield).
[0526] LCMS m / z=401.0[M+H] + ;
[0527] Step 3: 46B (0.80 g, 1.99 mmol), 1B (0.46 g, 2.59 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.10 g, 0.20 mmol), potassium carbonate (0.41 g, 2.98 mmol), and tris(dibenzylidene-BASE acetone)dipalladium (0.11 g, 0.19 mmol) were added to dry 1,4-dioxane (16 mL), purged with nitrogen for 2 min, and then microwaved at 120 °C for 1 hr. After the reaction was complete, the filtrate was concentrated and dissolved in ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and the pH was adjusted to neutral with saturated ammonium chloride. The product was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 2) and then resolved by chiral SFC to afford compound 46 (retention time: 2.08 min). Separation method: Instrument name: Waters 150Prep-SFC F; Column: Chiralcel AD column; Mobile phase: A for CO2 and B for MeOH (0.1% NH3·H2O); Gradient: B 40%; Flow rate: 100 mL / min; Column pressure: 100 bar; Column temperature: 25°C; Absorption wavelength: 220 nm (Cycle time: 3.8 min). Sample preparation: The compound was dissolved in acetonitrile at a concentration of 10 mg / mL; injection: 3.5 mL was injected each time; treatment: after separation, it was concentrated by rotary evaporation at 35°C, and then the solvent was dried by lyophilization at -80°C to obtain compound 46 (0.18 mg, yield 18%).
[0528] LCMS m / z=497.8[M+H] + ;
[0529] 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.10-8.09(d,1H),8.02-7.99(d,1H),7.78-7.77(d,1H ),7.62–7.58(m,2H),7.50-7.46(m,1H),3.79(s,4H),2.10-2.06(t,4H),1.75–1.67(m,2H).
[0530] Example 47
[0531] Step 1: In a 250 mL single-necked flask, compound 5B (0.55 g, 3.39 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (1.42 g, 4.36 mmol) was added and the mixture was reacted at 50°C for 0.5 h. A solution of 26C (1 g, 2.90 mmol) in N,N-dimethylformamide (10 mL) was then added dropwise. After complete addition, the reaction mixture was stirred at 85°C for 12 h. After the reaction, ethyl acetate (100 mL) was added, followed by washing with water (70 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 25%-65% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 47 (700 mg, yield 49%).
[0532] LCMS m / z=488.30[M+H] + ;
[0533] 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.33(s,1H),7.88(t,1H),7.80(d,1H),7.76-7.68(m,1H), 7.61-7.56(m,1H),7.41(d,1H),4.79-4.62(m,2H),4.36-4.25(m,2H),3.97(s,4H),0.61(s,4H).
[0534] Example 48
[0535] Step 1: In a 250 mL single-necked flask, compound 5B (8.2 g, 50.55 mmol) was dissolved in dry N,N-dimethylformamide (50 mL). Cesium carbonate (16.6 g, 7.41 mmol) was added and stirred at 50°C for 0.5 h. A solution of 9E (2.5 g, 6.88 mmol) in N,N-dimethylformamide (15 mL) was then added dropwise. After complete addition, the reaction mixture was stirred at 85°C for 12 h. After the reaction, the product was filtered and the filtrate was concentrated. The residue was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 10 minutes) to obtain compound 48 (250 mg, 7% yield).
[0536] LCMS m / z=506.90[M+H] + ;
[0537] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.93(t,1H),7.86-7.76(m,3H),7.74-7.69(m,1H),7 .48(d,1H),6.54-6.18(m,1H),4.53-4.43(m,1H),3.55(s,2H),3.25(s,2H),0.64(s,4H).
[0538] Example 49
[0539] Step 1: Dissolve raw material 5B (0.45 g, 2.77 mmol) in DMF (10 mL). Add cesium carbonate (0.91 g, 2.79 mmol). Heat the reaction to 50°C and stir for 30 min. Add raw material 22D (0.6 g, 1.86 mmol), and heat the reaction to 85°C and stir overnight. After the reaction, filter through Celite. The filtrate is concentrated, and the resulting residue is purified by slurrying with EA to yield 0.50 g of a white solid. This solid is then purified on a silica gel column (dichloromethane:methanol = 20:1) to afford compound 49 (0.38 g, 43.99%).
[0540] LCMS m / z=465.3[M+H] + .
[0541] 1H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.09(d,1H),8.01(d,1H),7.74(t,1H),7.63(d,1H),7.60–7.52(m,3H),3.89(s,4H),0.57(s,4H).
[0542] Example 50
[0543] Step 1: In a 100 mL single-necked flask, 39D (500 mg, 1.18 mmol), 5B (230 mg, 1.42 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (100 mg, 0.24 mmol), allylpalladium chloride (65 mg, 0.18 mmol), and potassium carbonate (571 mg, 4.13 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70°C for 5 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated. The resulting oily liquid was purified by column chromatography (DCM:EA=1:2) to obtain a crude compound. The crude product was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 30%-80% acetonitrile isocratic elution; cycle time: 20 minutes) to obtain compound 50 (72 mg, yield: 12%).
[0544] LCMS m / z=506.1[M+H] + ;
[0545] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.79(d,1H),7.74(dd,1H),7.57(d,1H),7.51(dd,1H),4.71(dt,2H),4.32(dt,2H),3.93(s,4H),0.59(s,4H).
[0546] Example 51
[0547] Step 1: In a 100 mL single-necked bottle, 39D (500 mg, 1.18 mmol), (3R)-3-fluoropyrrolidine-1-sulfonamide (238 mg, 1.42 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (100 mg, 0.24 mmol), allylpalladium chloride (65 mg, 0.18 mmol), and potassium carbonate (571 mg, 4.13 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70°C for 5 h. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated. The resulting oily liquid was purified by column chromatography (DCM:EA=1:2) to obtain a crude compound. The crude product was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1 / 1000 trifluoroacetic acid); gradient: 20%-80% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 51 (210 mg, yield: 31%).
[0548] LCMS m / z=512.1[M+H] + ;
[0549] 1 H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.80(d,1H),7.74(dd,1H),7.58(d,1H),7.52(dd,1H), 5.40(s,1H),5.26(s,1H),4.72(dt,2H),4.32(dt,2H),3.57–3.31(m,4H),2.23–1.99(m,2H).
[0550] Example 52
[0551] Step 1: Dissolve 43D (800 mg, 1.81 mmol), 5B (352 mg, 2.17 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (80 mg, 0.18 mmol), and potassium carbonate (876 mg, 6.33 mmol) in dry 1,4-dioxane (40 mL). Add allylpalladium chloride (33 mg, 0.09 mmol). After the addition, replace the nitrogen atmosphere and stir at 85°C for 10 h. After completion of the reaction, monitored by TLC (dichloromethane:methanol = 20:1 (v / v)), the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 50:1 (v / v)) to obtain the target compound 52 (340 mg, 36% yield).
[0552] LCMS m / z=524.2[M+1] + .
[0553] 1 H NMR(400MHZ,DMSO-d6)δ8.35(s,1H),7.81(d,1H),7.77(dd,1H),7.62(d,1H),7.57(dd,1H),6.37(tt,1H),4.49(td,2H),3.99(s,4H),0.61(s,4H).
[0554] Example 53
[0555] Step 1: Dissolve 43D (800 mg, 1.81 mmol), (3R)-3-fluoropyrrolidine-1-sulfonamide (365 mg, 2.17 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (80 mg, 0.18 mmol), and potassium carbonate (876 mg, 6.33 mmol) in dry 1,4-dioxane (40 mL). Add allylpalladium chloride (33 mg, 0.09 mmol). After the addition, the atmosphere was replaced with nitrogen and the mixture was stirred at 85°C for 10 h. After completion of the reaction, as monitored by TLC (dichloromethane:methanol = 20:1 (v / v)), the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: dichloromethane:methanol = 65:1 (v / v)) to obtain the title compound 53 (650 mg, 68% yield).
[0556] LCMS m / z=530.1[M+1] + .
[0557] 1 H NMR(400MHZ,DMSO-d6)δ8.35(s,1H),7.81(d,1H),7.75(dd,1H),7.60(d,1H),7.52(dd ,1H),6.37(tt,1H),5.33(d,1H),4.49(td,2H),3.58–3.34(m,4H),2.21–2.01(m,2H).
[0558] Preparation of preparation:
[0559] 1. Preparation 1-1: Specification 20 mg / tablet:
[0560] 2. Preparation 1-2; Specification: 20 mg / tablet
[0561] 3. Preparation 1-3; Specification: 20 mg / tablet
[0562] 4. Preparation 1-4: Specification 200 mg / tablet:
[0563] 5. Preparation 1-5: Specification 1000 mg / tablet:
[0564] Preparation method of the above prescription preparation:
[0565] 1) API-excipient micronized product: Compound 10 and surfactant (if any) or pH adjuster (if any) are weighed and mixed according to the prescription ratio. After mixing evenly, micronized.
[0566] 2) Weighing: Weigh the API - excipient micronized material, filler, binder, glidant, disintegrant, and lubricant according to the prescription;
[0567] 3) Mixing: Mix the API, excipient micronized material, filler, binder, glidant, and disintegrant for 5 minutes, then add lubricant and mix for 2 minutes.
[0568] 4) Tabletting: Compress the powder in 3) into tablets using a die of appropriate specifications, and control the tablet weight and hardness during the tableting process.
[0569] Other compounds of the present invention, such as the example compounds, were prepared into corresponding preparations by referring to the above preparation methods.
[0570] Biological test cases
[0571] 1. BRAF V600E Enzyme activity test
[0572] 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 K97RTo 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, 5 μL of the above reaction product is transferred to another 384-well plate, and 5 μL of the prepared ADP-GloTM Reagent (Promega, V9101) is added and pipetted to mix, and placed at room temperature for 40 minutes. Add 10 μL of Kinase Detection Reagent to the 384-well plate and incubate at room temperature for 40 minutes. Finally, use a microplate reader (BMG LRBTECH) to select the Luminescence module to detect each well (the gain value is fixed at 3600), and the LUM fluorescence value is calculated by the formula
[0573] 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.
[0574] 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.
[0575] Table 1 Inhibitory activity of compounds against BRAFV600E
[0576] A stands for IC 50 ≤10nM, B means 10nM<IC 50 ≤50nM, C means 50nM<IC 50 ≤100nM.
[0577] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an inhibitory effect on BRAF. V600E Shows high inhibitory activity.
[0578] 2. Inhibition of A375 cell proliferation
[0579] 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 4Cells / 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 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).
[0580] 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 ).
[0581] 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.
[0582] Table 2 Inhibitory activity of compounds on A375 cells
[0583] A stands for IC 50 ≤10nM, B means 10nM<IC 50 ≤50nM, C means 50nM<IC 50 ≤100nM.
[0584] Conclusion: The compounds of the present invention, such as the compounds in the examples, showed high inhibitory activity at the cellular level.
[0585] 3. Pharmacokinetic test in mice
[0586] 1.1 Experimental Animals: Male ICR mice, 20-25 g, 12 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
[0587] 1.2 Experimental Design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.
[0588] Table 3. Dosing Information
[0589] Note: Reference compound 1 is compound Example 1 in document WO2021116055A1;
[0590] Intravenous administration solvent: 5% DMA + 5% HS-15 + 90% NS; oral administration solvent: 0.5% MC
[0591] 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, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.
[0592] Table 4. Pharmacokinetic parameters of test compounds in mouse plasma Note: Reference compound 1 is compound Example 1 in document WO2021116055A1; -: not applicable.
[0593] Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic characteristics in mice and have better brain penetration properties than the control compounds.
[0594] 4. Beagle dog pharmacokinetic test
[0595] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.
[0596] 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 resumed 4 hours after dosing. Dosing was performed according to Table 5.
[0597] Table 5. Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC
[0598] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose solution;)
[0599] 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.
[0600] Table 6. Pharmacokinetic parameters of test compounds in beagle dog plasma Note: Reference compound 1 is compound Example 1 in document WO2021116055A1;
[0601] -:not applicable.
[0602] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.
[0603] 5. Pharmacokinetic test in rats
[0604] 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.
[0605] 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.
[0606] Table 7 Dosage information Dosing vehicle: 0.5% MC
[0607] 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, and 24 hours; from the gavage group at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours. All samples were stored at −80°C prior to analysis.
[0608] Table 8 Pharmacokinetic parameters of test compounds in rat plasma Note: Reference compound 1 is compound Example 1 in document WO2021116055A1; -: not applicable.
[0609] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good bioavailability and pharmacokinetic characteristics in rats.
[0610] 6. Preparation stability study
[0611] 6.1 High temperature (60°C) inspection test
[0612] Bare chips from formulations 1-4 were placed at 60°C for testing, and samples were taken for testing after 5 and 10 days. The test results are shown in the following table.
[0613] Table 9 High temperature test results Note: RRT: Relative Retention Time
[0614] 6.2 High humidity (RH92.5%) test
[0615] Bare chips from formulations 1-4 were placed in a high humidity environment (RH 92.5%) for testing, and samples were taken for testing after 5 and 10 days. The test results are shown in the following table.
[0616] Table 10 High humidity test results
[0617] 6.3 Accelerated test
[0618] Samples of formulations 1-4 were placed in a simulated commercial packaging at 40°C ± 2°C and RH 75% ± 5% for testing. The test results are shown in the following table.
[0619] Table 11 Accelerated test results
[0620] Conclusion: The compound preparations of the present invention have good high temperature, high humidity and accelerated stability.
Claims
1. A pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises an active ingredient M and a pharmaceutical excipient, and the active ingredient M is selected from the compounds represented by the general formula I or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, Among them, Cy is selected from P1, P2, P3, P4, P5, P6, P7 or P8; Ring A is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, S, and O, and the 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, halo-C 1-4 alkoxy, and halo-C 1-4 alkyl; Ring B is a 5-membered heterocycle containing 1-3 heteroatoms selected from N, S, O, and the heterocycle is optionally substituted with 1-3 groups selected from =O, halogen, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, OH, and halo C 1-4 alkoxy; # indicates that the selected site is connected to Y; n is selected from 0 or 1; Each X1 is independently N or C; X2 is N or CR3; X3 is N or CR 31 ; X4 is N or CR 32 ; X5 is N or Cr 33 ; X6 is C(O), S(O) or S(O)2; X7 is CR7 or N; R1, R2, and R4 are independently H, halogen, OH, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, CN, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, halo-C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl; R3, R 31 , R 32 , R 33 are independently H, halogen, C 1-4 alkyl, halo-C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, CN or C 3-6 cycloalkyl, or R 31 together with R 32 , or R 32 together with R 33 and the atoms to which it is attached form a C 3-6 carbocycle or a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O, said carbocycle or heterocycle being optionally substituted by 1 to 3 groups selected from halogen, C 1-4 alkyl, halo-C 1-4 alkyl, C 1-4 alkoxy, OH, NH2 and CN; R5 is C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, C 1-4 alkoxy, halo C 1-4 alkoxy or C 3-6 cycloalkyloxy, and optionally substituted by 1 to 3 groups selected from halogen, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, C 1-4 alkoxy, halo C 1-4 alkoxy, halo C 1-4 alkyl, CN, C 1-4 alkyl or a group of =O; R6 is H, halogen, C 1-4 alkyl or halo-C 1-4 alkyl; or R5 and R6 together with their connecting atoms form a 5- or 6-membered heterocycle containing 1-3 heteroatoms selected from N, S, and O, and the heterocycle is optionally substituted with 1-3 groups selected from halogen, OH, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, CN, and C 1-4 alkyl; R7, R8, and R9 are independently H, halogen, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4-ynyl, halo-C 1-4 alkyl, C 1-4 alkoxy or halo-C 1-4 alkoxy; Y is C 1-2 an alkylene group, O or NR y ; R y is H or C 1-4 alkyl; M is C 1-2 an alkylene, O or NR m ; W is a key, O or NR w ; R m and R w are each independently H or C 1-4 alkyl; R is selected from C 1-4 alkyl, C 3-8 cycloalkyl, a 4- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from N, S, O or -O-C 3-6 cycloalkyl, and the alkyl, cycloalkyl and heterocycle are optionally substituted by 1 to 3 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, OH, NH2, -NHC 1-4 alkyl, -N(C 1-4 alkyl)2 and halo-C 1-4 alkyl; When Cy is P2, R is a 4- to 10-membered saturated heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, and O, and is optionally substituted with 1 to 3 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, OH, NH2, -NH-C 1-4 alkyl, -N(C 1-4 alkyl)2, and halo-C 1-4 alkyl; The pharmaceutical composition or pharmaceutical preparation contains 1 - 1000 mg of the active ingredient M, and the excipient contains one or more of a filler, a binder, a glidant, a lubricant, and a disintegrant.
2. The pharmaceutical composition or pharmaceutical preparation according to claim 1, wherein the pharmaceutical composition or pharmaceutical preparation contains 5 - 800 mg, 5 - 600 mg or 5 - 400 mg of the active ingredient M.
3. The pharmaceutical composition or pharmaceutical preparation according to claim 2, wherein the pharmaceutical composition or pharmaceutical preparation contains 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg of the active ingredient M.
4. The pharmaceutical composition or pharmaceutical preparation according to claim 1, wherein the pharmaceutical composition or pharmaceutical preparation comprises an active ingredient M and a pharmaceutical excipient, and the active ingredient M is selected from the compounds represented by general formula I or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, having the structure of formula II: Wherein, R6 and R9 are H; Y is O; M is NH; X2 is CR3; X3 is CR 31 ; X4 is CR 32 ; X5 is CH; X6 is SO2; X7 is CH; R3 is C 1-2 alkyl, halo C 1-2 alkyl, C 1-2 alkoxy, halo C 1-2 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -NHC 1- 2 alkyl, -N(C 1-2 alkyl)2 or CN; R 31 、R 32 each independently is H, F, Cl, C 1-2 alkyl, halo-C 1-2 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-2 alkoxy, halo-C 1-2 alkoxy, -NHC 1-2 alkyl, -N(C 1-2 alkyl) 2、 CN or C 3-6 cycloalkyl; R5 is C 1-2 alkyl, CN or =O-substituted C 1-2 alkyl, halogenated C 1-2 alkyl, C 3-4 cycloalkyl, 4- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, C 1-2 alkoxy, halogenated C 1-2 alkoxy or C 3-4 cycloalkyloxy; R8 is selected from H, F, Cl, CN, C 1-2 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-C 1-2 alkyl, C 1-2 alkoxy or halo-C 1-2 alkoxy; R is a 4- to 5-membered monocyclic heterocycloalkyl, 6- to 8-membered monocyclic heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl, 5- to 10-membered fused heterocycloalkyl, 5- to 10-membered bridged heterocycloalkyl, 6- to 10-membered spiro heterocycloalkyl or -O-C containing 1 to 3 heteroatoms selected from N, S, and O 3-6 cycloalkyl, wherein the 4-membered monocyclic heterocycloalkyl is substituted with 1 to 3 groups selected from F, Cl, C 1-2 alkyl, C 1-2 alkoxy, OH, NH2, -NHC 1-2 alkyl, -N(C 1-2 alkyl)2 and halo C 1-2 alkyl, and the 6- to 8-membered monocyclic heterocycloalkyl, 5- to 6-membered monocyclic heteroaryl, 5- to 10-membered fused heterocycloalkyl, 5- to 10-membered bridged heterocycloalkyl, 6- to 10-membered spiro heterocycloalkyl or C 3-6 cycloalkyl is optionally substituted with 1 to 3 groups selected from F, Cl, C 1-2 alkyl, C 1-2 alkoxy, OH, NH2, -NHC 1-2 alkyl, -N(C 1-2 alkyl)2 and halo C 1-2 alkyl.
5. The pharmaceutical composition or pharmaceutical preparation according to claim 1, wherein the pharmaceutical composition or pharmaceutical preparation contains the active ingredient M and a pharmaceutical excipient, and the active ingredient M is selected from the compounds represented by General Formula I or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein R3 is CN; R 31 、R 32 each independently is H, F, Cl or C 3-6 cycloalkyl; R5 is selected from C 1-2 alkyl, halo C 1-2 alkyl, C 1-2 alkoxy, or C 1-2 alkyl substituted by CN or =O; R8 is H; R is a 6- to 10-membered spiroheterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, a 4- to 5-membered monocyclic heterocycloalkyl containing 1 to 3 heteroatoms selected from N, S, O, or -O-C 3-6 cycloalkyl, and the 6- to 10-membered spiroheterocycloalkyl, 4- to 5-membered monocyclic heterocycloalkyl, C 3-6 cycloalkyl is optionally substituted with 1 to 3 groups selected from F, Cl, C 1-2 alkyl or C 1-2 alkoxy.
6. The pharmaceutical composition or pharmaceutical preparation according to claim 1, wherein the active ingredient M is selected from one of the structures in Table 1 or Table 2.
7. A pharmaceutical composition or pharmaceutical preparation, comprising the active ingredient M according to any one of claims 1 - 6 and a pharmaceutical excipient, wherein the pharmaceutical excipient contains a filler, a binder, a glidant, a lubricant, and a disintegrant, and preferably further contains one or more of a solubilizer, a pH regulator, and a surfactant.
8. The pharmaceutical composition or pharmaceutical preparation according to claim 7, wherein the content of the active ingredient M is 0.5% - 99%, preferably 5% - 60%.
9. The pharmaceutical composition or pharmaceutical preparation according to claim 7, wherein the filler is one or more of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, siliconized microcrystalline cellulose, sucrose, sorbitol, dextran, calcium dihydrogen phosphate or starch, preferably one or more of microcrystalline cellulose, siliconized microcrystalline cellulose or sorbitol, and preferably the filler content is 10% - 90%, preferably 10 - 80%, more preferably 10% - 50%, or / and wherein the binder is one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose or sodium carboxymethylcellulose, preferably one or more of hydroxypropyl methylcellulose, methylcellulose or sodium carboxymethylcellulose, and preferably the binder content is 1% - 10%, preferably 1% - 5%, more preferably 1% - 2.5%, or / and Wherein the glidant is one or more of talc, silicon dioxide, colloidal silicon dioxide, polyethylene glycol, or magnesium lauryl sulfate, preferably one or more of silicon dioxide or colloidal silicon dioxide. Preferably, the content of the glidant is 0.5%-10%, more preferably 0.5%-5%, still more preferably 0.5%-3%, or / and Wherein the lubricant is one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, preferably sodium stearyl fumarate. Preferably, the content of the lubricant is 0.1%-10%, more preferably 0.1%-5%, still more preferably 0.5%-2.0%, or / and Wherein the disintegrant is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, or calcium carboxymethyl cellulose, preferably one or more of crospovidone, croscarmellose sodium, or calcium carboxymethyl cellulose. Preferably, the content of the disintegrant is 0.5%-10%, more preferably 2%-10%.
10. The pharmaceutical composition or pharmaceutical preparation according to claim 7, wherein the solubilizer is one or more of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polysorbate, polyethylene glycol 15-hydroxystearate, poloxamer, cyclodextrin, hydroxypropyl betacyclodextrin, sodium docusate, or vitamin E polyethylene glycol succinate, preferably one or more of cyclodextrin or hydroxypropyl betacyclodextrin. Preferably, the content of the solubilizer is 5%-50%, more preferably 10%-50%.
11. The pharmaceutical composition or pharmaceutical preparation according to claim 7, which comprises: (i) Active ingredient M, with a content of 0.5%-99%, preferably 5%-60%; (ii) Filler, the filler is one or more of microcrystalline cellulose, siliconized microcrystalline cellulose, or sorbitol, with a content of 10%-90%, preferably 10%-70%, more preferably 10%-50%; (iii) Binder, the binder is one or more of hydroxypropyl methylcellulose, methylcellulose, or sodium carboxymethyl cellulose, with a content of 1%-10%, preferably 1%-5%, more preferably 1%-2.5%; (iv) Glidant, the glidant is one or more of silicon dioxide or colloidal silicon dioxide, with a content of 0.5%-10%, preferably 0.5%-5%, more preferably 0.5%-3%; (v) Lubricant, the lubricant is sodium stearyl fumarate, with a content of 0.1%-10%, preferably 0.1%-5%, more preferably 0.5%-2.0%; (vi) Disintegrant, the disintegrant is one or more of crospovidone, croscarmellose sodium, or calcium carboxymethyl cellulose, with a content of 0.5%-10%, preferably 2%-10%.
12. The pharmaceutical composition or pharmaceutical preparation according to claim 11 further comprises one or more of solubilizers, surfactants, and pH regulators; the solubilizer is one or more of cyclodextrin or hydroxypropyl beta-cyclodextrin, with a content of 5% - 50%, preferably 10% - 50%; the surfactant is sodium dodecyl sulfate, with a content of 1% - 40%, preferably 10% - 20%; the pH regulator is magnesium oxide, with a content of 1% - 50%, preferably 1% - 5%.
13. Use of the pharmaceutical composition or pharmaceutical preparation according to any one of claims 1 - 12 in the preparation of a medicament for treating cancer-related diseases.
14. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of active ingredient M, the therapeutically effective amount preferably being 1 - 1000 mg, and the disease preferably being cancer.